Understanding Pathophysiology [ANZ 3rd Edition] 9780729586337, 0729586332
Written by Judy Craft and Christopher Gordon, Understanding Pathophysiology 3e remains Australia and New Zealand's
892 135 102MB
English Pages [1313] Year 2018
Understanding Pathophysiology ANZ
Copyright Page
About the Authors
Australian and New Zealand Contributors
US Contributors
Reviewers
Preface
Organisation of content
The Australian and New Zealand context
Concept maps: a unique feature of the text
Acknowledgments
Text Features
1 Introduction to clinical science
Chapter outline
Key terms
Introduction
Essential pathophysiology
Pathophysiology and clinical manifestations
Disorders and diseases
The onset of disease
Population-level indicators of disease
Age groups within the population
Evaluation and treatment
Essential anatomy
Anatomical position
Body sections and planes
Anatomical directional terminology
Body cavities and quadrants
Health science terminology
Essential physiology
The hierarchy from microscopic to whole body level
Organ systems
Essential chemistry
Elements
Ions and electrolytes
Molecules and compounds
Water
Acids and bases
Acidosis and alkalosis
Chemical reactions
Energy
Molecules of life
Proteins
Lipids
Carbohydrates
Nucleic acids
Essential physics
Pressure within an enclosed area of the body
Pressure from the atmosphere
Review questions
2 Homeostasis
Chapter outline
Key terms
Introduction
Homeostasis
The cellular environment
Homeostasis at the cellular and local level
Homeostasis at the body level
Regulation of homeostasis
Disturbances of homeostasis lead to pathophysiology
Review questions
3 Cellular structure and function
Chapter outline
Key terms
Introduction
Cellular structure and function
Cellular components
The organelles
The nucleus
The ribosomes
Endoplasmic reticulum
The Golgi apparatus
Lysosomes
Peroxisomes
Mitochondria
The cytoskeleton
The cytoplasm
The cell membrane
Lipids
Proteins
Cellular receptors and communication
Membrane transport
Movement of water and solutes
Passive transport
Filtration
Simple diffusion
Facilitated diffusion
Osmosis
Active transport
Endocytosis and exocytosis
Cellular metabolism
The role of ATP
Tissues
Types of tissues
Epithelial tissue
Connective tissue
Muscle tissue
Nervous tissue
Review questions
4 Altered cellular function
Chapter outline
Key terms
Introduction
Causes of cellular injury
Hypoxia
Chemical agents
Physical agents
Infectious agents
Genetic causes
Mechanisms of cellular injury
Hypoxic injury
The impact of oxygen and oxygen-derived free radicals
Alteration to calcium homeostasis
Cellular adaptation
Atrophy
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia
Reversible and irreversible cell injury
Reversible cell injury
Irreversible cell injury
Apoptosis
Necrosis
Death
Review questions
5 Genes
Chapter outline
Key terms
Introduction
The nucleus
Cell proliferation
The cell cycle
Control of cell division
DNA, RNA and proteins: heredity at the molecular level
Chemical composition of DNA
From genes to proteins
Elements of genetics
Genes, alleles and mutations
Phenotype and genotype
Dominance and recessiveness
Inheritance of traits
Autosomal and X-linked inheritance
Codominance and multiple alleles
Newborn screening
Review questions
6 The structure and function of the neurological system
Chapter outline
Key terms
Introduction
Organisation of the nervous system
Cells of the nervous system
Neurons
The structure of neurons
The function of neurons
Neuroglia
Nerve injury and regeneration
The nerve impulse
Membrane potentials
Resting membrane potential
Action potential
Synapses
Neurotransmitters
Myelin
The central nervous system
The brain
The cerebral hemispheres
The cerebral cortex
Cerebral tracts
Basal nuclei
The limbic system
The diencephalon
The brainstem
The sleep process
The importance of sleep
Control of the sleep–wake cycle
The cerebellum
The spinal cord
Reflexes
Sensory pathways
Motor pathways
Protective structures of the central nervous system
The cranium and vertebral column
The meninges
The dura mater
The arachnoid
The pia mater
Cerebrospinal fluid and the ventricular system
The blood–brain barrier
Blood supply of the central nervous system
Blood supply to the brain
Blood supply to the spinal cord
The peripheral nervous system
The autonomic nervous system
Anatomy of the sympathetic nervous system
Anatomy of the parasympathetic nervous system
Neurotransmitters and receptors
Neurotransmitters and receptors of the sympathetic nervous system
Neurotransmitters and receptors of the parasympathetic nervous system
Physiology of the autonomic nervous system
Sympathetic nervous system: functions
Parasympathetic nervous system: functions
Sensory function
Somatosensory function
Touch
Temperature
Chemical
Proprioception
Vision
Hearing
Olfaction and taste
Alterations of sensory function
Visual dysfunction
Alterations in ocular movements
Alterations in visual acuity
Alterations in refraction
Alterations in colour vision
Neurological disorders causing visual dysfunction
External eye structure disorders
Auditory dysfunction
Conductive hearing loss
Sensorineural hearing loss
Ménière’s disease
Ear infections
Olfactory and taste dysfunction
Review questions
7 Pain
Chapter outline
Key terms
Introduction
The definition of pain
Types of pain
Nociceptive pain
Neuropathic pain
Psychogenic pain
Pain terminology
The physiology of pain
Nociceptors
Cutaneous nociceptors
High threshold mechanoreceptors
Polymodal nociceptors
Musculoskeletal and visceral nociceptors
Spinothalamic tract neurons
Thalamocortical neurons
Cortical representation of pain
Neuromodulation of pain
Clinical manifestations of pain
Evaluation and treatment
Pathophysiology of pain
Peripheral neuropathic pain
Central pain syndromes
Review questions
8 Concepts of neurological dysfunction
Chapter outline
Key terms
Introduction
Alterations in cerebral homeostasis
Cerebral haemodynamics
Intracranial pressure
Cerebral oedema
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hydrocephalus
Pathophysiology
Clinical manifestations
Evaluation and treatment
Alterations in cognitive function
Alterations in arousal
Pathophysiology
Clinical manifestations and evaluation
Level of consciousness
Breathing pattern
Pupillary changes
Oculomotor responses
Motor responses
Vomiting
Post-coma unresponsiveness
Brain death
Seizures
Pathophysiology
Types of seizure disorders
Evaluation and treatment
Cognitive disorders
Acute confusional states
Pathophysiology
Clinical manifestations
Evaluation and treatment
Dementia
Pathophysiology
Clinical manifestations
Evaluation and treatment
Depression
Alterations in motor function
Alterations in muscle tone
Hypotonia
Hypertonia
Alterations in movement
Review questions
9 Alterations of neurological function across the life span
Chapter outline
Key terms
Introduction
Cerebrovascular disorders
Stroke
Ischaemic strokes
Thrombotic stroke
Embolic stroke
Haemorrhagic stroke
Clinical manifestations
Ischaemic stroke
Haemorrhagic stroke
Evaluation and treatment
The longer-term consequences of stroke
Cerebral aneurysm
Pathophysiology
Classification
Clinical manifestations
Evaluation and treatment
Vascular malformation
Pathophysiology
Clinical manifestations
Evaluation and treatment
Headache and migraine
Headache
Migraine
Trauma to the central nervous system
Brain trauma
Pathophysiology
Focal brain injury
Diffuse brain injury
Clinical manifestations
Focal brain injury
Diffuse brain injury
Evaluation and treatment
Spinal cord trauma
Pathophysiology
Clinical manifestations
Evaluation and treatment
Degenerative disorders of the central nervous system
Alzheimer’s disease
Pathophysiology
Clinical manifestations
Evaluation and treatment
Parkinson’s disease
Pathophysiology
Clinical manifestations
Evaluation and treatment
Huntington’s disease
Pathophysiology
Clinical manifestations
Evaluation and treatment
Multiple sclerosis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Motor neuron disease
Pathophysiology
Clinical manifestations
Evaluation and treatment
Peripheral nervous system and neuromuscular junction disorders
Guillain-Barré syndrome
Pathophysiology
Clinical manifestations
Treatment
Myasthenia gravis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Infection and inflammation of the central nervous system
Meningitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Encephalitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Abscesses
Pathophysiology
Clinical manifestations
Evaluation and treatment
Tumours of the nervous system
Cranial tumours
Primary intracerebral tumours
Astrocytomas
Oligodendrogliomas
Ependymomas
Primary extracerebral tumours
Meningiomas
Nerve sheath tumours
Secondary (metastatic) brain carcinomas
Review questions
10 The structure and function of the endocrine system
Chapter outline
Key terms
Introduction
Mechanisms of hormonal regulation
Regulation of hormone release
Mechanisms of hormone action
Hormone receptors
Protein-based hormones
Steroid-based hormones
The structure and function of the endocrine glands
The hypothalamic–pituitary system
The anterior pituitary
Growth hormone
Function of growth hormone
Regulation of growth hormone secretion
Other anterior pituitary hormones
The posterior pituitary
Antidiuretic hormone
Function of antidiuretic hormone
Regulation of antidiuretic hormone secretion
The thyroid and parathyroid glands
The thyroid gland
Thyroid hormone
Function of thyroid hormone
Regulation of thyroid hormone secretion
Calcitonin
The parathyroid glands
Parathyroid hormone
Function of parathyroid hormone
Regulation of parathyroid hormone secretion
Homeostasis of blood calcium levels
The pancreas
Insulin
Function of insulin
Regulation of insulin secretion
Glucagon
Function of glucagon
Regulation of glucagon secretion
Homeostasis of blood glucose levels
The adrenal glands
The adrenal cortex
Cortisol
Functions of cortisol
Regulation of cortisol secretion
Aldosterone
Functions of aldosterone
Regulation of aldosterone secretion
Oestrogens and androgens
The adrenal medulla
Adrenaline and noradrenaline
Function of adrenaline and noradrenaline
Regulation of adrenaline and noradrenaline secretion
Neuroendocrine response to stressors
The pineal gland
The thymus gland
The testes and ovaries
Review questions
11 Alterations of endocrine function across the life span
Chapter outline
Key terms
Introduction
Mechanisms of hormonal alterations
Alterations of pituitary function
Syndrome of inappropriate antidiuretic hormone secretion
Pathophysiology
Clinical manifestations
Evaluation and treatment
Diabetes insipidus
Pathophysiology
Clinical manifestations
Evaluation and treatment
Alterations of adrenal function
Hyperaldosteronism
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hypercortisolism
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hypoadrenalism
Pathophysiology
Clinical manifestations
Evaluation and treatment
Alterations of pancreatic function
Type 1 diabetes mellitus
Pathophysiology
Clinical manifestations
Evaluation and treatment
Diabetes in pregnancy
Alterations of thyroid function
Hyperthyroidism
Graves’ disease
Hyperthyroidism resulting from nodular thyroid disease
Hyperthyroidism resulting from thyroiditis
Clinical manifestations
Evaluation and treatment
Thyrotoxic crisis
Hypothyroidism
Primary hypothyroidism
Pathophysiology
Clinical manifestations
Evaluation and treatment
Thyroid disease and pregnancy
Hyperthyroidism
Hypothyroidism
Alterations of parathyroid function
Hyperparathyroidism
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hypoparathyroidism
Pathophysiology
Clinical manifestations
Evaluation and treatment
Review questions
12 The structure and function of the immune system
Chapter outline
Key terms
Introduction
Human defence mechanisms
Innate immunity
Epithelial barriers
Cellular components
Phagocytes
Natural killer cells
Chemical mediators
Cytokines
Interferons
Adaptive immunity
Antigens
Cells of the immune system
Lymphocytes
B lymphocytes
T lymphocytes
Antigen-presenting cells
Humoral and cell-mediated immunity
Humoral immune response
Antibodies
Antigen binding
The function of antibodies
Direct effects
Indirect effects
IgE
B cell antigen receptor
Cell-mediated immune response
T cell recognition of a target cell
T cell receptor complex
Antigen presentation molecules
CD molecules
T lymphocyte function
Cytotoxic T lymphocytes
Other cells that kill abnormal cells
Regulatory T lymphocytes
Helper T lymphocytes
Induction of the immune response
Review questions
13 Inflammation and fever
Chapter outline
Key terms
Introduction
Acute inflammation
Cellular components of inflammation
Mast cells and basophils
Neutrophils
Monocytes and macrophages
Eosinophils
Platelets
Phagocytosis
Inflammatory mediators
Histamine
Chemotactic factors
Leukotrienes
Nitric oxide
Prostaglandins
Platelet-activating factor
Cytokines
Interleukins
Tumour necrosis factor-alpha
Plasma protein systems
The complement system
The coagulation system
The kinin system
Plasma protein system interactions
Chronic inflammation
Clinical manifestations of inflammation
Fever
Body temperature
Thermoregulation
Body temperature abnormalities
Hyperthermia
Hypothermia
The pathogenesis of fever
The benefits of fever
Clinical patterns of fever
Wound healing
The reconstructive phase
The maturation phase
Dysfunctional wound healing
Dysfunction during the inflammatory response
Dysfunction during the reconstructive phase
Impaired collagen production
Impaired epithelialisation
Wound disruption
Impaired contraction
Review questions
14 Infection
Chapter outline
Key terms
Introduction
Infection rates
Definitions
Microorganisms
Normal flora
Pathogens
Classes of microorganisms
Bacteria
Viruses
Fungi
Methods of infection
Clinical manifestations of infection
Detection and treatment of microorganisms
Antimicrobials
Vaccines
Infections
Common infections
The common cold
Helicobacter pylori infection
Urinary tract infection
Infection control and healthcare-acquired infections
Antimicrobial resistance
Review questions
15 Alterations of immune function across the life span
Chapter outline
Key terms
Introduction
Hypersensitivity reactions
Type I: IgE-mediated hypersensitivity reactions
Mechanisms of IgE-mediated hypersensitivity
Clinical manifestations
Evaluation and treatment
Anaphylaxis
Type II: tissue-specific hypersensitivity reactions
Type III: immune complex–mediated hypersensitivity reactions
Type IV: cell-mediated hypersensitivity reactions
Transplantation
Transplantation rejection
Blood transfusion reactions
The ABO blood group system
The Rhesus system
The universal donor
Autoimmune diseases
The breakdown of tolerance
Systemic lupus erythematosus
Immune deficiencies
Primary immune deficiencies
Secondary immune deficiencies
Acquired immunodeficiency syndrome
Epidemiology
Pathogenesis
Clinical manifestations
Treatment and prevention
Review questions
16 The structure and function of the haematological system
Chapter outline
Key terms
Introduction
Components of the haematological system
The composition of blood
Plasma and plasma proteins
Plasma versus serum
Cellular components of blood
Erythrocytes
Leucocytes
Granulocytes
Agranulocytes
Platelets
Lymphoid organs
The spleen
Lymph nodes
The mononuclear phagocyte system
The development of blood cells
Haematopoiesis
Bone marrow
Cellular differentiation
The development of erythrocytes
Haemoglobin production
Nutritional requirements for erythropoiesis
Iron cycle
Normal destruction of aged erythrocytes
The development of leucocytes
The development of platelets
The mechanisms of haemostasis
The function of platelets and blood vessels
The function of clotting factors
Natural substances that limit coagulation and platelet plug formation
Clot retraction and fibrinolysis
Review questions
17 Alterations of haematological function across the life span
Chapter outline
Key terms
Introduction
Alterations of erythrocyte function
Anaemia
Classification of anaemia
General clinical manifestations of anaemia
Anaemia due to insufficient erythrocyte production
Iron deficiency anaemia
Pathophysiology
Clinical manifestations
Evaluation and treatment
Folate deficiency anaemia
Clinical manifestations
Evaluation and treatment
Pernicious anaemia
Clinical manifestations
Evaluation and treatment
Aplastic anaemia
Renal anaemia
Anaemia due to excessive erythrocyte loss
Post-haemorrhagic anaemia
Malarial anaemia
Inherited blood disorders
Haemolytic disease of the newborn
Myeloproliferative red cell disorders
Alterations of platelets and coagulation
Platelet disorders
Thrombocytopenia
Pathophysiology
Heparin-induced thrombocytopenia syndrome
Clinical manifestations
Evaluation and treatment
Alterations of platelet function
Disorders of coagulation
Haemophilia
Clinical manifestations
Evaluation and treatment
Impaired haemostasis
Vitamin K deficiency
Liver disease
Thromboembolic disorders
Disseminated intravascular coagulation
Pathophysiology
Clinical manifestations
Evaluation and treatment
Haemostasis therapy
Alterations of leucocytes
Alterations of leucocyte count
Granulocyte and monocyte alterations
Infectious mononucleosis
Clinical manifestations
Evaluation and treatment
Alterations of leucocyte function
Leukaemia
Pathophysiology
Acute leukaemia
Clinical manifestations
Evaluation and treatment
Chronic leukaemia
Pathophysiology and clinical manifestations
Evaluation and treatment
Alterations of lymphoid function
Lymphadenopathy
Malignant lymphomas
Non-Hodgkin’s lymphomas
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hodgkin’s lymphoma
Pathophysiology
Clinical manifestations
Evaluation and treatment
Multiple myeloma
Pathophysiology
Clinical manifestations
Evaluation and treatment
Review questions
18 The structure and function of the integumentary system
Chapter outline
Key terms
Introduction
The structure of the skin
Layers of the skin
The epidermis
The dermis
The dermal–epidermal junction
Skin colour
Appendages of the skin
Hair
Nails
Sweat glands
Eccrine sweat glands
Apocrine sweat glands
Sebaceous glands
The function of the integumentary system
Protection
Physical barrier
Chemical barrier
Biological barrier
Regulation of body temperature
Cutaneous sensation
Production of vitamin D
Excretion
Review questions
19 Alterations of the integumentary system across the life span
Chapter outline
Key terms
Introduction
Skin lesions
Skin cancer
Basal cell carcinoma
Squamous cell carcinoma
Solar (acitinic) keratosis
Squamous cell carcinoma in situ (Bowen’s disease)
Melanoma
Pathophysiology
Clinical manifestations
Evaluation and treatment
Inflammatory disorders of the skin
Dermatitis
Irritant contact dermatitis
Allergic contact dermatitis
Latex allergy
Atopic dermatitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Seborrhoeic dermatitis
Acne vulgaris
Acne rosacea
Cutaneous lupus erythematosus
Papulosquamous disorders
Infections of the integumentary system
Bacterial infections
Folliculitis
Furuncles and carbuncles
Cellulitis
Staphylococcal scalded skin syndrome
Paronychia
Viral infections
Herpes simplex virus
Herpes zoster and varicella
Warts
Molluscum contagiosum
Fungal infections
Tinea infections
Candidiasis
Parasitic infestations
Scabies
Pediculosis
Ticks
Traumatic conditions of the integumentary system
Pressure injuries
Pathophysiology
Clinical manifestations
Evaluation and treatment
Skin tears
Burns
Pathophysiology
Clinical manifestations
Evaluation and treatment
Vascular disorders
Cutaneous vasculitis
Scleroderma
Port-wine stain
Review questions
20 The structure and function of the musculoskeletal system
Chapter outline
Key terms
Introduction
The structure and function of bones
Elements of bone tissue
Bone cells
Osteoblasts
Osteoclasts
Osteocytes
Bone matrix
Collagen fibres
Proteoglycans
Glycoproteins
Bone minerals
Types of bone tissue
Characteristics of bone
Maintenance of bone integrity
Remodelling
Repair
The structure and function of joints
Fibrous joints
Cartilaginous joints
Synovial joints
Joint capsule
Synovial membrane
Joint cavity
Synovial fluid
Articular cartilage
Intraarticular menisci
The movement of synovial joints
The structure and function of skeletal muscles
Whole muscle
Motor unit
Sensory receptors
Muscle fibres
Myofibrils, sarcomeres and myofilaments
Non-protein constituents of muscle
Components of muscle function
Neuromuscular junction
Muscle contraction at the molecular level
Muscle metabolism
Muscle mechanics
Types of muscle contraction
The movement of muscle groups
The effect of training on muscle
The clinical relevance of skeletal muscle
Review questions
21 Alterations of musculoskeletal function across the life span
Chapter outline
Key terms
Introduction
Musculoskeletal injuries
Skeletal trauma
Fractures
Classification of fractures
Pathophysiology
Clinical manifestations
Evaluation and treatment
Dislocation and subluxation
Pathophysiology
Clinical manifestations
Evaluation and treatment
Support structures
Sprains and strains of tendons and ligaments
Pathophysiology
Clinical manifestations
Evaluation and treatment
Tendonitis, epicondylitis and bursitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Muscle strains
Post-exercise muscle soreness
Myoglobinuria
Pathophysiology
Clinical manifestations
Evaluation and treatment
Disorders of bone and joints
Metabolic bone disease
Osteoporosis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Paget’s disease
Pathophysiology
Clinical manifestations
Evaluation and treatment
Disorders of joints
Inflammatory joint disease
Rheumatoid arthritis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Ankylosing spondylitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Gout
Pathophysiology
Clinical manifestations
Treatment
Osteoarthritis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Infectious bone disease
Osteomyelitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Disorders of skeletal muscle
Contractures
Stress-induced muscle tension
Disuse atrophy
Fibromyalgia
Pathophysiology
Clinical manifestations
Evaluation and treatment
Integrative conditions related to the musculoskeletal system
Lower back pain
Pathophysiology
Evaluation and treatment
Bone pain
Myasthenia gravis
Review questions
22 The structure and function of the cardiovascular and lymphatic systems
Chapter outline
Key terms
Introduction
The circulatory system
The structure of the heart
The size and location of the heart
The heart wall
Heart chambers and great vessels
Valves of the heart
Heart sounds
Blood flow during the cardiac cycle
The coronary circulation
Coronary arteries
Collateral arteries
Coronary capillaries
Coronary veins and lymphatic vessels
Structures that control heart function
Myocardial cells
Myocardial excitation–contraction coupling
Myocardial relaxation
Myocardial metabolism
The cardiac conduction system
Action potentials of the cardiac conduction system
Cardiac innervation
The electrocardiogram
Factors affecting cardiac performance
Preload
Afterload
Myocardial contractility
Heart rate
Pulse
The physiology of cardiovascular control
Cardiovascular control centres in the brain
Neural reflexes
Atrial receptors
Hormones and biochemicals
The systemic circulation
Blood vessels
Arteries
Capillaries
Endothelium
Veins
Blood pressure and blood flow
Factors affecting blood flow
Pressure and resistance
Blood vessel radius
Blood vessel length
Viscosity
Total resistance
Neural control of total peripheral resistance
Laminar versus turbulent flow
Vascular compliance
Regulation of blood pressure
Arterial pressure
Baroreceptors
Arterial chemoreceptors
Hormones
Venous pressure
Regulation of the coronary circulation
Autoregulation
The lymphatic system
Lymphatic capillaries
Lymphatic vessels and ducts
Lymph nodes
Review questions
23 Alterations of cardiovascular function across the life span
Chapter outline
Key terms
Introduction
Alterations of blood flow and pressure
Hypertension
Factors associated with primary hypertension
Primary hypertension
Secondary hypertension
Isolated systolic hypertension
Complicated hypertension
Clinical manifestations
Evaluation and treatment
Orthostatic hypotension
Arteriosclerosis
Atherosclerosis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Coronary heart disease
The development of coronary heart disease
Dyslipidaemia and atherosclerosis-promoting diet
Hypertension
Cigarette smoking
Diabetes mellitus and insulin resistance
Obesity and sedentary lifestyle
Myocardial ischaemia
Pathophysiology
Clinical manifestations
Angina
Evaluation and treatment
The acute coronary syndromes
Unstable angina
Acute myocardial infarction
Pathophysiology
Cellular death
Structural and functional changes
Repair
Clinical manifestations
Evaluation and treatment
Treatment
Aneurysm
Thrombus formation
Embolism
Peripheral artery disease
Alterations to veins
Venous thromboembolus
Varicose veins
Alterations of the heart wall
Disorders of the pericardium
Acute pericarditis
Pericardial effusion
Disorders of the myocardium: the cardiomyopathies
Disorders of the endocardium
Valvular dysfunction
Stenosis
Aortic stenosis
Mitral stenosis
Regurgitation
Aortic regurgitation
Mitral regurgitation
Tricuspid regurgitation
Rheumatic heart disease
Pathophysiology
Clinical manifestations
Evaluation and treatment
Infective endocarditis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Alterations of cardiac conduction
Arrhythmias
Heart failure
Left heart failure
Systolic heart failure
Diastolic heart failure
Right heart failure
Shock
Impairment of cellular metabolism
Impairment of oxygen use
Impairment of glucose use
Types of shock
Cardiogenic shock
Hypovolaemic shock
Neurogenic shock
Anaphylactic shock
Septic shock
Clinical manifestations of shock
Treatment for shock
Multiple organ dysfunction syndrome
Pathophysiology
Clinical manifestations
Evaluation and treatment
Review questions
24 The structure and function of the pulmonary system
Chapter outline
Key terms
Introduction
The structure of the pulmonary system
The conducting zone
The respiratory zone
The pulmonary and bronchial circulation
The chest wall and pleura
The function of the pulmonary system
The mechanics of breathing
Major and accessory muscles
Alveolar surface tension
Elastic properties of the lung and chest wall
Airway resistance
The work of breathing
Ventilation
Control of ventilation
Neural control
Mechanical control
Chemical control
Gas transport
Gas pressure
Distribution of ventilation and perfusion
Oxygen transport
Diffusion across the alveolar–capillary membrane
Determinants of arterial oxygenation
The oxygen–haemoglobin dissociation curve
Carbon dioxide transport
Review questions
25 Alterations of pulmonary function across the life span
Chapter outline
Key terms
Introduction
Disorders of the pulmonary system
Obstructive airway diseases
Asthma
Pathophysiology
Clinical manifestations
Evaluation and treatment
Chronic obstructive pulmonary disease
Chronic bronchitis
Pathophysiology
Emphysema
Pathophysiology
Clinical manifestations of COPD
Evaluation and management of COPD
Cystic fibrosis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Bronchiectasis
Restrictive airway diseases
Acute respiratory distress syndrome
Pathophysiology
Clinical manifestations
Evaluation and treatment
Inhalation disorders
Exposure to toxic gases
Pneumoconiosis
Infections of the pulmonary system
Pneumonia
Pathophysiology
Clinical manifestations
Evaluation and treatment
Tuberculosis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Acute bronchitis
Influenza
Pathophysiology
Clinical manifestations
Evaluation and treatment
Lung cancer
Types of lung cancer
Non-small cell carcinoma
Small cell carcinoma
Pathophysiology
Clinical manifestations
Evaluation and treatment
Obstructive sleep apnoea
Pathophysiology
Clinical manifestations
Evaluation and treatment
Alterations of pulmonary blood flow and pressure
Pulmonary embolism
Pathophysiology
Clinical manifestations
Evaluation and treatment
Cor pulmonale
Pathophysiology
Clinical manifestations
Evaluation and treatment
Clinical manifestations of pulmonary alterations
Conditions caused by pulmonary alterations
Pulmonary oedema
Hypoxaemia
Hypercapnia
Acute respiratory failure
Atelectasis
Pneumothorax
Pleural effusion
Empyema
Aspiration
Signs and symptoms of pulmonary alterations
Dyspnoea
Cough
Hypoventilation and hyperventilation
Abnormal breathing patterns
Haemoptysis
Cyanosis
Review questions
26 The structure and function of the digestive system
Chapter outline
Key terms
Introduction
An overview of the digestive system
The gastrointestinal tract and accessory organs
Layers of the gastrointestinal tract
Neural control of the digestive system
Motility
Splanchnic blood flow
The main nutrients
The mouth, pharynx and oesophagus
Anatomy and physiology of the mouth, pharynx and oesophagus
Salivation
Swallowing
Digestion in the mouth, pharynx and oesophagus
The stomach
Anatomy and physiology of the stomach
Gastric motility
Gastric secretion
Acid
Pepsin
Mucus
Phases of gastric secretion
Digestion in the stomach
Absorption from the stomach
The small intestine
Anatomy and physiology of the small intestine
Intestinal motility
Digestion in the small intestine
Absorption from the small intestine
Accessory organs of digestion
The liver
Secretion of bile
Vascular and haematological functions
Metabolism of nutrients
Fats
Proteins
Carbohydrates
Storage of minerals and vitamins
Metabolism of bilirubin
Metabolic detoxification
Liver immunity
The gallbladder
The pancreas
The large intestine
Anatomy and physiology of the large intestine
Intestinal bacteria
Defecation reflex
Digestion in the large intestine
Absorption in the large intestine
Fluid movements in the digestive system
The gastrointestinal tract and immunity
An overview of nutrition
Review questions
27 Alterations of digestive function across the life span
Chapter outline
Key terms
Introduction
Disorders of the gastrointestinal tract
Cancers of the gastrointestinal tract
Colorectal cancer
Pathophysiology
Clinical manifestations
Evaluation and treatment
Oesophageal cancer
Pathophysiology
Clinical manifestations
EVALUATION and TREATMENT
Gastric cancer
Pathophysiology
Clinical manifestations
EVALUATION and TREATMENT
Inflammatory disorders of the gastrointestinal tract
Ulcerative colitis
Pathophysiology
Clinical manifestations
Crohn’s disease
Pathophysiology
Clinical manifestations
Evaluation and treatment of inflammatory bowel disease
Irritable bowel syndrome
Pathophysiology
Clinical manifestations
Evaluation and treatment
Diverticular disease
Pathophysiology
Clinical manifestations
Evaluation and treatment
Appendicitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Gastritis
Peptic ulcer disease
Gastric ulcers
Pathophysiology
Clinical manifestations
Duodenal ulcers
Pathophysiology
Clinical manifestations
Stress ulcers
Evaluation and treatment of peptic ulcer disease
Nutritional disorders
Lactose intolerance
Pathophysiology
Clinical manifestations
Evaluation and treatment
Coeliac disease
Pathophysiology
Clinical manifestations
Evaluation and treatment
Malnutrition
Starvation
Obesity
Disorders of motility
Gastro-oesophageal reflux and GORD
Pathophysiology
Clinical manifestations
Evaluation and treatment
Faecal incontinence
Structural abnormalities of the gastrointestinal tract
Hiatal hernia
Pathophysiology
Clinical manifestations
Evaluation and treatment
Intestinal obstruction
Clinical manifestations of gastrointestinal tract alterations
Vomiting
Pathophysiology
Clinical manifestations
Treatment
Nausea
Constipation
Pathophysiology
Clinical manifestations
Evaluation and treatment
Diarrhoea
Pathophysiology
Clinical manifestations
Evaluation and treatment
Dysphagia
Clinical manifestations
Evaluation and treatment
Anorexia
Gastrointestinal bleeding
Disorders of the hepatobiliary system and pancreas
Hepatic disorders
Inflammatory processes of the liver
Non-alcoholic liver disease
Alcoholic liver disease
Pathophysiology of non-alcoholic and alcoholic liver disease
Clinical manifestations of non-alcoholic and alcoholic liver disease
EVALUATION and TREATMENT of non-alcoholic and alcoholic liver disease
Viral hepatitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hepatic cancer
Pathophysiology
Clinical manifestations
Evaluation and treatment
Clinical manifestations of hepatobiliary alterations
Portal hypertension
Pathophysiology
Clinical manifestations
Evaluation and treatment
Ascites
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hepatic encephalopathy
Pathophysiology
Clinical manifestations
Evaluation and treatment
Jaundice
Pathophysiology
Clinical manifestations
Evaluation and treatment
Biliary disorders
Cholelithiasis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Cholecystitis
Pancreatic disorders
Pancreatitis
Acute pancreatitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Chronic pancreatitis
Pancreatic cancer
Pathophysiology
Clinical manifestations
Evaluation and treatment
Review questions
28 The structure and function of the urinary system
Chapter outline
Key terms
Introduction
The structure of the kidneys
External anatomy
Internal anatomy
The nephrons
The glomerular filtration membrane
Blood supply to the kidneys and nephrons
The juxtaglomerular apparatus
The function of the kidneys
Urine formation
Glomerular filtration
Tubular reabsorption
The proximal convoluted tubule
The loop of henle
The distal convoluted tubule and collecting duct
Tubular secretion
Urine concentration
Antidiuretic hormone
Aldosterone
Atrial natriuretic peptide
Diuretics as a factor in urine flow
Renal hormones
Urodilatin
Vitamin D
Erythropoietin
Glomerular filtration rate
Intrinsic control
Extrinsic control
Sympathetic nervous system control
The renin-angiotensin- aldosterone system
Urine
Acidification of urine
Measures of renal function
Urinalysis
Urea
Creatinine
Urinary structures
The ureters
The bladder
The urethra
Micturition
Review questions
29 Fluids and electrolytes, acids and bases
Chapter outline
Key terms
Introduction
Fluid balance
The distribution of body fluids
Water intake and output
Water movement between the plasma and interstitial fluid
Water movement between the interstitial fluid and intracellular fluid
Alterations in water movement
Oedema
Pathophysiology
Clinical manifestations
Evaluation and treatment
Fluid spacing
Water balance
Electrolyte balance
Sodium, chloride and potassium balance
Sodium
Chloride
Potassium
Alterations in sodium, chloride and water balance
Isotonic alterations
Hypovolaemia
Hypervolaemia
Hypertonic alterations
Hypernatraemia
Pathophysiology
Clinical manifestations
Evaluation and treatment
Water deficit
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hypotonic alterations
Hyponatraemia
Pathophysiology
Clinical manifestations
Evaluation and treatment
Water excess
Pathophysiology
Clinical manifestations
Evaluation and treatment
Alterations in potassium balance
Hypokalaemia
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hyperkalaemia
Pathophysiology
Clinical manifestations
Evaluation and treatment
Calcium, phosphate and magnesium
Calcium
Hypercalcaemia
Hypocalcaemia
Phosphate
Hypophosphataemia
Magnesium
Hypomagnesaemia
Acid–base balance
Acid and pH
Buffer systems
Protein buffering
Carbonic acid–bicarbonate buffering
Respiratory buffering
Renal buffering
Acid–base imbalances
Respiratory acidosis
Respiratory alkalosis
Metabolic acidosis
Metabolic alkalosis
Review questions
30 Alterations of renal and urinary tract function across the life span
Chapter outline
Key terms
Introduction
Urinary tract obstruction
Upper urinary tract obstruction
Kidney stones
Pathophysiology
Clinical manifestations
Evaluation and treatment
Lower urinary tract obstruction
Neurogenic bladder
Overactive bladder syndrome
Obstructions to urine flow
Evaluation and treatment
Urinary tract infection
Causes of urinary tract infection
Types of urinary tract infection
Acute cystitis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Painful bladder syndrome/interstitial cystitis
Acute pyelonephritis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Chronic pyelonephritis
Pathophysiology
Clinical manifestations
Evaluation and treatment
Glomerular disorders
Glomerulonephritis
Types of glomerulonephritis
Acute glomerulonephritis
Chronic glomerulonephritis
Pathophysiology of glomerulonephritis
Clinical manifestations of glomerulonephritis
Evaluation and treatment of glomerulonephritis
Nephrotic syndrome
Pathophysiology
Clinical manifestations
Evaluation and treatment
Chronic kidney disease
Stages of chronic kidney disease
Pathophysiology
Clinical manifestations
Creatinine and urea clearance
Fluid and electrolyte balance
Calcium, phosphate, and bone
Protein, carbohydrate, and fat metabolism
Musculoskeletal system
Cardiovascular system
Pulmonary system
Haematological system
Immune system
Neurological system
Digestive system
Endocrine and reproductive systems
Integumentary system
Evaluation and treatment
Acute kidney injury
Pathophysiology
Clinical manifestations
Evaluation and treatment
Tumours
Renal tumours
Pathogenesis
Clinical manifestations
Evaluation and treatment
Bladder tumours
Pathogenesis
Clinical manifestations
Evaluation and treatment
Review questions
31 The structure and function of the reproductive systems
Chapter outline
Key terms
Introduction
The structure and function of the male reproductive system
External structures
Testes
Penis
Internal structures
Spermatic ducts
Accessory glands
The structure and function of the female reproductive system
External structures
Internal structures
Vagina
Uterus, cervix and uterine tubes
Ovaries
Breast structure
Puberty in males and females
The effects of testosterone in males
The effects of oestrogen and progesterone in females
Gametogenesis
General principles
Meiosis
Spermatogenesis
Oogenesis
The ovarian cycle
The uterine (menstrual) cycle
Ovarian and uterine cycle timing
Male and female sexual responses
The female sexual response
The male sexual response
Conception, gestation and parturition
Fertilisation
Implantation
The development and function of the placenta
Fetal placental circulation
Maternal placental circulation
Transfer (exchange) across the placenta
The embryonic sac
The origin, composition and significance of amniotic fluid
The mother’s adaptations to pregnancy
Weight gain
Endocrine changes
Changes in reproductive and other organs during gestation
Uterus
Cervix
Breasts
Respiratory changes
Cardiovascular changes
Water and electrolytes
Nutrition and metabolism
Fetal development
Development of the reproductive systems in utero
The immune system of the fetus
The neonate
Changes in the cardiovascular system at birth
Changes in the respiratory system at birth
Changes in liver function at birth
Review questions
32 Alterations of the reproductive systems across the life span
Chapter outline
Key terms
Introduction
Classification of reproductive system alterations
Growths
The endocrine system
The reproductive system
Cancer
Cancers of the female reproductive system
Breast cancer
Risk factors
Reproductive factors
Hormonal factors
Environmental factors
Familial factors
Pathogenesis
Clinical manifestations
Evaluation and treatment
Cervical cancer
Ovarian cancer
Cancers of the male reproductive system
Prostate cancer
Risk factors
Diet
Hormones
Chronic inflammation
Familial factors
Pathogenesis
Clinical manifestations
Evaluation and treatment
Testicular cancer
Pathophysiology
Clinical manifestations
Evaluation and treatment
Disorders of the female reproductive system
Benign growths and proliferative conditions
Benign ovarian cysts
Endometrial polyps
Leiomyomas
Pathophysiology
Clinical manifestations
Evaluation and treatment
Adenomyosis
Endometriosis
Polycystic ovary syndrome
Pathophysiology
Clinical manifestations
Evaluation and treatment
Hormonal and menstrual alterations
Dysmenorrhoea
Amenorrhoea
Abnormal uterine bleeding
Premenstrual syndrome
Pathophysiology
Clinical manifestations
Evaluation and treatment
Infection and inflammation
Pelvic inflammatory disease
Vaginitis
Cervicitis
Vulvitis
Bartholinitis
Pelvic relaxation disorders
Reproductive and sexual dysfunction
Disorders of the male reproductive system
Disorders of the urethra
Urethritis
Urethral strictures
Disorders of the penis
Phimosis and paraphimosis
Peyronie’s disease
Priapism
Disorders of the scrotum, testis and epididymis
Disorders of the scrotum
Cryptorchidism
Torsion of the testis
Orchitis
Impairment of sperm production and quality
Epididymitis
Disorders of the prostate gland
Benign prostatic hyperplasia
Prostatitis
Bacterial prostatitis
Non-bacterial prostatitis
Sexual dysfunction
Disorders of the breast
Disorders of the female breast
Disorders of the male breast
Fertility
Control of fertility
Surgical sterilisation
Barrier methods
Hormonal methods
Other methods of contraception
The failure of contraception
Impaired fertility
Assisted reproductive technologies
Major sexually transmitted infections
Gonorrhoea
Syphilis
Chlamydia trachomatis
Herpes simplex virus
Human papillomavirus
Human immunodeficiency virus
Other infections
Review questions
Bacterial sources
33 Introduction to contemporary health issues
Chapter outline
Introduction
Australia and New Zealand: demographics
Current population
Population projections
Ageing
Hospitalisations
Mortality
Chronic diseases
Mental health
Indigenous health
Contemporary lifestyle
Stress
Dietary factors
Physical activity
Obesity
Health promotion initiatives
Review questions
34 Stress and chronic disease
Chapter outline
Key terms
Introduction
The general adaptation syndrome
Stressors
Physical stress
Psychological stress
Contemporary stressors
The detection of stress
The alarm stage
The resistance stage
The exhaustion stage
Physiological processes of the stress response
The sympathetic nervous system
The hypothalamic–pituitary–adrenal axis
Physiological effects of the stress response
Increased cardiac output and breathing rate
Elevated blood pressure
Increased blood glucose and lipid levels
Altered immune response
Stress and the innate defences
Stress and the adaptive defences
Immune system signalling to the hypothalamus
A delicate balance
Suppression of pain
Effects of cortisol used as a therapeutic agent
Benefits of the stress response
Health alterations with chronic stress
Stress, inflammation and chronic disease
Modulation of the stress response
Psychological influences on stress
Personality characteristics and stress
Sex hormone influences on stress
Strategies for coping with stress
Physical activity
Stress and sleep
Hormonal fluctuations with circadian rhythm
Sleep and circadian regulation of stress hormones
Cortisol and sleep
Sleep, stress and immunity
Shift work and disease
Review questions
35 Obesity
Chapter outline
Key terms
Introduction
The progression to overweight and obesity
Evaluation of body size
Body mass index
Waist circumference
Body composition
Obesity
The extent of the issue
Risk factors for the development of obesity
Steady state weight
Lifestyle factors
Unhealthy diet
Physical inactivity
Stress
Smoking
Socioeconomic factors
Genetic factors
Metabolic disorders
Pathophysiology
Adipose cells
Control of appetite
Health complications associated with obesity
Cardiovascular disease
Type 2 diabetes
Cancer
Respiratory disorders
Gallbladder and liver disease
Osteoarthritis
Mortality
Management of obesity
Dietary factors
Physical activity
Pharmacological agents
Surgical treatment
Complications of weight loss
Metabolic syndrome
Evaluation of metabolic syndrome
Chronic complications associated with metabolic syndrome
Coronary heart disease
Type 2 diabetes
Treatment of metabolic syndrome
Review questions
36 Type 2 diabetes
Chapter outline
Key terms
Introduction
Diabetes mellitus
The extent of the issue
Diagnosis of diabetes
Clinical manifestations of diabetes
Pathophysiology
Insulin resistance
Beta cell destruction
Risk factors for the development of type 2 diabetes
Obesity
Understanding the relationship between obesity and diabetes
Pre-diabetes
Metabolic syndrome
Physical inactivity
Unhealthy diet
Tobacco smoking
Genetic factors
Management of diabetes
Glucose lowering oral therapies
Insulin
Complications of pharmacological insulin treatments
Monitoring blood glucose control
Acute complications of diabetes
Hypoglycaemia
Hyperglycaemia
Diabetic ketoacidosis
Hyperglycaemic hyperosmolar state
Chronic complications of diabetes
Mechanisms of microvascular disease and macrovascular disease
Cardiovascular disease
Stroke
Visual disturbances
Kidney damage
Liver disease
Nervous system alterations
Infection
Lower limb disease and amputation
Mortality
Review questions
37 Cancer
Chapter outline
Key terms
Introduction
Cancer is a chronic disease
Cancer characteristics and terminology
What is cancer?
Carcinogenesis
Cancer names
The genetic basis of cancer
Types of gene mutations in cancer
Alteration of progrowth and antigrowth signals — epigenetics
Oncogenes, tumour-suppressor genes and DNA repair genes
Genetics and cancer risk in families
Cancer growth rates
Cancer growth, spread and metastasis
Cancer, immunity, inflammation and infection
Cancer and the immune system
Chronic inflammation
Viral causes of cancer
Bacterial causes of cancer
Gene–environment interaction
Factors that increase the risk of cancer
Cigarette smoking
Dietary factors
Obesity
Alcohol consumption
Ultraviolet radiation
Occupational hazards
Air pollution
Ionising radiation
Electromagnetic fields
Cancer prevention
Physical activity
Dietary factors
Diagnosis and evaluation of cancer
Tumour markers
Evaluation
Clinical staging
Clinical manifestations of cancer and cancer treatments
Infection, anaemia and thrombocytopenia
Pain
Fatigue
Cachexia
Paraneoplastic syndromes
Cancer treatments
Chemotherapy
Hormone therapy
Immunotherapy
Gene therapy
Radiation
Surgery
Complementary and alternative medicines
Adverse effects of cancer treatments
Gastrointestinal tract
Bone marrow
Hair and skin
Reproductive tract
Cancers of greatest significance in Australia and New Zealand
The incidence and mortality rates of specific cancers
Breast and prostate cancers
Colorectal cancer
Melanoma
Lung cancer
The role of cancer screening
Cervical cancer
Breast cancer
Colorectal cancer
Melanoma
Prostate cancer
Cancer across the life span
Review questions
38 Genes, genetic diseases and the environment
Chapter outline
Key terms
Introduction
Studying genetic disease
Studying populations
Studying families
Genetic disorders
Chromosomal disorders
Non-disjunction of autosomes
Non-disjunction of sex chromosomes
Single gene disorders
Autosomal dominant disorders
Autosomal recessive disorders
Sex-linked disorders
Fragile X syndrome
Multifactorial inheritance
Conditions arising from genetic and environmental factors
Congenital abnormalities
Neural tube defects
Fetal alcohol syndrome
Cardiovascular disease
Coronary heart disease
Hypertension
Obesity
Metabolic syndrome
Diabetes mellitus
Mental illness
Drug and alcohol addiction
Cancers
The relative importance of genetic and environmental contributions to disease
The prevention of disease
Genetic screening
The future of disease prevention and treatment
Review questions
39 Neurobiology of mental illness
Chapter outline
Key terms
Introduction
The epidemiology of mental illness in Australia and New Zealand
Genetics and mental illness
Neurotransmitters
Classification systems
Anxiety disorders
Pathophysiology of anxiety
Pathophysiology of obsessive-compulsive disorder
Pathophysiology of posttraumatic stress disorder
Evaluation and treatment
Mood disorders
Signs and symptoms of mood disorders
Mania (or the milder form, hypomania)
Major depression
Pathophysiology
Genetic factors and the gene–environment interaction
Neurochemical factors, hormonal systems, circadian rhythms and environmental factors
Gender differences
Evaluation and treatment
Bipolar disorder
Pathophysiology
Genetic influences
Other biological influences
Evaluation and treatment
Schizophrenia
Pathophysiology
Genetics
Environment and genetic interactions
Neurodevelopment and neuroanatomy
Clinical manifestations
Evaluation and treatment
Substance use
The pathophysiology of reward and addiction
Drug intoxication
Drug withdrawal
Clinical manifestations
Stimulants
Depressants
Opioids
Cannabis
Evaluation and treatment
Eating disorders
Pathophysiology
Evaluation and treatment
Personality disorders
Pathophysiology
Evaluation and treatment
Review questions
40 Indigenous health issues in Australia
Chapter outline
Key terms
Introduction
The Indigenous Australian population
Indigenous health
Mortality
Infant mortality
Morbidity
Fertility
Birth rates
Conditions affecting the wellbeing of Indigenous Australians
Cardiovascular disease
Coronary heart disease
Stroke
Rheumatic heart disease
Diabetes mellitus
Cancer
Chronic kidney disease
Respiratory diseases
Mental health, social and emotional wellbeing
Dementia
Infection
Eye problems
Common threads — factors contributing to health problems
Injuries
Smoking
Alcohol misuse
Social determinants of Indigenous health
Education
Employment
Housing
Closing the Gap
Review questions
41 Maori health in Aotearoa New Zealand
Chapter outline
Key terms
Introduction
The New Zealand Maori population
Distribution
Maori health
Mortality
Infant mortality
Morbidity
Fertility
Conditions affecting the wellbeing of Maori
Cardiovascular disease
Coronary heart disease
Stroke
Rheumatic fever
Diabetes mellitus
Chronic kidney disease
Cancer
Asthma
Mental illness
Infection
Oral health
Factors contributing to health problems
Injuries
Smoking
Alcohol misuse
Social determinants of Maori health
Poverty
Education
Income and employment
Housing
Review questions
Appendix A Normal reference laboratory values
Appendix B Prefixes, suffixes and root words commonly used in health sciences
Image and text credits
Chapter 1
Figures
Chapter 2
Figures
Chapter 3
Figures
Tables
Ageing box
Chapter 4
Figures
Boxes
Ageing box
Research in focus
Chapter 5
Figures
Chapter 6
Figures
Tables
Boxes
Research in focus
Chapter 7
Figures
Tables
Boxes
Research in focus
Chapter 8
Figures
Tables
Boxes
Research in focus
Chapter 9
Figures
Tables
Boxes
Paediatrics box
Research in focus
Chapter 10
Figures
Tables
Chapter 11
Figures
Tables
Boxes
Research in focus
Chapter 12
Figures
Ageing box
Research in focus
Chapter 13
Figures
Tables
Research in focus
Boxes
Chapter 14
Figures
Tables
Research in focus
Chapter 15
Figures
Tables
Boxes
Research in focus
Ageing box
Paediatrics box
Chapter 16
Figures
Tables
Research in focus
Ageing box
Chapter 17
Figures
Tables
Research in focus
Chapter 18
Figures
Tables
Boxes
Chapter 19
Figures
Tables
Research in focus
Paediatrics boxes
Chapter 20
Figures
Tables
Ageing box
Research in focus
Chapter 21
Figures
Boxes
Paediatrics boxes
Research in focus
Chapter 22
Figures
Tables
Research in focus
Chapter 23
Figures
Tables
Research in focus
Chapter 24
Figures
Boxes
Chapter 25
Figures
Tables
Research in focus
Chapter 26
Figures
Tables
Boxes
Chapter 27
Figures
Tables
Boxes
Paediatrics boxes
Research in focus
Chapter 28
Figures
Tables
Boxes
Research in focus
Chapter 29
Figures
Tables
Paediatrics box
Chapter 30
Figures
Tables
Paediatrics boxes
Research in focus
Chapter 31
Figures
Ageing box
Research in focus
Chapter 32
Figures
Tables
Boxes
Research in focus
Chapter 33
Figures
Tables
Boxes
Chapter 34
Figures
Tables
Research in focus
Chapter 35
Figures
Tables
Research in focus
Chapter 36
Figures
Tables
Paediatrics box
Research in focus
Chapter 37
Tables
Boxes
Research in focus
Chapter 38
Figures
Tables
Research in focus
Chapter 39
Figures
Tables
Research in focus
Chapter 40
Figures
Tables
Boxes
Research in focus
Chapter 41
Figures
Tables
Boxes
Research in focus
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AUSTRALIA AND NEW ZEALAND EDITION
3e UNDERSTANDING
PATHOPHYSIOLOGY
AUSTRALIA AND NEW ZEALAND EDITION
3e UNDERSTANDING
PATHOPHYSIOLOGY JUDY A CRAFT CHRISTOPHER J GORDON SUE E HUETHER KATHRYN L McCANCE VALENTINA L BRASHERS NEAL S ROTE
Elsevier Australia. ACN 001 002 357 (a division of Reed International Books Australia Pty Ltd) Tower 1, 475 Victoria Avenue, Chatswood, NSW 2067 Understanding Pathophysiology Copyright © 2017, Elsevier Inc. All rights reserved. Previous editions copyrighted 2012, 2008, 2004, 2000, 1996. ISBN: 978-0-323-35409-7 This adaptation of Understanding Pathophysiology, 6e, by Sue E. Huether and Kathryn L. McCance, was undertaken by Elsevier Australia and is published by arrangement with Elsevier Inc. This edition © 2019 Elsevier Australia. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organisations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/ permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). ISBN: 978-0-7295-4264-7 Notice The adaptation has been undertaken by Elsevier Australia at its sole responsibility. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors in relation to the adaptation or for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. National Library of Australia Cataloguing-in-Publication Data
Senior Content Strategist: Libby Houston Content Development Specialist: Vanessa Ridehalgh Senior Project Manager: Karthikeyan Murthy Edited by Sybil Kesteven Proofread by Forsyth Publishing Services Design by Natalie Bowra Index by Innodata Indexing Typeset by Toppan Best-set Premedia Limited Printed in China by 1010
ABOUT THE AUTHORS
Judy A Craft BAppSc (Hons), Grad Cert Acad Pract, PhD, SFHEA Judy Craft is a physiologist who has undertaken research into cardiovascular disease and has a strong interest in preventable disease. She has taught extensively in pathophysiology, anatomy, physiology and pharmacology for biomedical science and allied health students, with a current focus on teaching nursing students. She now researches into the teaching and learning of bioscience for nursing students, and is a Senior Lecturer in the School of Nursing, Midwifery and Paramedicine at the University of the Sunshine Coast.
Christopher J Gordon RN, BN, MExSc, PhD Christopher Gordon is a registered nurse who has worked extensively in acute and critical care settings. He is a nurse scientist who has a human research background in body fluid regulation, thermoregulation and the cardiovascular system. His research now focuses on translational sleep health in insomnia and chronobiology. He is currently an Associate Professor at the University of Sydney, Susan Wakil School of Nursing and Midwifery where he teaches bioscience, pathophysiology and clinical nursing in preregistration and postgraduate programs.
AUSTRALIAN AND NEW ZEALAND
CONTRIBUTORS
Peter Athanasos RGN, RPN, BA, BSc (Hons), PhD Emergency Department, Cramond Clinic, The Queen Elizabeth Hospital, Woodville, SA, Australia Adjunct Senior Lecturer, Griffith Health Institute, Griffith University, Logan Campus, QLD, Australia Adjunct Senior Lecturer, Psychiatry, Flinders University, Adelaide, SA, Australia
Matthew Barton BMSc (Hons), MN, PhD, Grad Cert (Higher Ed) Senior Lecturer, Biosciences: School of Nursing & Midwifery Research Fellow, Menzies Health Institute Queensland, Clem Jones Centre for Neurobiology and Stem Cell Research
Ann Bonner BAppSci (Nsg), MA, PhD Professor, School of Nursing, Queensland University of Technology, Brisbane, QLD, Australia Honorary Research Fellow, Kidney Health Service, Metro North Hospital and Health Service, Brisbane, QLD, Australia
Thomas Buckley BSc (Hons), MN, PhD Associate Professor, Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
Elizabeth Anne Cayanan PhD, BAppSc (Ex,SpSc&Nutr) (Hons) Academic Fellow (Associate Lecturer Human Biology), Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia Clinical Fellow, Sleep Medicine, The Woolcock Institute of Sleep and Respiratory Medicine, Sydney, NSW, Australia
Judy Craft BAppSc (Hons), Grad Cert Acad Pract, PhD, SFHEA Senior Lecturer in Pathophysiology, School of Nursing, Midwifery and Paramedicine, University of the Sunshine Coast, QLD, Australia
Christopher Gordon RN, BN, MExSc, PhD Associate Professor, Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
Lynne Hendrick BSc Lecturer, Sydney Nursing School, The University of Sydney, Sydney, NSW, Australia
Karole Hogarth RN, BSc, PhD Principal Lecturer, School of Nursing, Otago Polytechnic, Dunedin, Otago, New Zealand
Deanne Hryciw PhD Deputy Dean, Learning and Teaching (Sciences) Senior Lecturer, School of Environment and Sciences, Griffith University, Nathan, QLD, Australia
Australian and New Zealand Contributors
Amy Nicole Burne Johnston BSc (Hons), BN, RN, Grad Dip (Ad Ed), MEd, PhD Conjoint Senior Lecturer, School of Nursing, Midwifery and Social Work, University of Queensland, Brisbane, QLD, Australia and Department of Emergency Medicine, Emergency Care, Princess Alexandra Hospital Metro South, QLD, Australia
Carolien Koreneff CDE-RN, FADEA, PACFA (Clin) Director, Credentialed Diabetes Educator and Somatic Psychotherapist, Shire Total Healthcare, Sutherland, NSW, Australia Credentialed Diabetes Educator, Clinical Nurse Specialist, Training and Development Coordinator, Diabetes Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
Sarah List PhD, BSc (Hons), BA Lecturer, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
Steven Maltby PhD Research Academic, Centre of Excellence in Severe Asthma, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
Vanessa Marie McDonald PhD, BNurs, Dip Hlth Sci, FThorSoc Professor, School of Nursing and Midwifery, The University of Newcastle, Newcastle, NSW, Australia Co-Director, Centre of Excellence in Severe Asthma, The University of Newcastle, Newcastle, NSW, Australia Deputy Director, Priority Research Centre for Healthy Lungs, The University of Newcastle, Newcastle, NSW, Australia Honorary Clinical Nurse Consultant, Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton, NSW, Australia
Paul McLiesh BN, Grad Dip (Orth), MNSc Lecturer, Adelaide Nursing School, University of Adelaide, Adelaide, SA, Australia
Derek Nash MSc (Hons), DipEd Senior Lecturer, Department of Nursing, Faculty of Social and Health Sciences, Unitec Institute of Technology, Auckland, New Zealand
Rose Neild MBChB, MPHC, FAChAM Psychiatry Registrar, Southern Adelaide Local Health Network, Adelaide, SA, Australia Adjunct Senior Lecturer, School of Public Health, Flinders University, Adelaide, SA, Australia Affiliate Senior Lecturer, School of Health Sciences, University of Adelaide, Adelaide, SA, Australia
Kulmira Nurgali MBBS, MSc, PhD Associate Professor, College of Health and Biomedicine, Institute for Health and Sport, Victoria University, VIC, Australia Associate Professor, Department of Medicine Western Health, Melbourne University, VIC, Australia Associate Professor, Regenerative Medicine & Stem Cells Program, Australian Institute for Musculoskeletal Sciences, Melbourne, VIC, Australia
Darrin Penola MN (Crit Care) Clinical Nurse Consultant, Thoracic Medicine, St Vincent’s Hospital, Sydney, Australia
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Australian and New Zealand Contributors
Mereana Rapata-Hanning MNurs Principal Lecturer, School of Nursing, Te Kura Matatini ki Otago — Otago Polytechnic, Dunedin, New Zealand
Julija Sipavicius MNurs Prac, MNurs Lead, BAppSci (Nsg) Nurse Practitioner, Bone Marrow Transplantation, Department of Haematology, Royal North Shore Hospital, Sydney, NSW, Australia Clinical Senior Lecturer — Honorary Affiliation, Cancer Research Nursing Unit, Susan Wakil School of Nursing and Midwifery, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
Moira Stephens PhD, MSc, BSc (Hons), Cert Ed, Cert Onc, RN Senior Lecturer, School of Nursing, University of Wollongong, Wollongong, NSW, Australia
Susanne Thompson MNursSci (Nurse Practitioner), MEmergNurs, BN Nurse Practitioner, Emergency Department, Logan Hospital, Brisbane, QLD, Australia Adjunct Lecturer, School of Nursing and Midwifery, Griffith University, Brisbane, QLD, Australia
Adriana Tiziani MEdSt, BSc, DipEd, RN Course Director of Postgraduate Studies in Wound Care, Monash University, Melbourne, VIC, Australia
Thea F van de Mortel BSc (Hons), MHlthSc, PhD Associate Professor, School of Nursing and Midwifery, Griffith University, Southport, QLD, Australia
Carolyn Wildbore BN, MN, Grad Dip (Acute Care), Grad Cert (Cancer Nsg) Clinical Nurses Consultant, Gastroenterology and Upper Gastrointestinal Surgery, Concord General Repatriation Hospital, Sydney, NSW, Australia
Margaret Williamson BPharm, MPH, Grad Dip (App Epi) Principal and Epidemiologist, Health Research & Evaluation Services, Sydney, NSW, Australia
US CONTRIBUTORS US contributors listed as per the chapters in Understanding Pathophysiology, 6th edition by Huether, McCance, Brashers and Rote. 1 Cellular Biology Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah 2 Genes and Genetic Diseases Lynn B. Jorde, PhD H.A. and Edna Benning Presidential, Professor and Chair Department of Human Genetics University of Utah School of Medicine Salt Lake City, Utah 3 Epigenetics and Disease Diane P. Genereux, PhD Assistant Professor Department of Biology Westfield State Westfield, Massachusetts Lynn B. Jorde, PhD H.A. and Edna Benning Presidential Professor and Chair Department of Human Genetics University of Utah School of Medicine Salt Lake City, Utah 4 Altered Cellular and Tissue Biology Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah Todd C. Grey, MD Chief Medical Examiner, State of Utah Associate Clinical Professor of Pathology University of Utah, School of Medicine Salt Lake City, Utah 5 Fluids and Electrolytes, Acids and Bases Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah 6 Innate Immunity: Inflammation and Wound Healing Neal S. Rote, PhD Academic Vice-Chair and Director of Research Department of Obstetrics and Gynecology, University Hospitals of Cleveland Professor of Reproductive Biology and Pathology Case School of Medicine, Case Western Reserve University Cleveland, Ohio
7 Adaptive Immunity Neal S. Rote, PhD Academic Vice-Chair and Director of Research Department of Obstetrics and Gynecology, University Hospitals of Cleveland Professor of Reproductive Biology and Pathology Case School of Medicine, Case Western Reserve University Cleveland, Ohio 8 Infection and Defects in Mechanisms of Defense Neal S. Rote, PhD Academic Vice-Chair and Director of Research Department of Obstetrics and Gynecology, University Hospitals of Cleveland Professor of Reproductive Biology and Pathology Case School of Medicine, Case Western Reserve University Cleveland, Ohio 9 Stress and Disease Margaret F. Clayton, PhD, APRN-BC Assistant Professor College of Nursing, University of Utah Salt Lake City, Utah Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah and Beth A. Forshee, RN, PhD Lorey K. Takahashi, PhD Professor of Psychology Department of Psychology University of Hawaii at Manoa Honululu, Hawaii 10 Biology, Clinical Manifestations and Treatment of Cancer David Virshup, MD Professor and Director Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School Singapore Professor of Pediatrics Duke University School of Medicine Durham, North Carolina 11 Cancer Epidemiology Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah
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US Contributors
12 Cancer in Children and Adolescents Nancy E. Kline, PhD, RN, CPNP, FAAN* Director Research and Evidence-Based Practice, Department of Nursing Memorial Sloan-Kettering Cancer Center New York, New York Lauri A Linder, PhD, RN, CPNP, FAAN Director Nursing Research Medicine Patient Services/Emergency Department Boston Children’s Hospital Boston, Massachusetts 13 Structure and Function of the Neurologic System Richard A. Sugerman, PhD Professor of Anatomy College of Osteopathic Medicine, Western University of Health Sciences Pomona, California Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah Lynne M Kerr, MD, PhD Associate Professor Department of Pediatrics, Division of Pediatric Neurology University of Utah Medical Center Salt Lake City, Utah 14 Pain, Temperature, Sleep, and Sensory Function Jan Belden, MSN, RN-BC, FNP-BC Pain Management Nurse Practitioner Loma Linda University Medical Center Linda, California Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah George W. Rodway, PhD, APRN Associate Clinical Professor Betty Irene Moore School of Nursing at UC Davis Sacramento, California 14 Alterations in Cognitive Systems, Cerebral Hemodynamics and Motor Function Barbara J. Boss, PhD, RN, CFNP, CANP Director of DNP Program and Professor of Nursing School of Nursing, University of Mississippi Medical Center Jackson, Mississippi Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah *deceased
16 Disorders of the Central and Peripheral Nervous Systems and Neuromuscular Junction Barbara J. Boss, PhD, RN, CFNP, CANP Director of DNP Program and Professor of Nursing School of Nursing, University of Mississippi Medical Center Jackson, Mississippi Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah 17 Alterations of Neurologic Function in Children Vinodh Narayanan, MD Child Neurologist, St. Joseph’s Hospital and Medical Center Professor of Clinical Pediatrics and Neurology University of Arizona College of Medicine Phoenix, Arizona Lynne M Kerr, MD, PhD Associate Professor Department of Pediatrics, Division of Pediatric Neurology, University of Utah Medical Center Salt Lake City, Utah Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah 18 Mechanisms of Hormonal Regulation Valentina L. Brashers, MD Professor of Nursing and Attending Physician in Internal Medicine University of Virginia Health System Charlottesville, Virginia Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah 19 Alterations of Hormonal Regulation Robert E. Jones, MD, FACP, FACE Professor of Medicine, University of Utah School of Medicine Salt Lake City, Utah Valentina L. Brashers, MD Professor of Nursing and Attending Physician in Internal Medicine University of Virginia Health System Charlottesville, Virginia Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah
US Contributors
20 Structure and Function of the Hematologic System Neal S. Rote, PhD Academic Vice-Chair and Director of Research Department of Obstetrics and Gynecology, University Hospitals of Cleveland Professor of Reproductive Biology and Pathology, Case School of Medicine, Case Western Reserve University Cleveland, Ohio Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah 21 Alterations of Hematologic Function Anna L. Schwartz, PhD, FNP, FAAN Associate Professor School of Nursing, Idaho State University Oncology Nurse Practitioner, Wilson Medical Jackson, Wyoming Neal S. Rote, PhD Academic Vice-Chair and Director of Research Department of Obstetrics and Gynecology, University Hospitals of Cleveland Professor of Reproductive Biology and Pathology, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah 22 Alterations of Hematologic Function in Children Nancy E. Kline, PhD, RN, CPNP, FAAN Director, Research and Evidence-Based Practice Department of Nursing, Memorial Sloan-Kettering Cancer Center New York, New York Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah Anna E. Roche, MSN, RN, CPNP, CPON Pediatric Nurse Practitioner Dana Farber/Boston Children’s Cancer and Blood Disorders Center Boston, Massachusetts Joan Shea, MSN, RN, CPON Staff Nurse III Hematology/Oncology/Clinical Research Boston Children’s Hospital Boston, Massachusetts
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23 Structure and Function of the Cardiovascular and Lymphatic Systems Valentina L. Brashers, MD Professor of Nursing and Attending Physician in Internal Medicine University of Virginia Health System Charlottesville, Virginia Susanna G. Cunningham, BSN, MA, PhD, RN, FAHA, FAAN Professor Emeritus Department of Behavioral Nursing School of Nursing University of Washington Seattle, Washington Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah 24 Alterations of Cardiovascular Function Nancy Pike, PhD, RN, CPNP-AC, FAAN Assistant Professor UCLA School of Nursing Pediatric Nurse Practitioner Cardiothoracic Surgery Children’s Hospital Los Angeles Los Angeles, California 25 Alterations of Cardiovascular Function in Children Nancy L. McDaniel, MD Associate Professor of Pediatrics University of Virginia Charlottesville, Virginia Valentina L. Brashers, MD Professor of Nursing and Attending Physician in Internal Medicine University of Virginia Health System Charlottesville, Virginia 26 Structure and Function of the Pulmonary System Valentina L. Brashers, MD Professor of Nursing and Attending Physician in Internal Medicine University of Virginia Health System Charlottesville, Virginia 27 Alterations of Pulmonary Function Valentina L. Brashers, MD Professor of Nursing and Attending Physician in Internal Medicine University of Virginia Health System Charlottesville, Virginia Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah
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US Contributors
28 Alterations of Pulmonary Function in Children Sue E. Huether, MS, PhD Professor Emeritus, College of Nursing, University of Utah, Salt Lake City, Utah Valentina L. Brashers, MD Professor of Nursing and Attending Physician in Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 29 Structure and Function of the Renal and Urologic Systems Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah
Afsoon Moktar, PhD, EMBA, CT (ASCP) Associate Professor School of Physician Assistant Studies Massachusetts College of Pharmacy and Health Sciences University Boston, Massachusetts 34 Alterations of the Male Reproductive Systems Gwen Latendresse, PhD, CNM Assistant Professor University of Utah College of Nursing Salt Lake City, Utah Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah
30 Alterations of Renal and Urinary Tract Function Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah
35 Structure and Function of the Digestive System Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah
31 Alterations of Renal and Urinary Tract Function in Children Patricia Ring, RN, PNP-BC Pediatric Nephrology Nurse Practitioner Children’s Hospital of Wisconsin Milwaukee, Wisconsin
36 Alterations of Digestive Function Sharon Dudley-Brown, PhD, FNP-BC Assistant Professor Schools of Medicine and Nursing, Johns Hopkins University Baltimore, Maryland
Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah 32 Structure and Function of the Reproductive Systems Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah Afsoon Moktar, PhD, EMBA, CT (ASCP) Associate Professor School of Physician Assistant Studies Massachusetts College of Pharmacy and Health Sciences University Boston, Massachusetts George W. Rodway, PhD, APRN Associate Clinical Professor Betty Irene Moore School of Nursing at UC Davis Sacramento, California 33 Alterations of the Female Reproductive System Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah
Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah 37 Alterations of Digestive Function in Children Sara J. Fidanza, MS, RN, CNS-BC Digestive Health Institute Children’s Hospital Colorado Clinical Faculty University of Colorado College of Nursing Aurora, Colorado Sharon Sables-Baus, PhD, MPA, PCNS-BC Associate Professor University of Colorado College of Nursing and School of medicine Department of Pediatrics Pediatric Nurse Scientist Children’s Hospital Colorado Aurora, Colorado 38 Structure and Function of the Musculoskeletal System Christy L. Crowther-Radulewicz, RN, MS, CRNP Nurse Practitioner Anne Arundel Orthopaedic Surgeons Annapolis, Maryland Adjunct Faculty Johns Hopkins School of Nursing, Department of Community-Public Health Baltimore, Maryland
US Contributors
Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah 39 Alterations of Musculoskeletal Function Christy L. Crowther-Radulewicz, RN, MS, CRNP Nurse Practitioner Anne Arundel Orthopaedic Surgeons Annapolis, Maryland Adjunct Faculty Johns Hopkins School of Nursing, Department of Community-Public Health Baltimore, Maryland Kathryn L. McCance, MS, PhD Professor, College of Nursing, University of Utah, Salt Lake City, Utah 40 Alterations of Musculoskeletal Function in Children Kristen Lee Carroll, MD Associate Professor of Orthopedics Assistant Professor of Pediatric Neurology University of Utah Medical Center, Shriner’s Intermountain Unit Salt Lake City, Utah Lynne M. Kerr, MD, PhD Associate Professor Pediatric Neurology, Primary Children’s Medical Center Salt Lake City, Utah Kathryn L. McCance, MS, PhD Professor College of Nursing, University of Utah Salt Lake City, Utah
41 Structure, Function and Disorders of the Integument Noreen Heer Nicol, PhDc, RN, FNP, NEA-BC Clinical Quality Liaison University of Colorado School of Nursing Aurora, Colorado Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah Sue Ann McCann, MSN, RN, DNC Programmatic Nurse Specialist Nursing Clinical Research Coordinator Dermatology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania 42 Alterations of the Integument in Children Noreen Heer Nicol, PhDc, RN, FNP, NEA-BC Clinical Quality Liaison University of Colorado School of Nursing Aurora, Colorado Sue E. Huether, MS, PhD Professor Emeritus College of Nursing, University of Utah Salt Lake City, Utah
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REVIEWERS
Anupama Bangara Kulur MSc, PhD Lecturer, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia
Tracey Burrows BHSc (N&D), GCTT, PhD, Adv APD Associate Professor, Nutrition and Dietetics, Faculty of Health and Medicine, Priority Research Centre in Physical Activity and Nutrition, Callaghan, New South Wales, Australia
Frances Corrigan BHSci, PhD Senior Lecturer, University of South Australia, Head Injury Laboratory, School of Health Sciences, Adelaide, South Australia, Australia
Tim Crowe BSc(Hons), MNutrDiet, PhD Dietitian, Thinking Nutrition, Melbourne, Victoria, Australia
Doseena Fergie RN, RM, PhD, FCATSINAM Lecturer and Researcher, Indigenous Health and Culture, School of Nursing and Midwifery and Paramedicine, Australian Catholic University, Melbourne, Victoria, Australia
Judie Gardiner Lecturer, Eastern Institute of Technology, Taradale, Hawkes Bay, New Zealand
Tracey Giles RN, Grad Cert (High Dependency), MNg, PhD Senior Lecturer, Flinders University, College of Nursing and Health Sciences, Adelaide, South Australia, Australia
Courtney Hayes BNurs, Grad Dip CritCareNurs, MCritCareNurse Lecturer, Faculty of Health, Disciplines of Nursing & Midwifery, University of Canberra, Australian Capital Territory, Australia
Jed Montayre RN, MN, DipTchg, PhD Lecturer, School of Clinical Sciences, Auckland University of Technology, Auckland, New Zealand
Jacqueline Pich PhD, BNurs (Hons), BSc Lecturer, Faculty of Health, Uuniveristy of Technology Sydney, Sydney, New South Wales, Australia
Evan Plowman BSc, GCertEd, PhD Senior Lecturer, College of Public Health, Medical and Veterinary Sciences, James Cook University, Cairns, Queensland, Australia
Ross Richards MAppSc, PhD Senior Lecturer in Biomedical Science, School of Community Health, Faculty of Science, Charles Sturt University, NSW, Australia
Brian Robinson MSc (Physiology), PhD (Medicine) Senior Lecturer, Graduate School of Nursing, Midwifery and Health, Victoria University of Wellington, New Zealand
Melissa Robinson-Reilly PhD, MN (NP), MN (Palliative Care), BN, Prof UniCert in Assess, Grad Cert Onc, Cert Haem, Cert IV, Dip AppSc, RN
Lecturer and Program Convenor, School of Nursing and Midwifery, Faculty of Health and Medicine, The University of Newcastle, New South Wales, Australia
David Simcock BSc, GCertEd, PhD Senior Lecturer, College of Public Health, Medical and Veterinary Sciences, James Cook University, Cairns, Queensland, Australia
Renee Stone MIntensive Care Nrsg Lecturer, Griffith University, School of Nursing and Midwifery, Nathan, Queensland, Australia
Chris Taua PhD, MN, PGCHSc(MH), CATch, FNZCMHN Director/Nurse Consultant, Pumahara Consultants, North Canterbury, New Zealand
Alison Walsh BN, Grad Dip Oncology Lecturer, Oncology/Haematology, The University of Adelaide, Adelaide, South Australia, Australia
Reviewers
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PREFACE
We are delighted to present the third edition of Understanding Pathophysiology. The aim of this new edition was to revise and update the previous edition to meet the ever-changing landscape of pathophysiology for health professional students. We recognise that students need the latest evidence about diseases and disorders and that these disorders and diseases need to have high relevance to students’ clinical practice. Therefore we have drawn together a team of clinical and scientific experts for each chapter. The synergy between the scientific and clinical experts provides a unique perspective; one that we believe enhances the textbook. One main aspect that is new to this edition is the separation of obesity and type 2 diabetes into separate, stand-alone chapters within Part 6. As the populations of Australia and New Zealand encounter increasing rates of both these conditions, exploring them in distinct chapters has allowed greater focus on the most relevant pathophysiology and clinical issues of these topics. As with other health problems, discussion of the body systems affected by diseases, disorders and syndromes are highlighted in the chapters to allow students to see that pathophysiological changes are often interrelated. As in previous editions, local clinical terminology and current health statistics are integrated to identify and examine the conditions with the highest incidence, prevalence and relevance in our communities. The third edition also incorporates revisions to the Focus on Learning questions, Case Studies and the chapter Review Questions; answers for all of these are available online via the Evolve platform.
ORGANISATION OF CONTENT
The textbook is organised into six parts, which group areas of common pathophysiological concepts. Part 1 (Chapters 1–5) provides the necessary background knowledge of health science principles and processes relevant to pathophysiology. This includes an exploration of what constitutes pathophysiology, and how the disease process manifests in clinical signs and symptoms. It also encompasses relevant information about the population-level measures of disease, such as incidence, prevalence and mortality rates, to allow students to successfully interpret these in subsequent chapters. Chapter 1 provides an overview of the essentials of anatomy, physiology, chemistry and physics that are relevant to the study of pathophysiology. Chapter 2 is devoted to homeostasis — arguably one of the most important themes underlying all aspects of health, since disease results when homeostasis cannot be maintained. Chapter 3 explores the normal structure and function of
the cell, and Chapter 4 deals with alterations to cellular biology. Finally in this part, Chapter 5 examines genes and how genetic information controls events within the cell. Parts 2–5 provide an in-depth examination of body systems, and are grouped into areas of common and key concepts. Each part has chapters on normal anatomy and physiology, as well as pathophysiology. Although this textbook focuses on pathophysiology, we have included chapters on anatomy and physiology because an understanding of normal body processes is vital for an understanding of pathophysiology. Part 2 (Chapters 6–11) encompasses the nervous and endocrine systems, which undertake overall control and coordination of the body systems. Part 3 (Chapters 12–21) covers the different features relating to immunity, haematology, the integumentary system (skin) and the musculoskeletal system. Part 4 (Chapters 22–30) focuses on major body systems that provide the constituents essential for life: the cardiovascular and lymphatic systems, the pulmonary system, the digestive system and the urinary system. Part 5 (Chapters 31 and 32) explores the reproductive systems. Finally, Part 6 (Chapters 33–41), examines those diseases and disorders that have greatest significance in the current health environment in Australia and New Zealand. The main emphasis is on issues that are more encompassing than the body system diseases covered in Parts 2–5. Many of the concepts discussed in Part 6 are advanced, drawing on the knowledge that has been laid down earlier in the book. Chapter 34 looks at the impact of our modern lifestyle and the types of diseases that are strongly related to stress. Chapter 35 and 36 considers two conditions whose incidence has increased tremendously in recent years: obesity and type 2 diabetes; as these conditions now have an increasing impact on the health of our citizens, these topics have been moved to stand-alone chapters. Chapter 37 examines themes relating to a variety of cancers, the current state of cancers in Australia and New Zealand and current screening and prevention programs. Chapter 38 discusses the role of genes and the environment in disease pathogenesis — a hot topic given that so many conditions seen in developed countries are described as preventable. Chapter 39 explores the biological bases of mental illnesses, which remain poorly understood and yet are prevalent in our community. Chapters 40 and 41 examine the health of the Indigenous populations in Australia and New Zealand, respectively. We investigate the overall health of the Indigenous populations, often comparing it to the non-Indigenous population.
THE AUSTRALIAN AND NEW ZEALAND CONTEXT
While many say that pathophysiology is similar the world over, this is not the case. Australia and New Zealand both have disease and disorder profiles that are different from other countries. For instance, both countries have very high rates of asthma; Australia has the world’s highest rates of melanoma and the Indigenous populations have poor health outcomes, especially in comparison to other first world Indigenous peoples. Therefore, the diseases and disorders relevant to the Australian and New Zealand landscape are given precedence in this text. The pathophysiology of these diseases and disorders is explained in detail with an epidemiological focus relevant to the particular country.
CONCEPT MAPS: A UNIQUE FEATURE OF THE TEXT
We have populated the text heavily with concept maps, which are easily identified by their bright green background. Concept maps are a useful learning tool as they link concepts and processes in a visually stimulating way — our students often comment that using such maps helps the information to fall into place. The concepts within each map are boxed and may be an anatomical abnormality, a physiological process, a risk factor or an alteration of homeostasis. The different concepts are then linked by lines and arrows, and in many cases descriptive joining words are included to provide a crucial link demonstrating how the concepts relate to each other.
Preface
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We have included both simple and complex concept maps: simple maps are to be read from top to bottom, while to read the more complex maps start at the top and follow each loop around back to the starting point to complete a process.
ACKNOWLEDGMENTS
A textbook this size is constructed with a team of people. As such, we would like to formally acknowledge our colleagues whose expertise was sought in the refinement of this new edition and who have been part of the process of creating this text. We are particularly indebted to the many clinicians and academics who provided expert knowledge from their specialty domains. We thank them for their contribution and the time they gave to the contributors. Of course, we also are indebted to the Australian Elsevier team, which has provided the guidance and support needed in the construction of a new edition. We would particularly like to thank Libby Houston and Karthikeyan Murthy for assisting us in the completion of this edition. A special mention must also go to Vanessa Ridehalgh, our wonderful Developmental Editor who was part of the journey. And finally, we would like to thank our families who provided support and love during the writing of this textbook. They are at the coalface and often don’t see us for extended periods of time when we are in writing and editorial modes, but they are always there for us and this is greatly appreciated. Judy Craft Christopher Gordon
TEXT FEATURES
Key terms abdominal quadrants, 10 acid, 14 acidosis, 14 adolescent, 6 adult, 6 aetiology, 5 ageing, 6 alkaline, 14 alkalosis, 14 anatomical position, 7 anatomy, 4 anterior/posterior, 8 carbohydrates, 16 cell, 11 central/peripheral, 9 child, 6 clinical manifestations, 5 comorbidity, 6 compounds, 13 disease, 5 disorder (condition), 5 dorsal cavity, 9 electrolytes, 13 enzymes, 15 epidemiology, 6 frontal plane, 8 hydrophilic, 13 hydrophobic, 13 incidence, 6 infant, 6 insidious, 5 lipids, 16 localised, 5 medial/lateral, 9 metabolism, 15 molecules, 13 morbidity, 6 mortality, 6 nucleic acids, 16 organs, 11 pathophysiology, 4 physiology, 4 prevalence, 6 protein, 15 proximal/distal, 9 sagittal plane, 7 sign, 5 superior/inferior, 8 symptom, 5 syndrome, 5 systemic, 5 tissues, 11 transverse plane, 7 ventral cavity, 9 ventral/dorsal, 8
CHAPTER
Introduction to clinical science
1
Key terms are listed (with page numbers) at the beginning of each chapter. Important terms are also defined in the glossary at the back of the book.
Judy Craft and Christopher Gordon
Chapter outline Introduction, 4 Essential pathophysiology, 4 Pathophysiology and clinical manifestations, 4 Disorders and diseases, 5 The onset of disease, 5 Population-level indicators of disease, 6 Age groups within the population, 6 Evaluation and treatment, 6 Essential anatomy, 7 Anatomical position, 7 Body sections and planes, 7 Anatomical directional terminology, 8 Body cavities and quadrants, 9 Health science terminology, 10 Essential physiology, 11 The hierarchy from microscopic to whole body level, 11 Organ systems, 12
Key terms
Essential chemistry, 12 Elements, 12 Ions and electrolytes, 12 Molecules and compounds, 13 Water, 13 Acids and bases, 14 Acidosis and alkalosis, 14 Chemical reactions, 14 Energy, 15 Molecules of life, 15 Essential physics, 16 Pressure within an enclosed area of the body, 16 Pressure from the atmosphere, 17
Chapter outline
3
Chapter outlines summarise the content of each chapter (with page numbers) to help students navigate their way through the chapters.
CHAPTER 22 THE STRUCTURE AND FUNCTION OF THE CARDIOVASCULAR AND LYMPHATIC SYSTEMS
sleep. Substantial slowing of the heart rate to below 60 beats per minute is referred to as bradycardia. In highly trained athletes, the resting heart rate can be below 50 beats/minute, as training produces hypertrophy of the cardiac muscle, leading to a lower resting heart rate and greater stroke volume than before training. In addition, training lowers peripheral resistance in blood vessels by vasodilation in
Research in focus
contraction is more powerful than prior to athletic training,
Research in focus sections highlight areas of research that may offer insights or future treatments for particular pathophysiological conditions
accelerate to a state of tachycardia of more than 100 beats/ minute during muscular activity, emotional excitement or includes activity of the central nervous system, such as
With each ventricular contraction, the pressure entering the arterial system corresponds to a wave of pressure that spreads throughout the major arteries. Hence the pulse is
RESEARCH IN F CUS Heart rate and cardiovascular mortality
PART 1 ESSENTIAL CONCEPTS OF PATHOPHYSIOLOGY
is useful, as it provides an introduction to all areas of the body. Each organ system works with the other organ systems to achieve a healthy human body. nervous system consists of the brain, spinal cord and • neurons, which sense variables throughout the body and
•
•
•
•
critical regulation over all body processes, as well as having the extremely sophisticated tasks of personality, emotion and memory. endocrine system consists of the organs, glands and cells that secrete hormones to regulate the anatomy and physiology of particular targets; the endocrine system assists the nervous system in this function. immune system consists of a range of cell types and tissues that protects and defends the body from destruction by foreign particles including bacteria, viruses and cancer cells. integumentary system comprises the skin and mucous membranes (in areas without skin) that form the external covering of the body. It provides a barrier that assists with the protection of the body from foreign substances. haematological system comprises the blood and bone
functions of the blood are the transport of nutrients and wastes, and protection (working closely with the immune system). • musculoskeletal system (muscles and bones) allows the body to move, as well as providing physical support are far more critical than just allowing us to move — for example, breathing requires the function of the diaphragm (a large muscle), while the bones of the skull protect the brain. • cardiovascular system consists of the heart and blood vessels, which provide the means for the blood to travel to every body cell. respiratory system (respiratory tract and lungs) • exchanges oxygen and carbon dioxide with the environment, as well as enabling the production of speech. digestive system includes the mouth, oesophagus, • overall purpose of this system is to break down food into small products that can be absorbed into the bloodstream and become available for all body cells. Undigested food leaves the body as the faeces. • In the urinary system and a range of wastes exiting the body in the urine. Other components of the system include the urinary bladder for temporary storage of urine, the ureters and the urethra, which drains urine from the body. • reproductive system consists of glands and organs
Higher heart rate is associated with increased risk of cardiovascular mortality. A linear relationship exists between resting heart rate (RHR) and risk of mortality with metaanalysis of prospective studies to date reporting a 6% increase mortality risk for each 10 bpm increase in RHR.
males and females, it is the functioning of the two sexes together that achieves reproduction. Each system needs to function adequately to maintain of the reproductive system may be questioned; however,
Radial artery Femoral artery
Popliteal (posterior to knee)
Posterior tibial Dorsalis pedis
FIGURE 22.29
Pulse points. Each pulse point is named after the artery with which it is associated.
providing new life and continuation of the species. An overriding theme for all body processes is homeostasis, whereby the body maintains stable conditions despite FOCUS ON LEARNING
in Chapter 2.
1
Explain how to calculate cardiac output, including the normal values.
2
FOCUS ON LEARNING 1
Brachial artery
Pulse
behind it. Sites where the pulse points are most easily felt are shown in Fig. 22.29.
Organ systems
Carotid artery
(see Fig. 22.28).
various sites throughout the body, where the artery is located
12
587
Describe the hierarchy of the human body, starting at the smallest level.
2
preload and list the factors that determine
3
The physiology of cardiovascular control
preload.
Cardiovascular control centres in the brain
including why this is important clinically.
oblongata of the brainstem, along with other vital centres
4 5
system.
6
List the main factors that alter heart rate.
Essential chemistry
the cardiovascular control centres communicate with the
Before turning to the details of pathophysiology, it is necessary for you to understand some basic principles of chemistry, because the components of the body are made background for your understanding of the human body. Rest assured that only chemistry that is essential and relevant for your study of pathophysiology has been included.
Elements is a substance that cannot be broken down any further). Fortunately, you will have already heard of most of the relevant elements: the four listed in Table 1.3 are the main elements that make up most of the human body.
Ions and electrolytes
Elements in the body that have an electrical charge are called ions. A positively charged ion is called a cation and a negatively charged ion is an anion human body and their charges are listed in Table 1.4. If an
TABLE 1.3 Major elements of the human body NAME
SYMBOL
Carbon
C
Hydrogen
H
Oxygen
O
Nitrogen
N
Focus on learning Focus on learning boxes are scattered throughout each chapter and ask students to reflect on the main points just discussed. Answer guidelines are available online.
Text Features
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PART 4 ALTERATIONS TO BODY MAINTENANCE
the ventricles; and (3) adequacy of myocardial oxygen supply.
Myocardial contractility
Stroke volume (the volume of blood ejected per beat) depends on the force of contraction, which is determined by myocardial contractility, or the degree of myocardial
Concept map
(preload); (2) alterations in the sympathetic activation of
Cardiac output or stroke volume or stroke work or systolic muscle tension
200 Normal contractility
100
FIGURE 22.27
determine stroke volume and cardiac output.
CHAPTER 9 ALTERATIONS OF NEUROLOGICAL FUNCTION ACROSS THE LIFE SPAN
neural defects, thereby reducing the actual prevalence
Ageing and the digestive system
to excess catabolism, cachexia (severe tissue wasting), and reduced appetite. In addition, mood disorders, such as anxiety and depression, are powerful inhibitors of appetite. Loss of appetite, otherwise known as anorexia, occurs in up to 30% of elderly individuals.15
anencephaly (an = without; enkephalos = brain), whereby a major part of the brain is missing; encephalocele, where part of the brain or meninges protrudes through an abnormal opening with the cranial bones; and spina multifactorial — a combination of genes and environment. No single gene has been found to cause neural tube defects. Folic acid (folate) appears to be important, particularly in the very early stages of pregnancy. Folic acid is essential for healthy DNA replication, particularly
B
content of gastric juice may be reduced, particularly with decreased gastric secretion can impair absorption of vitamin B12 mucosal barrier decreases, so there is increased absorption due to degeneration of villi; loss of enteric
system growth and development for the fetus occur shortly stages of pregnancy increases the risk for neural tube defects. Preconception supplementation assures adequate folate levels, and in Australia it is now mandatory for
maturity during the school years. School-age children activities which might lead to constipation.
eurons leads to decline in intestinal motility and blood ore slowly and in smaller amounts.16 the ability to detoxify substances such as drugs decreases.17 Age-linked altered lipid handling leads to increased fat deposition in the liver and subsequent development of non-alcoholic fatty liver disease which ranges from steatosis (excessive amounts of triglycerides and other
×
Afterload
Venous return
Aortic pressure
Enddiastolic volume
Aortic valvular function
Contractility
Autonomic nervous system
Enddiastolic volume
Neural reflexes
Sympathetic stimulation
Atrial receptors Hormones
Myocardial oxygen supply
disorder called steatohepatitis, which is associated with high risk of developing cirrhosis (replacement of healthy deposits and atrophy occurs.18 decrease in pancreatic secretion of digestive enzymes, liver and pancreas to adapt to injury reduces. Although there are no obvious changes in the gallbladder and bile ducts, there is a reduction in production, secretion and metabolism of cholesterol, leading to increased serum cholesterol levels and an increased frequency of gallstone formation and cholecystitis (see Chapter 27).
Paediatrics and Ageing sections
weakens.19 Constipation is common and is related to and changes in enteric nervous system functions.20
Paediatrics and Ageing call out sections highlight and explore how body structures, organs and physiology alter across the life span.
Discuss the major sources and uses of the main nutrient groups.
2 3
When defects of neural tube closure occur, an accompanying vertebral defect allows the protrusion of and it is present in 3.4 per 10 000 births in Australia. Although
18
PART 1 ESSENTIAL CONCEPTS OF PATHOPHYSIOLOGY
Air enters
FIGURE 9.23
commonly associated with the defect. It may also occur without any visible exposure of the meninges or neural tissue, for which the term (occult =
Cutaneous and subcutaneous markers of occult spina bifida. A Note the hairy patch over the lumbar region. B The soft subcutaneous mass seen overlying the sacrum of this infant was determined to be a lipoma. C Sacral sinus tract associated with intraspinal dermoid tumour.
of the condition where the extent of the defect is relatively
Heart rate Central nervous system
FIGURE 22.28
C 1
Preload
Factors affecting cardiac performance. Cardiac output, which is the amount of blood (in litres) ejected by the heart per minute, depends on the heart rate (beats per minute) and stroke volume (millilitres of blood ejected during ventricular systole).
FOCUS ON LEARNING
risk of neural tube defects. Voluntary codes of folate supplementation have been implemented in many EU countries and New Zealand. Other risk factors include heredity, maternal blood glucose concentrations, use of anticonvulsant drugs (particularly valproic acid) and maternal hyperthermia.
which lowers on average by 10–20 beats/minute during
Stroke volume
AGEING
Defects of neural tube closure Neural tube defects occur in approximately 4.6 out of 10 000 live births in Australia each year, with about 25%
PAEDIATRICS
malformations account for one-third of all apparent congenital malformations, and 90% of CNS malformations are defects of neural tube closure. Other injury to the developing brain, such as occurs with cerebral palsy, appears to occur before birth, but the causes of this are poorly understood.
14
By 2–3 years of age children are able to control bowel
227
small. ItWith is extremely common occurring to some degree increasing age, the gastrointestinal in 10–25% infants. Approximately 80%funof these encesofa progressive decline in normal vertebralchanges defectscan are lead located the lumbosacral to aindecline in the quanregions, of food that is ingested, digested and abs to poorer nutrition for the individual. Teeth are lost as a result of periodontal disease and brittle (AFP) testing. About 3%easily. of normal have spina roots that break Taste adults buds decline in number and eventually become less sensitive; the sense of smell Certain may cutaneous subcutaneous abnormalities suggestSalivary also or diminish (although not always). secretion decreases, resulting in a dry mouth. Dysphagia 9.23): • is either very coarseAsoravery silky from stroke. result of these changes, eating is less pleasurable, appetite is reduced and food is not chewed A
Heart rate
Cardiac output
CONCEPT MAP
tract. Breast milk provides antibodies protecting the gastrointestinal tract until digestive mucosal lining matures and increases the ability to produce the infant’s own antibodies around the age of 6 months. Normal
decrease contractility, is acetylcholine released from the parasympathetic nervous system (via the vagus nerve). Many drugs have positive or negative inotropic properties that
793
CHAPTER 26 THE STRUCTURE AND FUNCTION OF THE DIGESTIVE SYSTEM
At birth the intestines are sterile. Exposure to the extrauterine environment and consumption of food/
contractility, are adrenaline and noradrenaline released from the sympathetic nervous system and adrenal glands. Other positive inotropes include thyroid hormone and dopamine.
carbon dioxide levels in the coronary blood. With severe hypoxaemia (arterial oxygen saturation less than 50% compared with a normal value of approximately 98%), contractility is decreased. On the other hand, with less severe hypoxaemia (oxygen saturation in range of 50–90%), contractility is stimulated, as there may be an increased myocardial response to circulating catecholamines. Preload,
0 Ventricular end-diastolic volume (mL)
The Frank-Starling law of the heart. The relationship between length and tension in the heart. Enddiastolic volume determines the end-diastolic length of the ventricular muscle fibres and is proportional to the tension generated during systole, as well as to cardiac output, stroke volume and stroke work.
Central nervous system malformations are responsible for 75% of fetal deaths and 40% of deaths during the
cavae into the heart distends (stretches) the ventricle by increasing preload, which increases the stroke volume and, subsequently, cardiac output.
of contraction: (1) changes in the stretching of the ventricular
Concept maps offer a visual representation of relationships between different concepts and processes. A number include joining words and illustrations to reinforce learning.
Paediatrics and developmental disorders
Atmosphere 760 mmHg
Lungs
Lungs
Continued
0 mmHg (760 mmHg)
Chapter summary
Movement of air into the lungs during breathing. A Before breathing in, the pressure within the lungs matches that in the atmosphere. B During breathing in, the pressure within the lungs
decreases because the lungs get bigger: as a result, air from the atmosphere is drawn into the lungs.
towards an area of lower pressure, air from the atmosphere is drawn into the lungs. It is the same principle that causes more and more air is forced into the enclosed area; when the air in the balloon is released, the air moves from the high-pressure area within the balloon to the atmosphere outside.
FOCUS ON LEARNING 1
the body cause substances to move. 2
processes.
chapter SUMMARY
PART 1 ESSENTIAL CONCEPTS OF PATHOPHYSIOLOGY
CASE STUDY
Essential pathophysiology •
ADULT Mr Jones is in hospital as he has been experiencing chest pain. Investigations reveal that he has high levels of cholesterol in his blood. Mr Jones takes the opportunity to talk with you to learn more about what is happening in his body. He explains that his chest pain has actually been occurring over the past few weeks. He asks you the following questions: 1 Have I been eating too much cholesterol in the past few weeks? Is that why this has happened? (Hint: consider whether heart disease is acute or chronic.) 2 If cholesterol is so bad, why do I have it in my body anyway? (Hint: in later chapters, you will learn how high
–1 mmHg (759 mmHg)
FIGURE 1.14
Chapter summaries remind students of each chapter’s key points and reinforce learning.
20
levels of cholesterol can lead to heart disease, but for now lipids in the body.) They want to check my electrolytes. What are electrolytes? The doctor said something about seeing if my cells are okay. What are cells? 5 They said they were checking the myocardium. What
•
3 4
Pathophysiology is the study of altered body function. Related disciplines include pathology (altered structure), anatomy (normal body structure) and physiology (normal body function). A sign is the measurement of a variable that is objective (such as heart rate). A symptom is a variable that is subjective (such as chest pain) and it may be interpreted are considered together as clinical manifestations.
•
myocardium.)
systemic means related to the whole body.
•
•
•
A disorder (or condition) is a disturbance in function. A syndrome is a group of signs and symptoms, often with signs and symptoms, usually with a set of treatment options. Acute disease usually develops and resolves quickly, whereas chronic disease lasts a longer time. Both types may be mild or severe. Insidious disease develops slowly without being apparent in the early stages. Incidence refers to the number of new cases diagnosed; prevalence refers to all those people with the disease, whether diagnosed recently or previously.
Case study REVIEW QUESTIONS 1 Compare and contrast signs and symptoms. 2 Compare acute and chronic disease and state which type is more severe. 3 4 Explain how the 3 body sections are obtained. 5 Using anatomical directional terminology, compare the position of the navel with an area of the small intestine located just a couple of centimetres below the body surface of the navel.
xxxi
6 List the subdivisions of the dorsal and ventral body cavities and the organs that belong in each cavity. 7 Draw a diagram that shows the hierarchical organisation from the microscopic to the whole body level. What is the smallest functional unit of the body? 8 major elements of the human body. 9 Compare acidosis and alkalosis. 10 Explain how pressure in an area might be lowered.
Case studies highlight the relevant symptoms of a given disease within a clinical setting. Critical thinking questions direct students to consider these symptoms, their effects on a particular body system and the best course of pharmacological treatment. Answer guidelines are available online. Review questions Review questions revise the important points made in each chapter. Answer guidelines are provided online to encourage classroom participation and discussion.
Key terms abdominal quadrants, 10 acid, 14 acidosis, 14 adolescent, 6 adult, 6 aetiology, 5 ageing, 6 alkaline, 14 alkalosis, 14 anatomical position, 7 anatomy, 4 anterior/posterior, 8 carbohydrates, 16 cell, 11 central/peripheral, 9 child, 6 clinical manifestations, 5 comorbidity, 6 compounds, 13 disease, 5 disorder (condition), 5 dorsal cavity, 9 electrolytes, 13 enzymes, 15 epidemiology, 6 frontal plane, 8 hydrophilic, 13 hydrophobic, 13 incidence, 6 infant, 6 insidious, 5 lipids, 16 localised, 5 medial/lateral, 9 metabolism, 15 molecules, 13 morbidity, 6 mortality, 6 nucleic acids, 16 organs, 11 pathophysiology, 4 physiology, 4 prevalence, 6 protein, 15 proximal/distal, 9 sagittal plane, 7 sign, 5 superficial/deep, 9 superior/inferior, 8 symptom, 5 syndrome, 5 systemic, 5 tissues, 11 transverse plane, 7 ventral cavity, 9 ventral/dorsal, 8
CHAPTER
Introduction to clinical science
1
Judy Craft and Christopher Gordon
Chapter outline Introduction, 4 Essential pathophysiology, 4 Pathophysiology and clinical manifestations, 4 Disorders and diseases, 5 The onset of disease, 5 Population-level indicators of disease, 6 Age groups within the population, 6 Evaluation and treatment, 6 Essential anatomy, 7 Anatomical position, 7 Body sections and planes, 7 Anatomical directional terminology, 8 Body cavities and quadrants, 9 Health science terminology, 10 Essential physiology, 11 The hierarchy from microscopic to whole body level, 11 Organ systems, 12
Essential chemistry, 12 Elements, 12 Ions and electrolytes, 12 Molecules and compounds, 13 Water, 13 Acids and bases, 14 Acidosis and alkalosis, 14 Chemical reactions, 14 Energy, 15 Molecules of life, 15 Essential physics, 16 Pressure within an enclosed area of the body, 16 Pressure from the atmosphere, 17
3
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Part 1 Essential concepts of pathophysiology
Introduction
Essential pathophysiology Pathophysiology and clinical manifestations
Many terms are associated with pathophysiology and these can be confusing, primarily because there is sometimes an
causes
result in
causes
result in
FIGURE 1.1
The relationship between pathophysiology, a disorder, signs and symptoms, and clinical manifestations. Mr Jones presents to hospital with chest pain, breathlessness and a decreased ability to perform work. Upon examination, he also states that he feels nauseous and anxious. His blood pressure, heart rate, electrocardiogram (ECG) and weight are measured and considered in the diagnosis. A blood test reveals an elevated blood cholesterol level, a condition that contributes to the pathophysiological process of atherosclerosis (blockage of the coronary arteries).
CONCEPT MAP
Pathophysiology is the study of changes in body function that result from a disease or disorder. This altered condition may arise from an abnormal process within the body, or it may be the body’s response to a foreign substance that has entered the body. Pathophysiological changes can be short term and hence corrected relatively quickly, or they may form the basis of an underlying long-term condition that remains with the patient for decades. In addition, the functional changes may be minor and not noticeable, or they may be more extensive, producing distinct clinical symptoms. Pathophysiology focuses on alterations in function, rather than alterations in structure (pathology is the study of changes in structure). However, because structure and function are related, a fundamental understanding of structural changes is necessary. When exploring pathophysiology, knowledge of the altered body process at the microscopic level constitutes an important link to understanding the effects and symptoms experienced by the patient. In addition, knowledge of the workings of the body at this microscopic level allows you to understand why the appropriate drugs and other treatment options are useful. In order to understand diseases, you first need grounding in the normal structure and functions of the human body. Therefore, studying pathophysiology also means understanding the disciplines of anatomy and physiology. Anatomy is the study of normal body structure — what the body and individual components look like, and how the body is organised. It includes the normal anatomical relationships between structures, as well as the appearance of the individual components. Physiology is the study of normal body functions — the activities of the body and how its individual components work. Anatomy and physiology are often studied together, because the structure and functions of organs are interrelated. In addition, having a basic knowledge of some concepts from the physical sciences, particularly chemistry and physics, contributes to understanding how the body works. The extremely small components of the body are actually molecules and electrolytes from the field of chemistry, while pressure changes during breathing can be explained using physics. Within this textbook, the focus on the physical sciences concentrates on using the sciences as a means to understand body processes. After learning some basic principles from the physical sciences, as well as normal anatomy and physiology, you will have the essential knowledge to commence studies in pathophysiology — the biological and physical manifestations of a disease or disorder that represent a disruption to normal physiological processes.
overlap in meaning. Nonetheless, it is important that you understand these terms, as they are used throughout this text and you will hear them in clinical practice. We will introduce the terms working through an example of a patient, Mr Jones, to allow you to see how theory relates to clinical practice. Mr Jones has presented to hospital with chest pain, and in the following section we explore how we might learn about his condition (see Fig. 1.1). Pathophysiology is the study of alterations to normal function that result from a disease or disorder. In clinical applications, the pathophysiology of the patient’s condition allows us to relate causes of disease processes to corresponding changes in the body. In our example, we need to consider the range of data that inform us about Mr Jones. This data comes from various sources, including a physical examination, medical history, family history, laboratory tests, medical imaging and other diagnostic tools. Mr Jones’ chest pain may be due to blocked coronary arteries, and diagnostic tools to confirm this would include
blood tests to measure his level of cholesterol and other associated substances, as well as an electrocardiogram (ECG), which looks at electrical conduction through the heart. This would provide the clinician with information about the extent of the coronary artery blockage, as well as any history of any heart disease. For example, Mr Jones’ blood tests show an increased level of cholesterol in the blood, which can result in the pathophysiological condition of blockage of the coronary arteries (known as atherosclerosis) and lead to myocardial infarction, commonly referred to as heart attack. A sign is a measurement or recording of something that is objective, such as a patient’s heart rate, temperature, blood pressure or urine output. You would expect that different healthcare professionals measuring the signs of one patient at one point in time would observe and record the same results. For Mr Jones, these signs include his heart rate, blood pressure and ECG findings. The healthcare professional observes these signs and combines them with the symptoms to provide evidence about the extent and type of the pathophysiological process. A symptom is a more subjective indication of the patient’s experience as reported by the patient — such as the amount of pain, or feeling bloated. Symptoms can vary from person to person, even if their clinical signs are similar. Mr Jones may describe the pain being more intense in the left of his chest and his left arm and less painful in his right shoulder. Another patient with the same medical condition may report differing degrees of pain. The patient’s perception of symptoms is individual but must be recognised. For example, if a patient reports discomfort due to nausea, this experience needs to be recognised and addressed, regardless of whether another person would consider the nausea to be of concern. Signs and symptoms are often considered together in practice, because both sources of information are used to assist with diagnosis. Healthcare professionals become quite expert in recognising particular signs and symptoms in diagnosing and treating diseases, and therefore they are particularly relevant to you as a student of health science. In this textbook, we usually consider signs and symptoms together as clinical manifestations and so use this term to encompass the range of consequences that would usually be anticipated for a person with a particular disorder. Clinical manifestations may be quite localised to a particular region of the body, or they may be systemic to the whole body, such as fatigue. Clinical manifestations for Mr Jones include chest pain and breathlessness, which in turn impair his ability to perform physical tasks (see Fig. 1.1).
Disorders and diseases
A disorder (or condition) refers to disturbances or abnormality of function and indicates incomplete health. (Other general terms that are used include illness and sickness.) An example of a disorder is hypertension (or high blood pressure), where the cardiovascular system is altered, which can lead to other body systems being affected. The disorder is unable to be corrected by the body.
CHAPTER 1 Introduction to clinical science
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Syndrome refers to a set of signs and symptoms that occur together and are often specific to a particular syndrome, but usually the actual cause of the syndrome is unknown. For example, metabolic syndrome is associated with a range of criteria and provides a link between obesity and the development of diabetes mellitus. There are several risk factors for this syndrome; however, the exact pathophysiological processes are not fully understood. Conversely, disease is a specific term reserved for the characteristic or distinguishing features that correspond to a particular pathophysiological condition. A disease usually has a well-defined series of events (including the cause, signs and symptoms) and a corresponding set of diagnostic and treatment strategies. For example, coronary heart disease refers to blockage of the coronary arteries of the heart, which decreases the flow of oxygen and nutrients to heart muscle. This causes chest pain and may lead to complete blockage and death of the tissue. The aetiology of a disorder or disease refers to the underlying cause. In some cases, the aetiology may be well known, while in other cases the underlying cause of the illness is poorly understood. For example, the scientific and medical communities have a relatively good understanding of the aetiology of coronary heart disease, compared to many mental health disorders.
The onset of disease
The onset of disease refers to how quickly a disease develops; this information usually assists in determining the correct diagnosis. An acute disease or condition usually develops quickly and resolves or heals quickly, but can be mild, severe or even fatal. However, because acute diseases usually last for only a relatively short period, often there is no permanent associated damage. Sometimes, acute diseases do not require complicated treatment procedures: it may be suitable to ensure that the individual is well hydrated and resting to allow the process to ‘run its course’. An example of an acute disease is pharyngitis (commonly referred to as a sore throat), resulting from inflammation of the upper airways and usually caused by a virus. In this case, treatment consists of support and monitoring for any worsening of symptoms. Finally, some acute diseases can progress to chronic conditions, for example, some acute kidney disorders can progress to chronic kidney disease. Conversely, a chronic disease or condition develops more gradually and lasts for a longer time, even a lifetime. Chronic diseases may also recur frequently. Similar to acute diseases, chronic diseases can be mild, severe or fatal. The most typical chronic diseases are often mild early in the disease process, when the patient is often unaware of the early stages of the disease, but by the time the disease has progressed substantially, there is usually permanent damage. Many chronic diseases are also insidious, meaning that onset is gradual such that the disease is well established before it is detected. The first symptoms are often vague and nonspecific and do not alert the patient or healthcare staff. Such symptoms may include tiredness, weakness or loss of weight. The most prevalent chronic diseases in
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Part 1 Essential concepts of pathophysiology
Australia and New Zealand are heart disease and cancer. Despite the best efforts of the patient and the medical treatment available, it is quite difficult to say that a patient has been completely cured of a chronic disease.
Population-level indicators of disease
Epidemiology is the study of factors that affect the health of populations and it includes information about each type of disease, how often it occurs and the type of people who acquire the disease, such as children, females, the elderly or a particular racial group. This information is vitally important for health professionals in determining who is likely to acquire the disease and the success of treatments. In this section we explain the main terms used to describe disease in a population. The incidence of a disease refers to the number of new cases that have been diagnosed and confirmed; it is usually calculated as the number of cases that are diagnosed within one year. It illustrates what is happening currently in the population, and is particularly useful for considering those diseases that appear to be increasing within a community. In addition, this data is an indication of the effectiveness of various national health strategies that are currently being promoted in Australia and New Zealand in an attempt to decrease the incidence of particular diseases, such as asthma and diabetes mellitus. In contrast, the prevalence of a disease includes the number of new cases, as well as those who have been diagnosed previously. It is used as an overall indication of the total number of people who are affected by a disease at a particular time, regardless of whether they have been diagnosed for a short or long time. We often refer to the prevalence of a disease in this textbook as it provides a measure of how common a disease is in the population. The prevalence of a disease can also be considered by looking at the morbidity, which is the proportion of the population with the disease (relating the number with the disease to the number without the disease). The term ‘morbidity’ is often restricted to those disorders that result in a substantial loss of function and therefore present a significant impact on individuals concerned as well as the healthcare system. Comorbidity refers to the presence of another disease or condition in the same patient or group of patients. The presence of comorbidities increases the risk of significant health problems. Comorbidities are particularly relevant when studying heart disease. For example, hypertension (high blood pressure) and hyperlipidaemia (high levels of lipids in the blood) are comorbidities that contribute to worsening of heart disease. Another way of examining the severity of a disease at the population level is to examine the mortality rate (or death rate). Diseases with a high mortality rate are of great concern regarding the health of the community. Individuals with an increased number of comorbidities often have a greater risk of death, and this contributes significantly to the mortality rate of particular diseases.
In this textbook, we have used the latest available population-level data as a guide to which conditions you are most likely to encounter clinically. Accordingly, we focus on the most prevalent diseases in Australia and New Zealand, which are remarkably similar. You will thus learn about the current health status of these countries, as well as which conditions have the greatest impact on our healthcare system and are therefore particularly common within the hospital environment.
Age groups within the population
Diseases and disorders may be more pertinent in certain age groups. The population is generally split into the following age groups: • Infant: from birth to one year. • Child: from year one to the onset of puberty (approximately age nine to 15 years). • Adolescent: from the onset of puberty until adulthood. • Adult: when an individual has fully matured. • Ageing: adults over the age of 65 years. As in many other countries, this part of the population is increasing in Australia and New Zealand. Such age groups are relevant for health professionals because the anatomical and physiological differences between the groups may impact on the clinical presentation and pathophysiological processes of the diseases that individuals acquire. Furthermore, certain populations are more prone to particular diseases; for example, cancer is usually associated with older individuals. Finally, when determining treatment options, social and psychological differences between groups usually need to be considered. These may impact on the implementation and even the success of the treatment.
Evaluation and treatment
Combining information from a patient’s history, signs and symptoms, laboratory tests and medical imaging allows medical staff to make a diagnosis. Establishing the correct diagnosis is important, because identification of the disease forms the basis for determining the appropriate treatment. Treatment options are often surgical or medical. Surgery involves an operation or a procedure to correct an abnormality or to remove an area of tissue; it ranges from minor skin procedures through to major surgery requiring opening of a body region and carrying a life-threatening risk for the patient. Treatment using medicine relies on the use of drugs or pharmacological agents. In this textbook we focus on why particular drugs are useful, whereas studies of pharmacology include more detailed information on dosing regimens and the safe administration of drugs. Other treatment and management options may include dietary changes or vitamin supplements, exercise, rest or avoiding triggers that worsen the condition (such as allergens). In many cases, these options may be as important as surgical and medical treatments.
CHAPTER 1 Introduction to clinical science
7
FOCUS O N L E A R N IN G
1 Describe the term pathophysiology and define the following commonly used related terms: signs, symptoms, localised, systemic, disorder, disease, acute, chronic, insidious, incidence, prevalence, morbidity, comorbidity and mortality. 2 Describe the different age groups within a population.
Essential anatomy Anatomy refers to the structure of the body, and is an essential discipline for all students of the health professions. Not only do you need to know the names of the main body parts, such as the organs, blood vessels and bones, but you also need a basic understanding of the language of anatomy. This language includes some directional terms that are more specific than in everyday language. For example, consider the word ‘upwards’. If you wish to move a part of the body upwards, the movement may vary depending on whether you are lying, standing or sitting. For clarity, anatomical language provides more precise descriptive terms.
Anatomical position
One of the first considerations in studying anatomy is the actual positioning of the patient’s body. Some patients will be sitting, some will be lying down and others will be curled up asleep on the bed — not to mention children who cannot keep still! How then can you describe the location of particular structures if patients’ bodies are not always in the same position? The answer is to describe the features of the body based on the anatomical position. This is a reference position, and it is useful to take a moment to put your own body into the anatomical position as you read this — it is a great way of helping you to remember the position. Stand upright, with your arms by your side and palms forwards, your thumbs facing out (away from your legs; see Fig. 1.2). You will notice that in the anatomical position, the inside of the elbow is always visible from the front; otherwise, it would be difficult to distinguish between the ‘front’ and ‘back’ of the arm. The patient does not move into the anatomical position to make things easier for you; rather, you need to consider the patient’s body as if it were in anatomical position, and to use that reference position whenever you think of or write about body parts. Another aspect of learning anatomical terminology is not actually learning new words, but learning how to appropriately use the words ‘left’ and ‘right’ — these must be used to describe the patient’s left and right sides (see Fig. 1.2). This can take a bit of getting used to. It is easier if you imagine the organ or limb of interest as part of your own body — then identifying left from right is not so confusing. Diagrams of the body or parts of the body are often included in patients’ medical records, so it is particularly important that you can identify the correct
Right
Left
FIGURE 1.2
The anatomical position and bilateral symmetry. In the anatomical position, the body is in an erect, or standing, posture with the arms at the sides and palms forward. The head and feet are also pointing forward. The dotted line shows the axis of the body’s bilateral symmetry: the right and left sides of the body are mirror images of each other.
orientation. Internal organs also need to be recognised and positioned correctly, separately from the rest of the body, for specific uses such as transplantation, and some surgeries and emergency medicine.
Body sections and planes
Correct orientation of organs is necessary not only when the organs are actually exposed or removed from the body, but also for regular viewing of images of internal structures, such as MRI (magnetic resonance imaging) and x-ray images. Look at the three images in Fig. 1.3. Although these images all show the brain, each one appears quite different, and at first it may seem that they cannot be from the same structure. However, it is important to remember that each image is a different two-dimensional view through a three-dimensional structure. Two-dimensional views can be taken from different angles, and therefore medical terminology requires us to use descriptions that inform the orientation of the image. The following terminology is used, based on the concept of passing a plane through the body to produce a two-dimensional anatomical section (see Fig. 1.4): • The sagittal plane divides the body into left and right. The term midsagittal means the exact middle of the body (through the nose and navel). • The transverse plane divides the body into upper and lower — imagine a horizontal slice being inserted into
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Part 1 Essential concepts of pathophysiology
A
B
C FIGURE 1.4
Anatomical planes. Sagittal, transverse and coronal (frontal) planes.
FIGURE 1.3
Anatomical sections through the brain. A Midsagittal section; B transverse section; and C frontal section.
the body (in the anatomical position of course, so the body would be upright). • The frontal (coronal) plane divides the body into front and back. Coronal sections are common in brain imaging, such as the images obtained from computed tomography (CT) scans.
Anatomical directional terminology
Anatomical directional terminology is used to give specific directions about body structures. For example, how would you describe the location of a suspicious mole on a patient’s back? The back has a reasonably large area, and if the patient
has many moles, finding a particular mole again may be difficult. It would be useful to be able to describe the location of the mole so that it can easily be found again. This is where directional terms are useful. The terms comprise opposite pairs. It is worth committing these terms to memory; you may like to stand up and point them out on yourself. Most terms have a similar meaning to their use in everyday language, which should assist you to remember the definitions (see Fig. 1.5). • Superior means towards the head; inferior means towards the feet. For example, the nose is superior to the navel (remember: the monarch is superior as the head of the kingdom; the inferior servants bow down towards the monarch’s feet). The transverse section divides the body into superior and inferior (see Fig. 1.5A). • Anterior means towards the front; posterior means towards the back. For example, the navel is anterior to the spine (remember: insect antennae are at the front of their bodies, while you sit down on your posterior). A coronal section divides the body into anterior and posterior. In humans, additional terms are used to describe anterior and posterior: ventral (anterior) and dorsal (posterior — towards the vertebral surface or back; dorsal actually means the same as superior in a four-legged animal; see Fig. 1.5B).
CHAPTER 1 Introduction to clinical science
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Cranial cavity Spinal cavity Thoracic cavity Pleural cavities Mediastinum Diaphragm Abdominal cavity Abdominopelvic cavity Pelvic cavity Dorsal body cavity Ventral body cavity FIGURE 1.6
Major body cavities. The dorsal cavity is in the dorsal (back) part of the body and contains the central nervous system. The ventral cavity is on the ventral (front) side of the trunk and contains most of the internal organs of the trunk.
FIGURE 1.5
Anatomical directional terms. A Superior and inferior; B anterior and posterior; C medial and lateral; D proximal and distal; E superficial and deep; and F central and peripheral.
• Medial means towards the middle or midsagittal section (the vertical line that extends through the nose and navel); lateral means away from the midline, or towards the side. For example, the nose is medial to the ear (remember: medial sounds like middle, while being a lateral thinker means that you can think ‘sideways’ about an issue — also, ipsilateral means on the same side, while contralateral means on the other side; see Fig. 1.5C). • Proximal means towards the point of attachment to the body trunk; distal means further from the point of attachment. For example, the foot is distal to the knee because the foot is further away from the attachment of the leg to the trunk compared to the knee (remember: something in close proximity is nearby, while distant is further away; see Fig. 1.5D). • Superficial means towards the body skin or surface; deep means towards the body centre or core. For example, the
stomach is deep to the skin (remember: if you have a superficial relationship with someone you know only the outer things about them; if you have a deep relationship with someone you know some deeper secrets about them; see Fig. 1.5E). • Central means towards the body core, usually the head and trunk; peripheral means towards the body periphery or extremities (towards the hands and feet). For example, the brain is central, while the nerves that can sense pain in the foot are located peripherally (remember: centre means towards the middle or main part of something, while peripheral refers to something spread out or further away; see Fig. 1.5F).
Body cavities and quadrants
In broad terms, the central part of the body, namely the head and trunk, can be divided into cavities (see Fig. 1.6). The dorsal cavity is in the dorsal (back) part of the body and contains the central nervous system. It is subdivided into the cranial cavity above and the spinal cavity below: the cranial cavity within the skull encloses the brain, while the spinal cavity within the bony vertebrae contains the spinal cord. The ventral cavity is on the ventral (front) side
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Part 1 Essential concepts of pathophysiology
of the trunk and contains most of the internal organs of the trunk. It is subdivided into the thoracic cavity and the abdominopelvic cavity. The superior part of the ventral cavity is the thoracic cavity within the chest (containing the heart, lungs, trachea and oesophagus). The thoracic cavity is subdivided into the mediastinum in the centre and the pleural cavities to the sides. The inferior part of the ventral cavity is known as the abdominopelvic cavity, which is subdivided into the abdominal cavity and the pelvic cavity. The abdominal cavity contains the stomach and intestines, pancreas, gallbladder, spleen, kidneys and adrenal glands; and the pelvic cavity contains the internal organs of reproduction and the urinary bladder. The abdominal quadrants are formed by passing a line through the umbilicus (navel) to form the left and right upper quadrants, and left and right lower quadrants (see Fig. 1.7). These terms are particularly useful for locating an area of interest, such as when a patient is describing where they are experiencing pain. The right upper quadrant contains the liver, gallbladder and part of the large intestine; the left upper quadrant contains the stomach, pancreas, spleen and some large intestine; the right lower quadrant
contains the right kidney, appendix and part of the small and large intestines; and the left lower quadrant contains the left kidney and part of the small and large intestines. We introduce the functions of these organs in the section ‘Essential physiology’.
Health science terminology
Many of the words that you will encounter in your studies are derived from Greek and Latin and will be easier to understand if you can split the words into their component parts. Some of the most commonly used prefixes (start of words) are shown in Table 1.1, while suffixes (end of words) are shown in Table 1.2. You may already be familiar with several of these. A full listing of prefixes and suffixes is provided in Appendix B for easy reference. For example, one term that you will notice repeatedly throughout this text, as well as in your career in the health industry, is hypoxia: ‘hypo’ meaning deficient, ‘ox’ for oxygen and ‘ia’ for a condition. So hypoxia is the condition of having low oxygen in the tissues. A similar term is hypoxaemia: ‘hypo’ meaning deficient, ‘ox’ for oxygen and
TABLE 1.1 Common prefixes
Right upper
Right lower
Left upper
Left lower
FIGURE 1.7
Abdominal quadrants. The diagram shows the relationship of the internal organs to the four abdominal quadrants.
PREFIX
MEANING
a-, an-
lack of
auto-
self
adip-
fat
cardio-
heart
cerebro-
brain
dys-
difficulty
endo-
inner, within
epi-
over
erythro-
red
exo-, extra-
outside
haem-
blood
hepat-
liver
hyper-
excess
hypo-
deficient
inter-
between
intra-
within
iso-
equal
leuco-
white
myo-
muscle
nephro-
kidney
osteo-
bone
peri-
around
pneum-
lungs, respiration
pulm-
lung
CHAPTER 1 Introduction to clinical science
TABLE 1.2 Common suffixes MEANING
-aemia
in the blood
-cyte
cell
-ectomy
cutting out
-ia
state or condition of
-itis
inflammation
-ology
study of
-oma
tumour
-stemy
surgical opening
‘aemia’ for in the blood. Both hypoxia and hypoxaemia refer to insufficient levels of oxygen, but one refers to tissues and the other to blood. It is worth mentioning several spelling conventions that differ between Australia/New Zealand and the United States. For example, in Australia/New Zealand we use the prefix ‘haem-’ and suffix ‘-aemia’, whereas Americans use ‘hem-’ and ‘-emia’. There are also some name differences between the United States and Australia/New Zealand. One very important example is the substance adrenaline, which is made by the body and is also used as a drug in cardiac arrest situations. In the United States, adrenaline is known as epinephrine (similarly, noradrenaline is known as norepinephrine).
Essential physiology Physiology is the study of normal body functions and forms a basis for understanding subsequent changes to the body during disorder and disease. Each structure in the body is specialised to perform a unique and important function. These functions are undertaken at the smallest level, the cell. Cells work together in functional units called organs, which are grouped into organ systems, which work together to maintain the healthy functioning of the body (system integration). Physiology and pathophysiology are usually approached at the level of the organ systems, with knowledge of the cellular level giving more detail of the mechanisms involved. The organ systems are interrelated and dependent on each other to achieve a fully functional body. FOCUS O N L E A R N IN G
1 Describe the anatomical position. 2 Describe the orientation of the 3 main anatomical sections. 3 Provide definitions for the 6 pairs of terms used in anatomy. 4 List the components of the body cavities. 5 Provide simple definitions for some commonly used anatomical prefixes and suffixes used in health science.
Chemistry (atoms, molecules, compounds) is the smallest level, which forms Cells (smallest functional unit of the body) grouped together to form Tissues and organs which are organised into
CONCEPT MAP
SUFFIX
11
Organ systems which function together as Human body
FIGURE 1.8
Hierarchical organisation of the human body. The cell is the smallest living component of the body and consists of chemical structures. Cells are grouped together into tissues, organs and organ systems, which function collectively to achieve the health of the whole body.
The hierarchy from microscopic to whole body level
The smallest functional unit of the human body is the cell. Cells can be viewed only by using a microscope: an average cell diameter is between 7 and 100 micrometres (1 micrometre is 1/1000 of a millimetre). Cells are often squashed closely together with little space between them. In schematic diagrams they may be depicted as simplified squares or circles, but cells are three dimensional, so you should visualise them more like cubes or spheres. The individual cells function by constantly exchanging material with the surrounding fluid. For example, nutrients and oxygen enter the cell; and wastes and carbon dioxide exit the cell. Cell size and function depend on cell type. The components of the cell may be examined on a substantially smaller scale to reveal the underlying chemistry. This chemistry is often the key to understanding cellular changes that result from disease, as well as how drugs are able to provide effective treatment. On a larger scale, cells are arranged together as tissues, and tissues are organised to form organs (see Fig. 1.8). Organ systems consist of organs working together to achieve a common goal. The organ systems are interrelated and depend on each other to achieve a fully functional and healthy body. As the components of a system work closely together, functions are usually studied according to systems.
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Organ systems
An overview of the function of different parts of the body is useful, as it provides an introduction to all areas of the body. Each organ system works with the other organ systems to achieve a healthy human body. • The nervous system consists of the brain, spinal cord and neurons, which sense variables throughout the body and stimulate the muscles to contract. The brain provides critical regulation over all body processes, as well as having the extremely sophisticated tasks of personality, emotion and memory. • The endocrine system consists of the organs, glands and cells that secrete hormones to regulate the anatomy and physiology of particular targets; the endocrine system assists the nervous system in this function. • The immune system consists of a range of cell types and tissues that protects and defends the body from destruction by foreign particles including bacteria, viruses and cancer cells. • The integumentary system comprises the skin and mucous membranes (in areas without skin) that form the external covering of the body. It provides a barrier that assists with the protection of the body from foreign substances. • The haematological system comprises the blood and bone marrow that form the blood components. The general functions of the blood are the transport of nutrients and wastes, and protection (working closely with the immune system). • The musculoskeletal system (muscles and bones) allows the body to move, as well as providing physical support for the internal organs. The functions of this system are far more critical than just allowing us to move — for example, breathing requires the function of the diaphragm (a large muscle), while the bones of the skull protect the brain. • The cardiovascular system consists of the heart and blood vessels, which provide the means for the blood to travel to every body cell. • The respiratory system (respiratory tract and lungs) exchanges oxygen and carbon dioxide with the environment, as well as enabling the production of speech. • The digestive system includes the mouth, oesophagus, stomach, intestines, liver, gallbladder and pancreas. The overall purpose of this system is to break down food into small products that can be absorbed into the bloodstream and become available for all body cells. Undigested food leaves the body as the faeces. • In the urinary system, fluid, electrolyte and acid–base balance is performed by the kidneys, with excess fluid and a range of wastes exiting the body in the urine. Other components of the system include the urinary bladder for temporary storage of urine, the ureters and the urethra, which drains urine from the body. • The reproductive system consists of glands and organs that allow for the production of offspring. Although the
anatomy of this system is distinctly different between males and females, it is the functioning of the two sexes together that achieves reproduction. Each system needs to function adequately to maintain a healthy body. In a scientific approach, the essential nature of the reproductive system may be questioned; however, this system is vital for the production of offspring, thereby providing new life and continuation of the species. An overriding theme for all body processes is homeostasis, whereby the body maintains stable conditions despite changes in the environment. This vital concept is explored in Chapter 2. FOCU S ON L EA RN IN G
1 Describe the hierarchy of the human body, starting at the smallest level. 2 Briefly describe the anatomy and physiology of each body system.
Essential chemistry Before turning to the details of pathophysiology, it is necessary for you to understand some basic principles of chemistry, because the components of the body are made of chemical structures. This section provides an important background for your understanding of the human body. Rest assured that only chemistry that is essential and relevant for your study of pathophysiology has been included.
Elements
The body is composed of a number of elements (an element is a substance that cannot be broken down any further). Fortunately, you will have already heard of most of the relevant elements: the four listed in Table 1.3 are the main elements that make up most of the human body.
Ions and electrolytes
Elements in the body that have an electrical charge are called ions. A positively charged ion is called a cation and a negatively charged ion is an anion. The main ions of the human body and their charges are listed in Table 1.4. If an
TABLE 1.3 Major elements of the human body NAME
SYMBOL
Carbon
C
Hydrogen
H
Oxygen
O
Nitrogen
N
CHAPTER 1 Introduction to clinical science
TABLE 1.4 Common electrolytes (ions) of the human body NAME
SYMBOL
Cation Sodium
Na
Potassium Hydrogen Calcium
K
+
H
+
Ca
Magnesium
+
2+
Mg
2+
13
TABLE 1.5 Common molecules and compounds of the human body NAME
SYMBOL
DESCRIPTION
Water
H2O
2 hydrogen, 1 oxygen
Oxygen
O2
2 oxygen
Carbon dioxide
CO2
1 carbon, 2 oxygen
Glucose
C6H12O6
6 carbon, 12 hydrogen, 6 oxygen
Sodium bicarbonate
NaHCO3
1 sodium, 1 hydrogen, 1 carbon, 3 oxygen
Anion Chloride
Cl–
Hydroxide
OH–
Bicarbonate
HCO3–
Sulfate
SO42–
Phosphate
PO43–
ion has two or more positive charges, the number of charges is written just before the ‘+’ sign in superscript, such as Ca2+. If an ion has only one positive charge, the number ‘1’ does not need to be written beside the ‘+’ sign; for example, Na+ has one positive charge. Ions with opposite charges attract each other. This allows the chemical substances to exist as a unit. An example that you will no doubt be familiar with is common table salt, NaCl, which occurs because the positive sodium and negative chloride interact, as follows: Na+ + Cl− ↔ NaCl sodium + chloride ↔ sodium chloride
This equation is written with a double-headed arrow, indicating that the process can move from left to right or from right to left, depending on the conditions at the time. This means that the sodium and chloride ions can exist independently of each other or combine to form sodium chloride. This process is vital to the body: by reversing chemical reactions, the body can maintain chemical equilibrium (or balance). Ions are also electrolytes, meaning they have the ability to conduct electricity. In water, NaCl will separate back out (dissociate) into the individual ions Na+ and Cl–. Electrolytes are of particular interest to healthcare staff who need to identify and replace lost electrolytes in patients who are suffering from vomiting, diarrhoea or blood loss. In fact, electrolyte replacements consist largely of the electrolytes covered in this section. Electrolytes are measured in millimoles per litre (mmol/L).
Molecules and compounds
Molecules contain two or more elements held together and compounds contain two or more different elements
together. Some of the main molecules and compounds found in the human body are listed in Table 1.5. You will no doubt have heard of many of them, and you can now become familiar with their symbols as well. The symbols contain a code for understanding how a compound is formulated; for example, carbon dioxide is written as CO2 — that is, one carbon atom (shown by the C) and two oxygen atoms (shown by the subscript ‘2’ after the O). Another clue is the use of ‘di’ in ‘dioxide’ — ‘di’ means two, indicating the presence of two oxygen atoms in the molecule.
Water
Two-thirds of your body weight is water; all body processes depend on adequate amounts of water. Body fluids such as blood, brain fluid (cerebrospinal fluid), mucus and saliva are water-based, and most substances dissolve in water. The following general properties of water have significance for the body: • It absorbs heat. Liquid water increases and decreases temperature relatively slowly. This is particularly useful in that it can prevent sudden and severe changes in the temperature of body fluids. • It is a lubricant. Water is an important component of lubricating fluids such as saliva, and it allows organs to slide against other tissues without causing friction. Substances that mix well with water are described as being hydrophilic (‘hydro’ = water, ‘philic’ = loving); while substances that do not mix well with water are hydrophobic (‘phobic’ = hating). Think about oily or fatty deposits that accumulate on greasy pans in the kitchen — these molecules are definitely hydrophobic and cannot be easily removed using water alone. Water molecules comprise two hydrogen atoms and one oxygen atom, thus forming H2O. These elements can separate out (dissociate), thereby producing a hydrogen ion (H+) and a hydroxide ion (OH–): H2O ↔ H+ + OH− water ↔ hydrogen ion + hydroxide ion
Again, this is a reversible reaction. If we consider what might happen to salt when it is mixed with water, we see
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Part 1 Essential concepts of pathophysiology
that the salt and water particles separate out and form new complexes: NaCl + H2O ↔ NaOH + HCl sodium + water ↔ sodium + hydrochloric chloride hydroxide acid
The new complexes are NaOH, sodium hydroxide, and HCl, hydrochloric acid. It is useful to understand how these ions and compounds behave within the watery environment of the body, as electrolytes can dissolve in water and form different substances.
Acids and bases
An acid is a substance that liberates hydrogen ions (H+) in solutions. Hydrochloric acid, HC1, is an acid, and can release the H+ when mixed in water: HCl ↔ H+ + Cl− hydrochloric acid ↔ hydrogen ion + chloride
Foods such as lemons and vinegar are acidic and have a characteristic sour flavour. The contents of the stomach are highly acidic, as this assists in the digestion of food, as well as destroying bacteria in the food. A base or alkaline substance is the opposite of an acid. While the term ‘base’ is used to mean the opposite of acidic in the discipline of chemistry, in biology we usually prefer the term ‘alkaline’. Household products such as bleach and oven cleaner are quite alkaline and have a slippery feel (although it is not recommended that you allow these products to contact your skin). An alkaline substance will take up the H+ that has been released from an acid. For example, if hydrochloric acid, HCl, is mixed with the compound sodium hydroxide, NaOH, the hydroxide will take up the H+ as follows: NaOH sodium
+ HCl = + hydrochloric ↔
NaCl sodium
hydroxide
acid
chloride
+ H2O + water
If your stomach contents are excessively acidic and cause severe pain, you may use antacids, which are alkaline substances that bind with some of the excess acid. The bicarbonate ion HCO3– is used on many occasions by the body to assist in neutralising acid, as it is able to take up the H+ released by an acid: HCO3 − + H+ = H2CO3 bicarbonate + hydrogen ion ↔ carbonic acid
For example, the stomach secretes large amounts of hydrochloric acid. This extremely acidic environment is important to facilitate the functioning of the stomach in digesting food. Because this highly acidic environment is harmful to body tissues, the stomach lining has a range of protective properties to prevent acidic destruction. However, the intestines do not have the protective properties that are
found within the stomach, so as the acidic content moves into the intestines, the acid must be neutralised to prevent damage to the intestinal tissues. When hydrochloric acid from the stomach mixes with sodium bicarbonate (NaHCO3) present within the intestines, the following chemical reaction occurs: NaHCO3
+
HCl
=
NaCl
+
H2 O
+
CO2
sodium + hydrochloric ↔ sodium + water + carbon bicarbonate acid chloride dioxide
In this way, the acid is neutralised by the sodium bicarbonate, leaving behind a solution of salt and water. In fact, the hydrogen ions are used to make molecules of water. This neutralisation of acid is essential to protect the lining of the intestines. The pH scale is used to indicate the relative proportion of acids and bases. The scale starts at pH 0 for the strongest acids, progresses through pH 7, which is neutral, and continues to pH 14, which is the strongest base. You will notice in Fig. 1.9 that the pH of blood is 7.35 to 7.45, which is quite a narrow range. Any deviation outside that range must be quickly corrected to keep the body functioning properly (this is discussed in Chapter 29). Maintaining an adequate balance between acidic and alkaline substances is tightly controlled within the human body. Normal body processes produce acids, such as lactic acid from working muscles, which requires buffering. If acids are allowed to accumulate, the delicate balance between acid and alkaline would be altered. The brain is particularly sensitive to fluctuations in acid–base balance, so the respiratory system and urinary system work together in removing excess acid. In the long term, the acids produced by the body are excreted in the urine, which is normally an acidic fluid for this reason. While excessive alkaline fluctuations are also detrimental for the body, this is less likely to occur than acid accumulation, because acid is a byproduct of many processes.
Acidosis and alkalosis
The normal pH of the blood is maintained in the range 7.35 to 7.45, making it slightly alkaline. A pH below 7.35 indicates that the blood has too much acid (acidosis), while a pH above 7.45 indicates that the blood is too alkaline (alkalosis). Remembering the relationship between acid and pH is easier if you think about a see-saw (see Fig. 1.10). Substantial changes in pH leading to acidosis and alkalosis are significant problems for the human body, as most body processes depend on a normal acid–base balance.
Chemical reactions
In addition to chemical reactions where molecules are added together to form new molecules, such as when the body manufactures hormones — the production of something is called synthesis or anabolism — another type of chemical reaction occurs when one molecule is broken down into smaller molecules (called catabolism), an example being
CHAPTER 1 Introduction to clinical science
pH Examples of value solutions 14
Sodium hydroxide
High concentration of acid
15
High pH B
13
Less hydrogen
increasingly basic
12 11
Household ammonia Bicarbonate of soda (sodium bicarbonate)
10
Soap solutions
9
Baking soda Intestinal contents (8–10)
8
More hydrogen
increasingly acidic
Neutral (acid and base are balanced 7 with each other) 6 5
Pure H2O Blood (7.35–7.45) Urine (5–8) Black coffee
Vinegar, wine Stomach contents (1–4)
2
Lemon juice
1 0
Hydrochloric acid
FIGURE 1.9
The pH value of various solutions. The scale indicates the H+ concentration. A pH of 0 is most acidic, whereas a pH of 14 is most alkaline. The pink colouring indicates the acidic range and the blue colouring the alkaline range.
digestion of food. Metabolism refers to all the chemical reactions that take place within the body.
Energy
We derive the energy to fuel the many and varied processes of the body from food. However, we cannot use this energy directly — it must first be transferred to a molecule called adenosine triphosphate, usually abbreviated to ATP. Adenosine triphosphate is the storage form for energy, so any time you consider energy usage, ATP will be involved.
A
Low pH
FIGURE 1.10
The relationship between acid and pH. A Acidosis; B alkalosis.
Molecules of life
There are three main categories of molecules that accommodate most of the compounds of the body: proteins, lipids and carbohydrates. These are also the three main nutrient groups from the food we eat.
Proteins
4 3
Low concentration of acid
A protein is a large molecule consisting of many amino acids linked together. An amino acid is the smallest building block of protein: a couple of amino acids joined together make a peptide, several more linked together become a polypeptide and even more become a protein. The ability of proteins to function within the body is dependent on the three-dimensional structure (folding) of this large molecule. A protein molecule consists largely of carbon, hydrogen, oxygen and nitrogen. The functions of proteins are widespread, as they contribute to the structure of body tissues such as muscle and bone. In fact, it would be difficult to list a body function that does not depend on proteins. Proteins are also responsible for muscle contraction, and special proteins called enzymes have an important role in speeding up some body functions. As an everyday example, enzymes in laundry detergents break down food stains quickly so that clothes are cleaned; laundry detergents without enzymes do not have this advantage, so that food stains may be only partly removed by the end of the wash cycle. In the body, not only do enzymes have the important function of breaking down food, but a wide variety of different enzymes enable thousands of cellular processes to operate quickly and efficiently. You will encounter an extensive array of protein functions as you learn about the body systems. Proteins from food are found in large amounts in animal products such as red and white meat, dairy products, legumes (peas and beans), cereals and nuts. After you consume these large molecules, the proteins are digested and broken down into the small amino acids, which the body then uses to produce new proteins.
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Part 1 Essential concepts of pathophysiology
Lipids
Lipids consist of fats (solid at room temperature) and oils (liquid at room temperature) comprised of the molecule glycerol, with some fatty acids linked to it. An example that you may know is triglyceride — one glycerol with three fatty acids attached. The level of triglycerides in the body can be monitored using blood tests to indicate risk of heart disease. A lipid molecule consists largely of carbon, hydrogen and some oxygen. Some lipids are used to store energy for the body; stored fat is also valuable in helping to protect some of the body’s internal organs. In addition, lipids provide the main structural component of the cell membrane, the boundary around body cells. One lipid of particular interest is cholesterol, and although excessive cholesterol contributes to the development of heart disease, appropriate levels of cholesterol are necessary for body functions such as the production of hormones. A range of other functions are attributed to different types of lipid molecules. Lipids from food are found in solids (usually of animal origin) such as butter and liquids (usually plant-derived) such as vegetable oils.
Carbohydrates
Similar to proteins, there are specific names for smaller and larger molecules of carbohydrates: the smallest are monosaccharides (mono = one; saccharide = sugar) or simple sugars, with the main one of interest being glucose; disaccharides (di = two) consist of two sugars, such as sucrose; and polysaccharides (poly = many) consist of many sugars linked together, such as starch found in potatoes. A carbohydrate molecule consists largely of carbon, hydrogen and oxygen. One of the key functions of carbohydrates is the use of glucose as a main fuel source for a number of processes. In later chapters, you will learn the processes involved in keeping glucose levels adequate in the body and how abnormal levels of glucose can lead to severe illness (such as diabetes mellitus). Dietary carbohydrates also contribute to the overall health of the intestines. Carbohydrates from food are found in breads, cereals, fruits and vegetables. Some carbohydrates cannot be digested by the intestines and these constitute dietary fibre.
Nucleic acids
The nucleic acids are another category of molecules in the body, and these form our genetic information. Although you may not have heard of nucleic acids, you most certainly will have heard of the type DNA (deoxyribonucleic acid) — the other type being ribonucleic acid (RNA). These important molecules store genetic information: DNA contains the code, while RNA carries a copy of the code for when it needs to be replicated. The main elements of these nucleic acids are carbon, hydrogen, oxygen, nitrogen and phosphorus, and these are organised into molecules that link together and form a double strand. We consider the role of DNA and RNA in Chapter 5 when we consider how cells replicate.
FOCU S ON L EA RN IN G
1 List the main elements and electrolytes of the body. 2 List common examples of molecules and compounds of the body. 3 Define the terms hydrophilic and hydrophobic. 4 Compare acid and alkaline substances. Provide the pH levels that define acidosis and alkalosis. 5 Briefly describe proteins, lipids and carbohydrates. Name the two nucleic acids.
Essential physics Pressure is a measure of force and it has some important applications when studying the human body. The main pressure that you already know about in the body is blood pressure: this pressure occurs within the body due to the presence of blood in an enclosed space (the blood vessels) — the force generated by the heart is the main generator of this pressure. Atmospheric pressure in the environment is another example of pressure, and it is critical in allowing air to move in and out of the lungs during respiration.
Pressure within an enclosed area of the body
Pressure occurs within the body due to the presence of gases, solids or fluids within confined spaces. These substances exert a pressure on the walls that enclose them. In the blood vessel system, for example, the enclosed blood vessels maintain the pressure provided by the contraction of the heart (see Fig. 1.11A). The substances within the bloodstream exert this pressure by pushing against the walls of the blood vessels. As a result, any small spaces in the blood vessel lining will allow small substances to exit the vessels — this is how valuable substances such as oxygen and water move from within the blood vessels to nearby cells that need them (see Fig. 1.11B). This concept may be explored by looking at the relationship between pressure and the number of particles. Consider two containers of the same size, one with more particles of oxygen than the other. The container with more particles of oxygen is under a higher pressure (see Fig. 1.12). If there was an opportunity to do so, the particles of oxygen would move out of the container in A where it is crowded with oxygen to the container in B where more space is available. Thus in the blood vessels, substances move from an area where they are in high abundance (and hence higher pressure) to an area where they are in a lower abundance (and lower pressure). So oxygen and water move from an area of higher pressure in the blood vessels to an
CHAPTER 1 Introduction to clinical science
10 particles of air at a higher pressure
17
10 particles of air at a lower pressure
FIGURE 1.13
Different pressures with different-sized containers. A Higher pressure in a smaller space. B Lower pressure in a bigger container.
FIGURE 1.11
Pressure within enclosed blood vessels. A The presence of blood within the enclosed system forces pressure against the blood vessel walls. B Small spaces in the blood vessel lining allow substances to exit the area of higher pressure.
FIGURE 1.12
Different pressures with different numbers of particles. A The pressure of particles in an enclosed space is higher when more particles are present. B Lower pressure in the same size enclosed space when fewer particles are present.
area of lower pressure outside the vessels. Within the cardiovascular system, the pressure inside the arteries is particularly high, while pressure in the veins is considerably lower — this facilitates the blood moving from the arteries towards the veins. Changing the volume of the container changes the pressure within. For example, although there are 10 particles of air in both containers in Fig. 1.13, the pressure is lower in B, as the particles are more spread out. So, one way of
lowering pressure within an area is to increase the size of the container.
Pressure from the atmosphere
Atmospheric pressure is essentially the weight of the air and it occurs due to the weight of particles within the air pushing down on everything within the environment, including you. Atmospheric pressure is measured by a barometer, hence the term ‘barometric pressure’. In applications relating to the human body, pressure is usually measured in millimetres of mercury, abbreviated to mmHg. At sea level, atmospheric pressure is 760 mmHg (or 1 atmosphere). Atmospheric pressure decreases at higher altitudes — as a result, there are fewer particles of substances such as oxygen within the air. So if you could be rapidly transported from sea level to the top of Mount Everest, the highest mountain in the world at 8848 metres above sea level, you would not have sufficient oxygen to survive and would collapse and die within a very short space of time. This is why aircraft cabins are pressurised when flying to increase the pressure to normal sea-level conditions. During breathing, air enters and exits the body through the respiratory tract, and exchanges with atmospheric air. It is the changes in pressure within the respiratory system that allow the atmospheric air to be drawn in and out of the lungs. Pressure measurements in the lungs are stated as variations from barometric pressure, rather than percentages of it, and barometric pressure is actually considered to be zero, with pressure variations given as up or down from zero. Hence a respiratory pressure of –1 mmHg is 1 mmHg lower than atmospheric pressure — in other words, 759 mmHg. During inspiration (breathing in), the relative size of the lungs increases, causing a lowering of pressure inside the lungs compared with the outside pressure (see Fig. 1.14). Since particles move away from an area of higher pressure
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Part 1 Essential concepts of pathophysiology
Air enters Atmosphere 760 mmHg
Lungs
Lungs
0 mmHg (760 mmHg)
–1 mmHg (759 mmHg)
FIGURE 1.14
Movement of air into the lungs during breathing. A Before breathing in, the pressure within the lungs matches that in the atmosphere. B During breathing in, the pressure within the lungs decreases because the lungs get bigger: as a result, air from the atmosphere is drawn into the lungs.
towards an area of lower pressure, air from the atmosphere is drawn into the lungs. It is the same principle that causes air to rush out of a balloon — as the balloon is inflated, more and more air is forced into the enclosed area; when the air in the balloon is released, the air moves from the high-pressure area within the balloon to the atmosphere outside.
FOCU S ON L EA RN IN G
1 Describe how changes in pressure in different areas within the body cause substances to move. 2 Describe how atmospheric pressure influences body processes.
chapter SUMMARY Essential pathophysiology • Pathophysiology is the study of altered body function. Related disciplines include pathology (altered structure), anatomy (normal body structure) and physiology (normal body function). • A sign is the measurement of a variable that is objective (such as heart rate). A symptom is a variable that is subjective (such as chest pain) and it may be interpreted differently from patient to patient. Signs and symptoms are considered together as clinical manifestations. • Localised means being confined to a small region; systemic means related to the whole body.
• A disorder (or condition) is a disturbance in function. A syndrome is a group of signs and symptoms, often with an unknown cause. A disease is a well-defined group of signs and symptoms, usually with a set of treatment options. • Acute disease usually develops and resolves quickly, whereas chronic disease lasts a longer time. Both types may be mild or severe. Insidious disease develops slowly without being apparent in the early stages. • Incidence refers to the number of new cases diagnosed; prevalence refers to all those people with the disease, whether diagnosed recently or previously.
• Morbidity refers to the proportion of people with a disease and is usually used in relation to diseases that have a significant impact on health. Comorbidity refers to the presence of another disease. Mortality is an indication of the death rate associated with a disease. • The ages of members of the population are categorised into infant, child, adolescent, adult and ageing. • A diagnosis defines an actual condition, which assists in guiding treatment. Usual treatment options are surgery (an operation) or medicine (use of medications).
Essential anatomy • The anatomical position is a reference position. It is adopted by standing, facing forwards, with the palms of the hands facing forwards too. • The words ‘left’ and ‘right’ must be used for the patient’s left and right. • A sagittal section is a view taken by dividing the body vertically; a transverse section divides the body into upper and lower; and a coronal section divides the body into front and back. • Superior means towards the head; inferior means towards the feet. Anterior (ventral) means towards the front; posterior (dorsal) means towards the back. Medial means towards the mid-line; lateral means away from the mid-line. Proximal means closer to the point of attachment; distal means further away. Superficial means towards the body surface; deep means towards the body core. Central means towards the body core; peripheral means towards the hands and feet. • The dorsal body cavity contains the brain and spinal cord, while the ventral body cavity contains the organs within the chest, abdomen and pelvis. Abdominal quadrants divide the abdomen into four areas to assist with locating features.
Essential physiology • The smallest functional unit of the body is the cell. Cells constantly exchange materials with their environment. • Cell components are actually chemical structures. Cells are grouped together to form tissues, tissues are grouped to form organs and organs are organised into organ systems. All organ systems contribute to overall body structure and function.
Essential chemistry • An element is a substance that cannot be broken down any further. The main elements of the body are carbon, hydrogen, nitrogen and oxygen.
CHAPTER 1 Introduction to clinical science
19
• An element with an electrical charge is known as an ion. A positive ion is a cation; a negative ion is an anion. Ions are also electrolytes, as they have the ability to conduct water. Electrolyte balance within the body is of particular interest in the healthcare setting. • Molecules have two or more of the same element; compounds have two or more different elements. • Water is a large component of the body, and is able to absorb heat as well as provide lubrication. A hydrophilic substance mixes well with water; a hydrophobic substance does not mix well with water. • An acid contains hydrogen ions; an alkaline substance (or base) is able to bind with (or accept) the hydrogen ion. Acid and alkaline substances are usually balanced or buffered in the body. A normal blood pH is 7.35–7.45; levels below 7.35 indicate acidosis and above 7.45 indicate alkalosis. • Energy from food is stored as ATP, which is the molecule of energy. • Proteins consist of amino acids and are used widely in the structure and function of a diverse array of processes throughout the body. Enzymes are specific proteins that allow chemical reactions in the body to occur quickly. • Lipids are made of glycerol and fatty acids. They are used as a storage form for excess energy, as well as providing support and insulation for organs. • Carbohydrates consist of sugars such as glucose. Glucose is an essential fuel source, particularly for the nervous system. • DNA and RNA contain genetic information.
Essential physics • Pressure in an enclosed area of the body causes substances to move from an area of higher pressure to an area of lower pressure. This assists the blood to travel from arteries to veins. • Atmospheric pressure is 760 mmHg. The differences between atmospheric pressure and pressure within the respiratory system assist in moving air in and out of the lungs. • If two different-sized containers have the same number of particles, the bigger container will have a lower internal pressure.
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Part 1 Essential concepts of pathophysiology
CASE STUDY
ADULT Mr Jones is in hospital as he has been experiencing chest pain. Investigations reveal that he has high levels of cholesterol in his blood. Mr Jones takes the opportunity to talk with you to learn more about what is happening in his body. He explains that his chest pain has actually been occurring over the past few weeks. He asks you the following questions: 1 Have I been eating too much cholesterol in the past few weeks? Is that why this has happened? (Hint: consider whether heart disease is acute or chronic.) 2 If cholesterol is so bad, why do I have it in my body anyway? (Hint: in later chapters, you will learn how high
levels of cholesterol can lead to heart disease, but for now you can explain some general benefits of cholesterol and lipids in the body.) 3 They want to check my electrolytes. What are electrolytes? 4 The doctor said something about seeing if my cells are okay. What are cells? 5 They said they were checking the myocardium. What is that? (Hint: use Table 1.1 to provide a definition for myocardium.)
REVIEW QUESTIONS 1 Compare and contrast signs and symptoms. 2 Compare acute and chronic disease and state which type is more severe. 3 Outline the different age divisions within the population. 4 Explain how the 3 body sections are obtained. 5 Using anatomical directional terminology, compare the position of the navel with an area of the small intestine located just a couple of centimetres below the body surface of the navel.
6 List the subdivisions of the dorsal and ventral body cavities and the organs that belong in each cavity. 7 Draw a diagram that shows the hierarchical organisation from the microscopic to the whole body level. What is the smallest functional unit of the body? 8 Define the terms element, ion and electrolyte. List the 4 major elements of the human body. 9 Compare acidosis and alkalosis. 10 Explain how pressure in an area might be lowered.
Key terms control centre, 27 cytoplasm, 22 effector, 27 extracellular fluid, 22 homeostasis, 22 interstitial fluid, 22 intracellular fluid, 22 intravascular fluid, 22 normal range, 22 plasma, 22 sensor, 27
CHAPTER
Homeostasis
2
Judy Craft and Christopher Gordon
Chapter outline Introduction, 22 Homeostasis, 22 The cellular environment, 22 Homeostasis at the cellular and local level, 23 Homeostasis at the body level, 24
Regulation of homeostasis, 26 Disturbances of homeostasis lead to pathophysiology, 29
21
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Part 1 Essential concepts of pathophysiology
Introduction The concept of homeostasis is essential to understanding how the human body is capable of maintaining normal function despite varying conditions and fluctuations in the environment. Homeostasis occurs continually. The body does not remain in a static state — it works towards a dynamic equilibrium, adjusting variables continuously. In a dynamic equilibrium, small changes are allowed to occur, but these changes are always corrected to keep the variables at normal levels.
Homeostasis The underlying principle of how physiological variables in the body maintain a constant state, despite changes in the external environment, was the underpinning theme of how homeostasis arose. The term homeostasis was developed by the physiologist Walter Cannon and is defined as the body maintaining stable, constant conditions, despite changes in the environment.1 The term is derived from homeo (meaning similar) and stasis (meaning steady). Cannon deliberately chose the prefix homeo, rather than homo (meaning the same), as homeostasis does not require a variable to be maintained at one precise set point. Instead, the normal level for a particular variable is usually a range of values. This is known as the normal range (or reference range), so that slight increases or decreases in value may still be within normal levels. For example, the normal range of blood pH is between 7.35 and 7.45 in a healthy individual (see Fig. 2.1). An important feature about homeostasis is that when there is a tendency towards change from the normal level, the change does not actually deviate significantly from the
14
7.55 Alkaline 7.45
Upper limit of normal
7.35
Lower limit of normal
7
Acidic 0
7.25
Time
FIGURE 2.1
Homeostasis of blood pH. Although the pH of the blood can undergo small changes, it must be maintained within the range 7.35 to 7.45. pH values outside this range indicate a disturbance to homeostasis.
normal level before it is corrected. In other words, as a result of constant monitoring and adjustments, small changes are corrected fairly quickly. Homeostasis operates by maintaining a stable internal environment by compensating automatically for changes in the surrounding environment. In order to understand how this works, we need to explore how a cell interacts with its local environment.
The cellular environment
The smallest functional living component of the body is the cell. This small area is enclosed by a thin cell membrane that allows the components inside the cell to be relatively separated from the surrounding environment. Nutrients and other required substances can enter the cell, while wastes and other substances produced by the cell can exit into the surrounding environment. In order for cells to maintain their normal structure and function, appropriate exchange with the extracellular environment is essential. The human body is approximately 60% water — all components are dispersed in fluids. Both inside and outside the cells is a water-based environment (see Fig. 2.2). Water can be found within cells, as well as in the blood (blood components travel through the watery plasma), brain fluid (cerebrospinal fluid) and other body fluids. The fluid inside the cells is known as the intracellular fluid, or cytoplasm. The fluid outside or between the cells — which is now known to be critical for maintaining the health of the cells — is known as the extracellular fluid. The extracellular fluid can be further subdivided into interstitial fluid between cells, and plasma or intravascular fluid within the bloodstream. In 1878 Claude Bernard described the extracellular fluid as the milieu intérieur — namely, the environment of the cell.2 Ongoing exchange between the cell and the extracellular fluid is vital for maintaining consistency of conditions inside the cell, which in turn is necessary for the cell to function normally. According to Bernard, the cell is able to maintain consistent conditions because it is located within the extracellular fluid — the extracellular fluid helps protect the cell from changes that occur in the environment outside the body. In fact, when Cannon developed the term homeostasis, he was expanding on this earlier work from Bernard regarding the importance of the local environment surrounding the cells. Nutrients, oxygen, fluid and other valuable substances for fuelling cells are delivered to the cells by the bloodstream (see Fig. 2.3). Almost all body cells have a blood vessel located in close proximity to allow this constant exchange (however, a couple of examples are avascular so exchange of substances uses other media, such as the cornea of the eye). Substances travel out of the blood vessel, through the surrounding extracellular fluid and into the cell (see Fig. 2.4). Cellular wastes such as carbon dioxide and lactic acid produced by the cell, as well as valuable substances produced by the cell, including hormones, travel to the bloodstream via the extracellular fluid.
CHAPTER 2 Homeostasis
23
Total body water (%) in relation to body weight Body build Normal Lean Obese
Adult male
Adult female
60 70 50
50 60 42
Infant 70 80 60
Note: Total body water is a percentage of body weight.
Intracellular fluid = 2/3 total body water (28 L)
FIGURE 2.3
Diffusion of fluid and dissolved constituents through the capillary walls and interstitial spaces. Water and solutes move between the blood vessels, the interstitial spaces, and the cells.
Oxygen
Fluid
Glucose
Nutrients
The composition of body fluid compartments in humans. The shaded areas depict the approximate size of each compartment as a function of body weight. The figures indicate the relative sizes of the various fluid compartments and the approximate volumes of the compartments (in litres) in a 70 kg adult. In a normally built individual, the total body water content is roughly 60% of body weight. Because adipose tissue has a low concentration of water, the relative water-to-total body weight ratio is lower in obese individuals (and infants), as shown in the insert.
d s Flui ces Ex te Was
FIGURE 2.2
ic acid Lact ioxide bon d Car
Total body Interstitial fluid = 3/4 Extracellular water = 60% weight extracellular fluid = (42 L) fluid (10.5 L) 1/3 total body water (14 L) Plasma = 1/4 extracellular fluid (13.5 L)
FIGURE 2.4
Homeostasis at the cellular and local level
The condition, temperature, pressure and amount of nutrients and wastes travelling through the blood and extracellular fluid vary, even in a resting individual. These changes within the blood and extracellular fluid can impact on cells’ ability to maintain normal function. All cells need to have a stable environment to continue functioning normally; thus homeostasis is necessary. When fluid levels inside the intracellular environment drop, the cell obtains additional fluid from the surrounding extracellular fluid (see Fig. 2.5). Similarly, if oxygen levels in the cell are too low and carbon dioxide is allowed to
The generalised process of constant exchange between the cell and its fluid environment, the extracellular fluid. The extracellular fluid ultimately exchanges with the blood. Many substances are allowed to pass into and out of the cell.
accumulate, then exchange with the blood and extracellular fluid restores these levels in the cell back to normal (see Fig. 2.6). The levels of ions (or electrolytes) within the cell also need to be maintained in the appropriate range for normal cellular function. In particular, the relative proportions of the ions sodium, potassium and calcium are arguably the most critical, as these are required for neurons (nerve cells) to function — if neurons cannot function normally, the consequences may be fatal. The relative proportions of
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Part 1 Essential concepts of pathophysiology
FIGURE 2.5
Homeostasis of cellular fluid levels. A The cell has inadequate levels of fluid, so in B fluid enters the cell from the extracellular fluid. This leads to a normal amount of fluid in the cell in C, and homeostasis is restored.
FIGURE 2.6
Homeostasis of oxygen and carbon dioxide levels within cells. Insufficient levels of oxygen and excessive carbon dioxide in the cell A are corrected by oxygen entering the cell and carbon dioxide exiting the cell via the blood and extracellular fluid B, so that cellular homeostasis is restored, C.
TABLE 2.1 Relative proportions of three essential ions (electrolytes) ION
PROPORTION +
PROPORTION
Sodium (Na )
Low
High
Potassium (K+)
High
Low
Calcium (Ca2+)
Low
High
sodium, potassium and calcium between the intracellular and extracellular fluid is shown in Table 2.1. You need to become familiar with this table, as it forms a basis for understanding physiology and pathophysiology in the coming chapters, as well as being of key importance for electrolyte balance in the body. Fig. 2.7 shows how sodium levels fluctuate in and around the cell during neuron
signalling; importantly, sodium levels within the cell need to be restored to allow the neuron to continue functioning. Cells of the immune system function in their environment to maintain local homeostasis by destroying foreign substances such as bacteria (see Fig. 2.8). This contributes to homeostasis of not just the cell, but also the local tissues. Other examples of local area homeostasis are wound healing after a small cut to the skin (see Fig. 2.9) and blood clotting (see Fig. 2.10). Although these are separate processes, a cut to the skin usually pierces a blood vessel, so both processes are generally working at the same time. These examples of homeostasis involve more than just one cell, but are still relatively localised.
Homeostasis at the body level
Constancy within the cells leads to homeostasis of the whole body; each cell benefits from and contributes to
CHAPTER 2 Homeostasis
25
FIGURE 2.7
Homeostasis of sodium at the cellular level. A When the neuron is at rest, most of the sodium is in the extracellular fluid. B During neuron signalling, sodium moves into the cell (across the cell membrane). C Towards the end of neuron signalling, an essential feature is the removal of the excess sodium from the cell. D Homeostasis is restored, with most sodium being returned to the extracellular fluid. If the sodium was not returned to the extracellular fluid, the neuron would not be able to send another signal.
FIGURE 2.8
Homeostasis of the local area. A Bacteria are identified as foreign by the immune cell. B The immune cell engulfs or consumes the bacteria and, once inside, the cell destroys the bacteria. C This destruction of the bacteria leads to homeostasis in the local environment.
homeostasis at the body level. Although each organ system has a distinct and unique role, the overarching function that is common to all systems is its contribution to homeostasis at the body level. Coordination of homeostasis on such a large scale requires the involvement of the central
nervous system (namely the brain and spinal cord), as well as the endocrine system (which uses hormones). In the next section, we explain how this regulation of essential processes maintains the harmony of all body systems.
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Part 1 Essential concepts of pathophysiology
FIGURE 2.10 FIGURE 2.9
Homeostasis of the skin. A A cut in the skin breaks the body’s protective cover, which may allow bacteria and harmful chemicals to enter the body. B This initiates a series of steps involved in wound healing. C The body’s protective covering is restored, resulting in homeostasis.
Homeostasis of the blood vessels. A A break in the blood vessel allows blood to escape. B The process of blood clotting begins, which results in a complete clot C, so that no further blood loss occurs and homeostasis is maintained. The clot stays in place while the vessel heals. D When the vessel is healed, the clot is removed.
Regulation of homeostasis F OCU S O N L E ARN IN G
1 Explain what is meant by homeostasis. 2 Discuss why homeostasis is important in the human body. 3 Describe the fluid composition of the body and its compartments. 4 Explain why the extracellular fluid is so important for cellular homeostasis. 5 Explain why homeostasis is vital for cells. 6 Give examples of homeostasis at the cellular or local level. 7 Briefly explain how homeostasis operates at the body level.
Homeostasis of the whole body is achieved via the relationships between the different body systems (introduced in Chapter 1). Each system functions towards the overall health of the body. As an example, valuable fuels from the digestion of food are found in abundance in the blood following a meal, but are less available in the hours afterwards. Glucose is one such fuel that is widely used by cells. A number of processes are involved in maintaining appropriate glucose levels in the bloodstream, so that consistent levels of glucose are available for cells. For instance, after a meal, when blood glucose levels rise, the pancreas secretes insulin (a hormone), returning blood glucose levels to normal and so maintaining homeostasis (see Fig. 2.11).
CHAPTER 2 Homeostasis
27
FIGURE 2.11
CONCEPT MAP
Blood glucose levels are maintained at a normal level after a meal by the pancreas releasing the hormone insulin. Blood glucose levels increase after a meal, and the release of insulin returns the blood glucose back to normal levels.
results in
Normal condition: hand not damaged
Prevent further damage
loss of homeostasis Hand touches sharp object
leads to Move hand away quickly
detected by Neurons in the hand
causes Effector neurons to arm muscles effector or output by
processed by Control centre in spinal cord
FIGURE 2.12
The pain reflex. The pain reflex results in immediate removal of the hand from the source of pain to prevent further tissue damage.
The pain reflex is another important way that normal function is maintained. If your hand touches something that is sharp and painful, this is detected by nerves that go to your spinal cord, which results in an extremely fast response causing your hand to be moved away — the withdrawal reflex (see Fig. 2.12). This reflex is extremely fast because it does not require processing of information by the brain — it can be controlled more quickly by the spinal cord. In this way, further damage to the hand is prevented in an attempt to restore homeostasis. Although slight fluctuations at the cellular level are usually restored locally, if homeostasis cannot be achieved by the cells, bloodstream and extracellular environment, responsibility shifts to the governing nervous system, which
can coordinate additional responses if the fluctuations become too great. So, minor corrections can be restored locally, but larger corrections require the central nervous system (the brain and spinal cord) to regulate the processes of homeostasis. In most instances, it is the brain that is responsible for coordination of the critical functions of homeostasis. If a short-term response is required, this is coordinated quite efficiently by the nervous system itself. However, if a longer response is needed, the nervous system activates the endocrine system to assist in mediating the correction using hormones. One way that the brain maintains homeostasis is by negative feedback pathways. There are three essential components of these feedback pathways: 1 sensor or detector: a neuron that can detect the variable, also referred to as a receptor 2 the control centre in the central nervous system: this matches the information from the sensor with information about the normal range to determine whether any correction is required 3 effector: the nervous system sends signals to appropriate regions of the body to mediate a response. Let us look at some common examples of negative feedback pathways, which will assist in your understanding of homeostasis. Levels of carbon dioxide in the body are regulated closely and corrected using negative feedback. As shown in Fig. 2.13, the nervous system senses any increase in carbon dioxide, and the breathing rate is increased to exhale the excess carbon dioxide, thereby lowering carbon dioxide levels back to normal. Fluid balance is critical for normal function of every cell (see Fig. 2.14). Fluids are lost through the urine and sweat (as well as other areas). This loss is sensed by the brain, which triggers the thirst reflex and causes you to feel thirsty and have a drink. If you are unable to drink, other processes are initiated to limit dehydration, such as a decline in urine production to keep fluid within the body (which is achieved via hormone signals to the kidneys to retain the fluid in the blood rather than losing it in the urine). This demonstrates how body cells can maintain homeostasis of their intracellular fluid volume, despite substantial increases and decreases in water availability (due to inconsistent fluid intake).
CONCEPT MAP
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Part 1 Essential concepts of pathophysiology
As noted previously, maintaining the appropriate sodium balance within the cells is vital for cell function. If sodium levels deviate too far from normal, this is sensed by the cells of the kidneys, which release a hormone to control the levels (see Fig. 2.15). For example, low sodium levels are corrected by the kidneys returning sodium to the blood instead of losing it to the urine. This example is an oversimplification of the negative feedback pathway system, as in reality multiple sensor and effector pathways work simultaneously to correct the imbalance. In fact, for the most vital functions, more than one process is used to restore variables to normal. The next example includes multiple feedback pathways to demonstrate the complexity of regulation. Blood pressure is arguably the most important variable that needs to be controlled in the body. Adequate blood pressure is needed for blood flow, and hence the transport of all nutrients and wastes to and from regions such as the brain, heart and lungs — this essential function keeps these organs alive. The negative feedback pathways for low blood pressure actually show three loops (see Fig. 2.16), which indicates that (at least) three different processes may be activated to keep blood pressure sufficient. In order to understand this negative feedback cycle, you need to be aware that when sodium is retained by the kidneys so that it remains in the blood instead of exiting the body in the
Normal levels of carbon loss of dioxide in tissues restoration of homeostasis homeostasis balance More carbon Build-up of dioxide is exhaled carbon dioxide which must first leads to be sensed by Increased breathing
Neurons in the brain and major to cause blood vessels Effector signals neural to lungs signals to the neuron signals Control centre in the brain brain compares actual carbon from the brain dioxide levels with the normal range; corrections are required FIGURE 2.13
CONCEPT MAP
Negative feedback pathway to return carbon dioxide levels to normal. The brain coordinates responses by the lungs to restore homeostasis — this is just one of several means of controlling levels of carbon dioxide in the body.
restoration of homeostasis Normal levels of fluid Less urine volume and restoration of greater volume of fluid homeostasis Increased fluid intake
leads to
loss of homeostasis
Decreased fluid levels
leads to Fluid loss in urine is decreased
hormone release causes
Thirst stimulated
sensed by
to cause Effector signals to region of brain responsible for awareness of thirst
Effector signals to endocrine system
neuron signals to brain control centre
neuron signals from the brain
neuron signals from the brain
Neurons in the brain
Control centre in the brain compares actual fluid levels with the normal range; corrections are required
FIGURE 2.14
Negative feedback pathways to regulate fluid balance. The pathways include a conscious awareness of thirst to stimulate fluid intake, as well as hormone signals to the kidneys to retain fluid in the blood rather than losing the fluid in the urine.
CONCEPT MAP
CHAPTER 2 Homeostasis
Normal extracellular (and blood) sodium levels
returns to
urine, water is also retained. This leads to an increase in blood volume and a corresponding increase in blood pressure.
loss of homeostasis
Disturbances of homeostasis lead to pathophysiology
Decreased sodium levels
Increased sodium levels
When the body’s ability to compensate for changes and maintain homeostasis is exceeded, disorders and disease ensue. The original cause of a problem may be a source external to the body, such as use of drugs, or a source internal to the body, such as occurs with ageing. As another example, a local infection is a disturbance in homeostasis. The immune system will attempt to remove the infection to restore homeostasis, and treatments such as antibiotics may also be used to assist. In some cases, the infection may become so severe and widespread throughout the body that the person dies. Throughout this textbook, as you learn about pathophysiology, think about what underlying processes of homeostasis have been altered. Remember that disturbances in homeostasis lead to disease, and possibly eventually death, when the body’s ability to compensate for change is exceeded.
detected by
leads to Kidney Kidney returns sodium to the blood
results in
FIGURE 2.15
Homeostasis of sodium is achieved using the endocrine system to regulate kidney function. If blood sodium levels are too low, the kidney responds by returning sodium to the blood to increase sodium levels back to normal.
Increased water in the blood
causes Effector signals to blood vessels
Water returned to blood (instead of the urine)
sends
hormone signal from gland
restoration of homeostasis Increased sodium and water in the blood resulting in Sodium and water returned to blood (instead of urine)
Cardiac control centre of brain
Effector signals cause release of hormone
Normal blood pressure
loss of homeostasis Decreased blood pressure
hormone signal from kidney
Cells of the kidney
sends neural Neurons signals in the brain and major to blood vessels sends neural signals
Sensed by (can be more than one sensor)
Neurons in the brain
FIGURE 2.16
Negative feedback pathways to restore low blood pressure to normal. Sufficient blood flow and blood pressure to the brain, heart and lungs are vital to keep those organs alive; several processes thus contribute to homeostasis of this system.
CONCEPT MAP
Vasoconstriction
29
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Part 1 Essential concepts of pathophysiology
F OC US O N L E ARN IN G
1 Compare how the correction of minor fluctuations at the cellular level is different from the correction of major fluctuations. 2 Describe the general components of a negative feedback pathway. 3 Discuss the consequences of an inability to maintain homeostasis in the body.
chapter SUMMARY Homeostasis
Regulation of homeostasis
• Homeostasis is the ability to maintain stable conditions in the body, despite major changes in the environment. Homeostasis does not require a variable to be maintained at one precise set point: variables are usually controlled within a range of values known as the normal range. • Slight changes in conditions are automatically corrected to maintain homeostasis. Such corrections are made continually. • The cell operates in a fluid environment. The fluid inside the cell, the intracellular fluid, exchanges nutrients and wastes with the fluid outside the cell, the extracellular fluid. This is how the cell maintains homeostasis. • Cellular homeostasis leads to homeostasis of the entire body. Homeostasis at the body level is coordinated mainly by the nervous system.
• The pain reflex is mediated by the spinal cord to allow fast withdrawal from damaging conditions, which assists in maintaining normal functions. • Minor fluctuations in conditions are corrected locally, but if fluctuations become more extensive, the nervous system coordinates regulation.
Disturbances of homeostasis lead to pathophysiology • An inability to maintain homeostasis leads to pathophysiology.
CASE STUDY
A DU LT In the first few days of semester you will no doubt form a study group with some classmates. This week, your group members will be helping each other to learn about homeostasis. Here are some general points for your group to discuss: 1 Explain what homeostasis means. 2 State why the local environment surrounding the cell — the milieu intérieur — is so important in homeostasis.
3
Give an example of homeostasis at the cellular or local level. 4 Discuss how homeostasis is regulated at the whole body level. 5 Describe the relationship between insufficient homeostasis and pathophysiology.
CHAPTER 2 Homeostasis
31
REVIEW QUESTIONS 1 Define homeostasis. 2 Compare the concept of a set value point with a normal range of values. Which is usually most applicable in the body? 3 Discuss how constant monitoring and adjustment usually prevent variables from deviating substantially from the normal range. 4 Describe the relationship between the cell and the fluid environment surrounding it. 5 How is the amount of fluid inside the cell maintained at a constant level?
6 Discuss how homeostasis is maintained at the body level. 7 Explain why the pain reflex is an example of homeostasis. 8 Draw a negative feedback pathway to show how carbon dioxide levels are controlled within the body, and include the sensor, control centre and effector. 9 Discuss how 3 different negative feedback loops contribute to maintaining blood pressure. 10 Explain what happens if homeostasis cannot be maintained.
Key terms
CHAPTER
3
Cellular structure and function Sarah List
Chapter outline Introduction, 33 Cellular structure and function, 33 Cellular components, 33 The organelles, 35 The cytoplasm, 39 The cell membrane, 40 Lipids, 41 Proteins, 41 Cellular receptors and communication, 42
32
Membrane transport, 44 Movement of water and solutes, 44 Cellular metabolism, 47 The role of ATP, 48 Tissues, 50 Types of tissues, 50 Ageing and cellular structure and function, 53
active transport, 44 aerobic respiration, 48 agonists, 43 anabolism, 48 anaerobic respiration, 49 antagonists, 43 catabolism, 48 cell membrane, 40 cellular metabolism, 48 cholesterol, 41 concentration gradient, 44 connective tissue, 50 cytoplasm, 39 cytoskeleton, 39 differentiation, 33 diffusion, 44 endocytosis, 44 endoplasmic reticulum, 36 epithelial tissue, 50 exocytosis, 44 extracellular matrix, 50 filtration, 44 Golgi apparatus, 38 hormonal signalling, 43 hydrostatic pressure, 44 hypertonic solution, 45 hypotonic solution, 45 integral membrane proteins, 41 isotonic solution, 45 lysosomes, 38 mitochondria, 38 muscle tissue, 50 nervous tissue, 53 neural signalling, 44 nuclear membrane, 35 nucleolus, 35 nucleus, 35 organelles, 35 osmosis, 45 osmotic pressure, 45 passive transport, 44 peripheral membrane proteins, 41 peroxisomes, 38 ribosomes, 35 sodium–potassium ATP pump, 46 solutes, 44 tonicity, 45
Introduction To truly understand pathophysiology you must first have a fundamental knowledge of the composition of the human body and how it functions. However, to fully appreciate the complexity of the human body you need to understand the structure and function of cells, because all body functions depend on the integrity of cells and their environment. Cells are the smallest functional units in the body and each cell comprises many different components that work together to allow it to carry out the functions that are vital to the human body. Thus a thorough understanding of human cellular anatomy and physiology is essential in order to comprehend how diseases arise and why they affect the body in particular ways. It is only over the last 200 years or so that our understanding of cellular structure and function has been developed, and this knowledge continues to be expanded today in an effort both to understand how the human body works and to discover how diseases form and what treatments may be beneficial. This chapter explores the cell — what components it comprises, how these components operate, and how individual cells communicate with other cells and thus coordinate physiological processes. We also look at the different body tissues — that is, groups of specialised cells — to explain how individual cells act in unison with other cells.
Cellular structure and function The human body is composed of trillions of individual cells. It is easy to think of these cells as small circular structures that are neatly arranged. The reality is far from this, however; in fact, there are more than 200 different cell types consisting of different shapes and sizes, and each performs quite different functions. There are a multitude of different cell sizes, some examples of which are shown in Fig. 3.1. For instance, a single nerve cell (neuron) may be up to a massive one metre in length, while a red blood cell (erythrocyte) is only a tiny 6–8 micrometres (1 micrometre is 1/1000 of a millimetre). However, most human cells average about 10–15 micrometres in diameter. Apart from size, there is considerable variation in shape as well. There are disc-shaped (discoid) cells, such as red blood cells and squamous cells that are thin and flat, which are typical of skin cells. The shape and structure of the cell can be very important for its function. For example, red blood cells are bi-concave meaning they have a ‘sunken’ centre. This structure allows a greater surface area for gas diffusion of oxygen and carbon dioxide, and so that the cell may ‘fold’ and squeeze its way through a narrow capillary. A nerve cell has the ability to conduct electrical signals along its very long length so that it may transfer instructions to and from distant parts of the body, while a squamous tissue of many layers thickness can prevent the entry of disease agents to our bodies. Cells become specialised
CHAPTER 3 Cellular structure and function
33
through the process of differentiation, or maturation, so that some cells eventually perform one kind of function while others perform other functions. For instance, some cells are primarily involved in movement (muscle cells); some transmit information (nerve cells); others secrete hormones (like the pancreatic cells, termed beta cells, which release insulin); some provide a barrier for the body (the epidermal cells of the skin); and some allow continuation of the human species (the sex cells, like sperm). Despite the variety of cell types with varied morphology (shape and structure) and functions, all cells are made up of the fundamental building blocks of life: carbon, hydrogen, oxygen, nitrogen and small amounts of other elements. Moreover, the typical cell has the following characteristic functions: 1 Cellular metabolism: All cells can take in and use oxygen, nutrients (fuel) and other substances from their surroundings. Nutrients undergo chemical reactions that produce a variety of responses, the most essential being the release of energy that is vital for cell function and survival. 2 Excretion: All cells can rid themselves of waste products resulting from the metabolic breakdown of nutrients. Cells have the ability to break down or digest large molecules, turning them into waste products that are then released from the cell. 3 Communication: Internal components within the cell have to be able to communicate with each other. Just as vital is intercellular communication between the cells. This communication comprises a variety of signals, such as chemical and electrical. Appropriate communication helps ensure the maintenance of a dynamic steady state — homeostasis. 4 Reproduction: Nearly every cell has genetic material that controls its processes and ability to replicate or reproduce. Growth occurs as cells enlarge and reproduce themselves. Even without growth, tissue maintenance requires new cells to be produced to replace cells that are lost naturally through cellular death. However, not all cells are capable of continuous division and some cells, such as nerve cells, cannot reproduce. Cell reproduction, referred to as the cell cycle, is discussed in detail in Chapter 5.
Cellular components A useful analogy to remember when trying to understand cellular structures and their respective functions is to consider that cells are like factories. The walls, roof and floors provide boundary limits and determine the size of the factory. Inside the factory, support structures provide structure to the building. The factory has workers and a manufacturing assembly line where products are produced. Raw materials brought into the factory are turned into finished items by the workers using the tools of the assembly line. When the items are completed, they are prepared for shipping, transported out and distributed to
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FIGURE 3.1
Examples of different cell forms and how they can facilitate function. A Cells involved in reproduction, sperm and ovum; B cells that permit movement; C cells that involve transport; D cells that line cavities and provide protection; E cells that transmit information and control physiological functions; F cells that are involved in metabolic process; and G cells that are involved in inflammation and immune responses. Note that cells are not drawn to scale.
the various customers. In addition, the factory managers and executives decide on the types and numbers of items to be produced and relay this information to the factory workers. Furthermore, energy is required at each manufacturing step to produce the items and move them out of the factory. Similarly for cells, the outer border — termed cell membrane (or plasma membrane) — provides structural integrity from the outside. Within the cell, which is similar to the space inside the factory, a fluid exists called the cytoplasm. The cell also contains many structures called organelles, literally meaning ‘little organs’, which are responsible for all the intracellular activities — these are like the workers and assembly-line equipment. Lastly, the cell has a nucleus, which is the control centre of the cell, housed within the cell and protected by a membrane as well. The nucleus is analogous to the factory managers and executives who control activities by communicating with workers about what is required. These structures are shown in Fig. 3.2, and a summary of the functions of the cell components is provided in Table 3.1. While this may seem a simplistic overview of the cell, it will aid your understanding of the cellular components and how they work in unison. We start by examining the components inside the cell, the organelles.
The organelles
The organelles are all the structures within the cell that are required to maintain normal cellular function. They are specialised structures that have distinct functions and may vary in number according to the primary function of the cell (see Fig. 3.2) — for instance, mitochondria, the organelle responsible for energy for the cell, are more numerous in muscle cells than other cells. In addition, the majority of organelles have a membrane that separates the internal structure from the cytoplasm of the cell. This allows the organelles to perform chemical reactions with enzymes (substances that speed up biological processes) that are distinct from the rest of the cellular components. This is very important, because the enzymes are required for specific processes that occur within the internal structure of the organelles, but are separated from other components of the cell which may alter the chemical reactions. The membranous organelles include the nucleus, endoplasmic reticulum, Golgi apparatus, lysosomes, peroxisomes and mitochondria. The non-membranous organelles, those that do not have a membrane, include the ribosomes and cytoskeleton. We start with the organelle that is found in nearly all cells in the body, the nucleus.
The nucleus
The nucleus is the control centre in most living cells containing genetic material essential for proper functioning of the cell. The cell is dependent on the nucleus; similarly to the brain in the human body, the nucleus controls and regulates functions, but also responds to signals that the
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cell may receive. Almost all cells in the human body have one nucleus. Interestingly, mature red blood cells do not have a nucleus and are referred to as anucleated cells (the ‘a’ at the beginning of the word means ‘without’; therefore, without a nucleus). These cells cannot reproduce, as the nucleus is responsible for cellular replication. Hence they have only a relatively short life span — approximately 120 days. In contrast, some cells have more than one nucleus; these are referred to as multinucleate (‘multi’ referring to many nuclei, the plural of nucleus). Although it might appear strange to have more than one nucleus in a cell, it is thought that cells which need to produce large amounts of proteins and have numerous intracellular components require multiple nuclei. Examples of multinucleated cells include skeletal muscle cells, some liver cells and bone-dissolving cells (osteoclasts). Generally, the nucleus is located in the centre of the cell and is approximately 5 micrometres in diameter. The shape of the nucleus can vary, although most are spherical or oval-shaped; the shape is dependent on the cell type. The nucleus has two main components: the nuclear membrane and the nucleolus (see Fig. 3.3). The nuclear membrane, or envelope, comprises two membranes that surround the nucleus and provide protection for its contents. Holes in the membrane, called nuclear pores, allow communication to and from the cell. These pores are vital to the nucleus, because every minute thousands of substances pass through the nuclear pores. Enzymes, hormones and substances required by the nucleus to build genetic material enter the nucleus and processed genetic material is ejected to control the manufacture of new proteins required by the cell. Within the nucleus, deoxyribonucleic acid (commonly abbreviated to DNA) and proteins are arranged to form chromosomes, the genetic material that determines human characteristics. DNA is confined to the nucleus; when genetic information is to be used in the production of new proteins, ribonucleic acid (RNA) is formed. DNA and associated proteins are normally arranged as clumps in the nucleus, termed chromatin. RNA is formed in a spherical dense region, called the nucleolus, composed largely of DNA and the DNA-binding proteins. The nucleolus is mainly responsible for producing a subunit of the ribosomes, essential for the production of new proteins. The primary functions of the nucleus are cell division and control of genetic information. This is achieved through a series of complex tasks which are examined in detail in Chapter 5. Other functions include the replication and repair of DNA and the transcription of information stored in DNA. Genetic information is transcribed into RNA, which can be processed into messenger, transport and ribosomal RNA and introduced into the cytoplasm, where it directs cellular activities. We now look at one of the recipients of the RNA, the ribosomes.
The ribosomes
The ribosomes are small granules of proteins and RNA responsible for the production of new proteins (protein production, also known as protein synthesis). The ribosomal
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Part 1 Essential concepts of pathophysiology
Nuclear Nuclear Smooth Nucleolus membrane pore endoplasmic Nucleus Rough reticulum Cell endoplasmic membrane reticulum
Microfilaments
Centrioles
Peroxisome
Lysosome
Cilia Cytoplasm
Mitochondria
Cell junction (gap junction)
Cell junction (desmosome)
Golgi apparatus
Free ribosome Ribosome Microtubule Vesicle Microvilli
FIGURE 3.2
The structure of a typical cell. Note that this is a general body cell; not all cells contain all these cellular components, but the components are common in many human body cells. For a description of the cell structures, see Table 3.1.
RNA, and the proteins produced in the nucleolus, move through the nuclear pores into the cytoplasm. Here they either float freely in the cytoplasm (known as free ribosomes) or form a complex with the membrane (termed the rough endoplasmic reticulum; see below). Both sites are responsible for protein production. These ribosomes combine with another two forms of RNA, messenger RNA (mRNA) and transfer RNA (tRNA), to translate the code for the new protein. Briefly, mRNA has the instructions for the assembly of a specific protein, while tRNA brings the amino acids (the building blocks of a protein) to the ribosome. In this way, amino acids are gathered to form the new protein. The entire process is called translation and is described in more detail in Chapter 5.
Endoplasmic reticulum
The endoplasmic reticulum is a network that is continuous with the nuclear membrane (see Fig. 3.4). It facilitates the movement of proteins and is also the
site of protein production. The name derives from endo meaning within, plasm meaning fluid and reticulum, which translates as network; therefore, it is a network within the cytoplasm of the cell. There are two types of endoplasmic reticulum: smooth and rough. These are easily differentiated because one looks rough and the other looks smooth! The rough endoplasmic reticulum comes about from the ribosomes that inhabit the internal surface of the network, while the smooth endoplasmic reticulum does not contain ribosomes. The rough endoplasmic reticulum is primarily responsible for the production of proteins, while the smooth endoplasmic reticulum produces phospholipids (lipids with phosphates attached) required in the cell membrane and performs other functions specific to the cell type. For instance, in the liver the smooth endoplasmic reticulum is involved in the detoxification of drugs, while in the muscle cells it primarily stores calcium, ready to be released during muscle contraction.
CHAPTER 3 Cellular structure and function
TABLE 3.1 Functions of the cell structures CELL STRUCTURE
FUNCTION
Cell membrane
Cell outer border, formed by a membrane
Cytoskeleton, microfilaments
The cell cytoskeleton provides structural support for the cell membrane; the cytoskeleton consists of microfilaments such as actin
Cytoplasm
The liquid component of the cells that houses all the organelles
Nucleus
Control centre of the cell; the main internal structure of the cell
Nucleolus
Site within the nucleus that forms ribosome subunits for production of proteins
Nuclear membrane, nuclear pores
The membrane that surrounds the nucleus, and the pores are small gaps in the membrane
Mitochondria
Cell powerhouse for the production of ATP
Smooth endoplasmic reticulum
Produces phospholipids for the cell membrane
Rough endoplasmic reticulum Contains ribosomes (the rough spots) for protein production Ribosome/Free ribosome
Produces proteins from RNA
Golgi apparatus
Cell transport for lipids and proteins from the endoplasmic reticulum to other parts of the cell
Peroxisome
Storage vessels with enzymes for breakdown of amino acids and fatty acids
Lysosome
Storage vessel for enzymes such as lysozyme for the digestion of old organelles or foreign matter like bacteria
Vesicle
A general term for a fluid-filled structure used in cellular digestion
Centrioles
Located in the cell, they allow attachment and separation of duplicate chromosomes during cell division
Cilia
Located on the outside of some cells, they move liquid past the cell surface. For example, in the trachea in combination with mucus (mucociliary escalator; see Table 24.1)
Microvilli
Outer membrane structure in the form of cell protrusions, creating increased surface area, such as for the absorption of nutrients in the digestive tract
Cell junction — desmosome
Cell to cell adhesion point
Cell junction — gap junction
Connection points that allow ions, other molecules and electrical impulses directly between cells
A
Nuclear pores
Nucleoplasm Nucleolus
B B
PORE Chromosome
Nuclear membrane
FIGURE 3.3
The nucleus. A The nucleus is composed of a double membrane called a nuclear membrane that encloses the fluid-filled interior. B An electron micrograph of a nucleus with the nuclear pores evident.
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Part 1 Essential concepts of pathophysiology
BB
A Plasma membrane
Ribosomes Endoplasmic reticulum
Smooth endoplasmic reticulum Cisternae Nucleus Nucleolus Nuclear membrane Rough endoplasmic recticulum FIGURE 3.4
Endoplasmic reticulum. A The endoplasmic reticulum is continuous with the nuclear membrane and consists of ribosome-coated cisternae (cavities); the smooth endoplasmic reticulum is attached to the rough component. B An electron micrograph of rough and smooth endoplasmic reticulum.
The Golgi apparatus
The Golgi apparatus, also referred to as the Golgi complex, is a network of flattened membranes that are folded back on each other (see Fig. 3.5). The folds tend to bulge at the ends forming cavities called cisternae, from the Latin meaning reservoir containing water. This is where secretory vesicles are formed (vesicles are small membrane-bound sacs involved in cellular transport). The vesicles either migrate to other cellular organelles or are released from the cell (see Fig. 3.6). Essentially, the Golgi apparatus receives lipids and proteins from the endoplasmic reticulum and then modifies, packages and redistributes them to various parts of the cell. In this way, the Golgi apparatus is synonymous with the packaging and distribution centre of the factory.
Lysosomes
Lysosomes are small storage vesicles that are formed from a pinching of the Golgi apparatus. They are rich in powerful enzymes that act as a digestive system for the cell; that is, they break down and dispose of organelles that do not function properly or are old, and they digest foreign substances such as bacteria (see Fig. 3.7). Because these enzymes are so destructive, lysosomes are encased in a membrane to protect the cell. However, in certain situations the enzymes are used to destroy an entire cell, which is like cellular ‘suicide’. This is termed apoptosis, or programmed cell death, and is discussed in Chapter 4.
Peroxisomes
Peroxisomes are similar to lysosomes, but contain different enzymes. These storage vesicles are smaller than lysosomes and are involved in the breakdown of amino acids and fatty acids (those that are responsible for making lipids). The chemical reactions that occur inside peroxisomes result in the creation of hydrogen peroxide (a weak acid, used as a bleach disinfectant or blonde hair dye), hence the name peroxisome.
Mitochondria
Mitochondria are the powerhouse of the cell. They are commonly small, rod-like structures (see Fig. 3.8); however, their shape is quite variable and has been shown to change considerably in living cells.1 By far their most important role is the production of adenosine triphosphate (ATP), the major energy source of the cell. It must be stressed that ATP is required for most cellular activities to occur. Like the nucleus, mitochondria have a double membrane, with the inner layer folding inwards to form cristae (which means crests). This greatly increases the surface area, which increases the number of sites where ATP can be produced. Energy is not actually produced, but rather is obtained from the breakdown of molecules (glucose) and incorporated into ATP molecules. The vast majority of ATP production occurs within the mitochondria using enzymes located on the inner membrane. The production of ATP is discussed later in the section on cellular metabolism.
CHAPTER 3 Cellular structure and function
A
39
Cell membrane
Cisternae
Protein expelled Golgi apparatus Secretory vesicles Secretory vesicle
Cisternae
B
Rough endoplasmic reticulum
Transport vesicle Smooth endoplasmic reticulum
Nuclear pore Nucleus
FIGURE 3.5
The Golgi apparatus. A Schematic representation of the Golgi apparatus showing a stack of flattened sacs (cisternae) and numerous small membranous secretory vesicles. B Transmission electron micrograph showing the Golgi apparatus highlighted with colour.
The cytoskeleton
The cytoskeleton is exactly what the name implies — a skeleton for the cell. It is easy to assume that cells are quite rigid structures, but this is not the case, as flexibility is allowed. The cytoskeleton provides the structural integrity that maintains the cell’s shape and also allows a pathway for intracellular transport. The cytoskeleton is made up of protein filaments that provide scaffolding that extends throughout the cytoplasm, as well as support for the cell membrane.
The cytoplasm
The cytoplasm is an aqueous solution that fills the cytoplasmic matrix — the space between the nuclear membrane and the outer layer of the cell, the cell membrane. It is also commonly referred to as intracellular fluid, and actually the majority of water in the body is contained inside the cells. The cytoplasm represents about half the volume of the cell and is primarily composed of water with a mixture of dissolved substances such as protein, sugars
FIGURE 3.6
Vesicle transport. The newly formed proteins are packaged and sent to the Golgi apparatus in the form of a secretory vesicle. This vesicle fuses with the Golgi apparatus and is further modified and then shunted to the ends of the Golgi apparatus (cisternae). In this example, the vesicle is secreted to the cell membrane and released outside the cell.
and waste products. However, the cytoplasm is quite viscous and the organelles are literally suspended in it. In addition, thousands of enzymes are involved in metabolism; thus the cytoplasm is crowded with ribosomes making proteins. Newly produced proteins remain in the cytoplasm if they lack a signal for transport to a cell organelle.2 In this way, they are available to be transported into an organelle when later required. The majority of cellular functions use the cytoplasm — for instance, the production of proteins and hormones and their transport out of the cell, the isolation and elimination of waste products from the cell, metabolic processes, the breakdown and disposal of cellular debris, and the maintenance of cellular structure and motility. In addition, the cytoplasm is a storage unit for fat, carbohydrates and secretory vesicles.
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FOCU S ON L EA RN IN G
1 Provide 3 examples of different cell shapes. 2 Describe the general arrangement of most cells, including the organelles and cytoplasm. 3 Describe at least 4 cellular functions and the organelles that are primarily responsible for each function. 4 List the membranous and non-membranous organelles. 5 Explain why some organelles have a membrane.
The cell membrane
FIGURE 3.7
Lysosomes. Lysosomes are abundant in some cell types such as macrophages. A Bacteria have been engulfed by the cell and the lysosomes fuse with the bacteria. B The bacteria have been digested by the lysosomes.
The cell membrane, also called the plasma membrane, is common to all cells and forms a barrier between outside and inside the cell (see Fig. 3.9). The cell membrane is exceedingly important to normal physiological function because it controls the composition of the space, or compartment, that it encloses. The membrane can include or exclude various molecules and by controlling the movement of substances from one compartment to another, it exerts a powerful influence on metabolic pathways. The cell membrane also has an important role in cell-to-cell recognition. Other functions of the cell membrane include cellular mobility and the maintenance of cellular shape (see Table 3.2). The outer surface of the cell is not smooth but rather is dimpled with cave-like indentations known as caveolae (‘tiny caves’). Caveolae serve as a storage site for many receptors and provide a route for transport into the cell (see later in the chapter).
A B
A
Outer membrane Inner membrane
Inner membrane
Matrix Cristae
Cristae
Matrix
Outer chamber
Outer membrane
FIGURE 3.8
Mitochondria. A The inner and outer membranes are shown in the cut-down figure. Note the many folds (cristae) of the inner membrane. B A transmission electron micrograph of a mitochondrion. Although some mitochondria have the capsule shape shown here, many are round or oval.
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Carbohydrate chains Glycolipid
External membrane surface
Polar region of phospholipid: Hydrophilic ‘water-loving’
Phospholipid bilayer
Internal membrane surface
Cholesterol Protein
Protein
Glycoprotein
Nonpolar region of phospholipid: Hydrophobic ‘water-hating’
FIGURE 3.9
The cell membrane. A three-dimensional view of the lipid bilayer that provides the basic cell structure and serves as a relatively impermeable barrier to most water-soluble molecules.
The major chemical components of all membranes are lipids and proteins, but the percentage of each varies among different membranes.
Lipids
The basic component of the cell membrane is a bilayer of lipid molecules chiefly composed of phospholipids and cholesterol. Phospholipids consist of fatty acids, which make up lipids and a phosphate group. They are integral to the cell membrane as lipids are responsible for the structural integrity of the membrane. Each phospholipid molecule is said to be polar, meaning that the head is hydrophobic (‘water hating’) and the tail is hydrophilic (‘water loving’) (see Fig. 3.9). The membrane organises itself into two layers because of the polar differences. The hydrophobic region (the hydrophobic tail) of each lipid molecule is protected from water, whereas the hydrophilic region (the hydrophilic head) is immersed in it. The bilayer serves as a barrier to the diffusion of water and hydrophilic substances such as glucose, while allowing lipid-soluble molecules such as oxygen and carbon dioxide to diffuse through it readily. Cholesterol is another major lipid within the cell membrane. High concentrations of cholesterol in the blood are often associated with cardiovascular disease; accordingly, many people believe that cholesterol is a ‘bad’ substance
that causes heart disease. Although excessive amounts of cholesterol are a strong risk factor for cardiovascular disease, it is important to realise that the body needs adequate amounts of cholesterol, as it is an essential component of cell membranes and is vitally important in maintaining membrane permeability.
Proteins
About 50% of the total mass of the cell membrane is protein. Proteins can be classified as integral or peripheral. Integral membrane proteins, also called transmembrane proteins, are embedded in the lipid bilayer and span the entire width of the cell membrane. They are involved in many processes but the main ones include acting as a channel or pump to allow water-soluble substances to cross the phospholipid bilayer, and acting as a receptor to allow signals from hormones and chemicals to be transmitted inside the cell (this is especially important for the nervous and endocrine systems, as detailed in Chapters 6 and 10, respectively). Peripheral membrane proteins are not embedded in the bilayer but reside at one surface or the other, bound to an integral protein. They are therefore mostly involved in providing support for the cell membrane and joining cells together. The interaction of cell membrane proteins with lipids is complex. The role of proteins in the onset and progression
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TABLE 3.2 Cell membrane functions CELLULAR MECHANISM
Structure
MEMBRANE FUNCTION
• Containment of cellular organelles and intracellular fluid • Maintenance of relationship with cytoskeleton, endoplasmic reticulum and other organelles
Protection
• Maintenance of fluid and electrolyte balance
FIGURE 3.10
• Outer surfaces of some cell membranes are studded with cilia or even smaller cylindrical projections called microvilli — both are capable of movement
The chemical configuration of cellular receptors. A The molecule binds (attaches) to the receptor. B A particularshaped molecule fits a specific receptor on the cell membrane. C The molecule cannot bind to a different cell receptor due to differences in chemical composition and structure.
• Barrier to toxic molecules and macromolecules such as proteins and nucleic acids • Barrier to foreign organisms and cells
Storage
• Storage site for many receptors • Transport • Diffusion and exchange • Endocytosis (pinocytosis, phagocytosis)
The concentration of cholesterol in the cell membrane affects membrane fluidity. Increased cholesterol concentration means less fluidity on the membrane’s hydrophilic outer surface and more fluidity at its hydrophobic core. This can impact on the cell’s normal functioning and is a factor in some diseases.
• Exocytosis (secretion) Cell-to-cell interaction
• Active transport
FOCU S ON L EA RN IN G
• Communication and attachment at junctional complexes
1 Describe the functions of the cell membrane.
• Release of enzymes and antibodies into extracellular environment
2 Describe the properties of the cell membrane and how the intracellular and extracellular fluids are kept separate.
• Relationships with extracellular matrix
of disease is important because of their enzymatic, transport and recognition-receptor functions in cellular physiology. In the 1960s, the fluid mosaic model for biological membranes was proposed. The model, which is continually being modified, proposes that the cell membrane is dynamic. Lipids and proteins move laterally on the membrane, and ions and other molecules move through it. However, cells can immobilise specific membrane proteins in a region of the membrane to allow certain functions to occur. The fluid mosaic model describes the membrane as existing in a state of change, allowing the cell to protect itself actively against injurious agents. Hormones, bacteria, viruses, drugs, antibodies (produced by the immune system to combat foreign substances) and chemicals that transmit nerve impulses (neurotransmitters) attach to the cell membrane by means of receptors on the outer layer. The number of receptors present may vary at different times and the cell can control the effects of injurious agents by altering receptor numbers and patterns.3 This aspect of the fluid mosaic model has drastically modified previously held concepts concerning the onset of disease.
Cellular receptors and communication We have examined what constitutes a cell and how the intracellular components function; however, you need to be aware of how cells react to their environment and communicate with each other, including cells close together and ones that are distant. Cells monitor their environment through receptors. These cellular receptors are protein molecules on the cell membrane, in the cytoplasm or in the nucleus that can recognise and bind with specific smaller molecules called ligands. These substances, such as hormones, bind with cell receptors. It should be stressed that there are many substances that can bind with cell receptors and these can either activate or inactivate the receptor. However, recognition and binding depend on the chemical configuration of the molecule and its receptor, which must fit together like pieces of a jigsaw puzzle (see Fig. 3.10). In this way, messages can be communicated to the cell or a cellular process can commence. Cell membrane receptors protrude from or are exposed at the external surface of the membrane and are often attached to integral proteins (see Fig. 3.11). The substances
CHAPTER 3 Cellular structure and function
Substance binds A to receptor
Substance binds to receptor
C C
43
Substance binds to receptor
B
Channel opens
Intracellular message
Channel opens
FIGURE 3.11
Cellular receptors. A Cell membrane receptor for a substance (here, a hormone molecule) on the surface of an integral protein. The substance binds with the receptor and this initiates a cellular process. B Channel-linked receptors, which open when a substance binds with the receptor outside of the cell. C Stimulation of the receptors results in an intracellular message being sent to a channel, causing the channel to open.
that bind with membrane receptors include hormones, neurotransmitters, infectious agents and metabolites. Many discoveries concerning the specific interactions of cellular receptors with their respective substances have provided a basis for understanding disease. It is important to realise that cell receptors often play a vital role in the pharmacological management of diseases and disorders. Fortunately for patients, drugs that are used in clinical practice can interact or bind with receptors too. When drugs bind with a receptor there are two basic types of interaction: drugs that stimulate the receptor are termed agonists, while drugs that block the action are termed antagonists. An example of an agonist is salbutamol, the most common drug used in the management of asthma. Salbutamol binds with receptors in the lung that when stimulated cause bronchodilation, or opening, of the bronchiole portion of the airways. Common examples of antagonists are the beta (β)-blockers. These work by binding to and hence blocking receptor action of β-adrenergic receptors on the heart (see Chapter 22). This lowers the heart rate and decreases the force of contraction, which reduces blood pressure (hence β-blockers are used in the treatment of high blood pressure, known as hypertension). Cells also need to communicate with each other to maintain a stable internal environment (homeostasis), to regulate their growth and division, to oversee their development and organisation into tissues, and to coordinate their functions. In fact when communication and coordination are altered, this can lead to an increased risk of cancer development. Cells communicate in a variety of ways. They form protein channels, called gap junctions, which directly coordinate the activities of adjacent cells, and they have receptors on the cell membrane that respond to signals that affect the cell itself and other cells in direct
Signalling cell
Target cell
Receptor
Signalling molecule Contact signalling by plasma membrane−bound molecules Gap junction
Contact signalling via gap junctions
FIGURE 3.12
Cellular communication. Two primary ways in which cells communicate with one another.
physical contact with it (see Fig. 3.12). There are two primary modes of signalling: hormonal and neural. • Hormonal signalling involves specialised endocrine cells, which secrete hormone chemicals released by one set of cells that travel to the tissues via the bloodstream to
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Part 1 Essential concepts of pathophysiology
produce a response in another set of cells. This is the basis of the endocrine system and is addressed in detail in Chapter 10. • The nervous system also is intimately involved in cell signalling. In neural signalling, the nerve cells (neurons) communicate directly with the cells they innervate by releasing substances called neurotransmitters at specialised junctions called chemical synapses (meaning gap); the neurotransmitters diffuse across the synapses and act on the target cells. The response time of neural signalling is rapid compared with hormonal signalling, and it can produce body-wide effects. For example, when an individual is frightened, the multiple responses are controlled by the nervous system. For more details on the nervous system, see Chapter 6. These systems act in a complementary manner in order to maintain short- and long-term homeostasis. The nervous signals are employed for short-term adjustments (e.g. increasing the respiration rate during exercise to increase the intake of oxygen), while the hormonal signals allow for long-term adjustments (e.g. production of the hormone erythropoietin which stimulates the production of red blood cells to increase oxygen-carrying capacity in low-oxygen conditions at high altitude).
F OCU S O N L E ARN IN G
1 Discuss the ways in which cells communicate with each other. 2 Differentiate between hormonal signalling and neural signalling.
Membrane transport The other important area to address is how substances are moved into and out of the cell. Cells continually take in nutrients, fluids and chemical messengers from the extracellular environment and expel metabolites, or the products of metabolism, and the end products of lysosomal digestion. The mechanisms involved depend on the characteristics of the substances to be transported. For example, in passive transport (which does not require energy to move substances), water and small electrically uncharged molecules move easily through pores in the cell membrane’s lipid bilayer. This process occurs naturally through any semi-permeable barrier, such as the cell membrane. Other molecules are too large to pass through pores. Some of these molecules are moved into and out of the cell by active transport, which requires cellular expenditure of metabolic energy (ATP). Other large molecules, called macromolecules, along with fluids, are transported by endocytosis (meaning taking in to the cell) and exocytosis (meaning expelling from the cell). Water and electrically
charged molecules are transported by protein channels embedded in the cell membrane.
Movement of water and solutes
Cell membranes are semi-permeable, which simply means that some substances can cross while others cannot. It allows the passage of water and small particles of dissolved substances, called solutes, depending on their size, solubility, electrical properties and concentration on either side of the membrane. Small, lipid-soluble particles, such as oxygen and carbon dioxide, readily pass through the lipid bilayers of the cell membrane. Larger, water-soluble particles may pass through pores in the membranes. Although large protein molecules pass through cell membranes by endocytosis, water is actually drawn towards these large proteins and hence they also cause a movement of water. Body fluids are composed of electrolytes such as sodium and potassium and non-electrolytes such as glucose. Electrolytes account for approximately 95% of the solute molecules in body water. For example, sodium (Na+) is the predominant extracellular cation (a positively charged ion in the fluid outside the cell) and potassium (K+) is the principal intracellular cation. The difference in intra- and extracellular concentrations of these ions is important for the transmission of electrical impulses across the cell membranes of nerve and muscle cells. Fluid and electrolyte balance between body compartments is discussed in detail in Chapter 29.
Passive transport FILTRATION
Filtration is the movement of water and solutes through a membrane because of a greater pushing pressure (force) on one side of the membrane than on the other side. Hydrostatic pressure is the mechanical force of water pushing against cellular membranes. In the vascular system, hydrostatic pressure is the blood pressure generated in the vessels when the heart contracts. The blood reaching the capillary bed has a hydrostatic pressure sufficient to force water across the thin capillary membranes into the spaces between the cells, called the interstitial spaces. Hydrostatic pressure is important for the cardiovascular and urinary systems and is discussed in more detail in Chapters 22 and 28, respectively. SIMPLE DIFFUSION
Diffusion is the movement of a solute molecule from an area of greater solute concentration to an area of lesser solute concentration. This difference in concentration is known as the concentration gradient (see Fig. 3.13). Although particles in a solution move randomly in any direction, if the concentration of particles in one part of the solution is greater than in another part, the particles distribute themselves evenly throughout the solution. According to the same principle, if the concentration of particles is greater on one side of a permeable membrane than on the other side, the particles will diffuse spontaneously
CHAPTER 3 Cellular structure and function
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substances are simply transported down the concentration gradient (so they move from a crowded area on one side of the membrane to the other side where there is less of that substance and hence more room is available). Channels that facilitate the movement of substances allow electrolytes to move down the concentration gradient due to the size and electrical charge of the substances. These channels can be specific for a particular substance. In carrier-mediated facilitated diffusion, the substance binds with the integral protein site and the protein essentially changes shape to allow the substance to pass through. In this way, water-soluble substances can enter and leave the cell without the need for energy expenditure. Examples of facilitated diffusion are presented in Fig. 3.14. OSMOSIS
FIGURE 3.13
Diffusion. The semi-permeable membrane allows glucose to move from an area of high concentration to an area of low concentration. A The container shows the distinct 10% and 20% glucose solutions, while in B the container shows the result of diffusion over time with an equal distribution of glucose in both compartments.
from the area of greater concentration to the area of lesser concentration until equilibrium is reached. The higher the concentration on one side, the greater the diffusion rate. The diffusion rate is influenced by many factors, including the size of the substance and its lipid solubility (that is, how well the substance dissolves in lipid). Usually, the smaller the molecule and the more soluble it is in lipid, the more hydrophobic it is and the more rapidly it will diffuse across the lipid bilayer. Oxygen, carbon dioxide and steroid hormones are all hydrophobic molecules. Water-soluble substances such as sugars diffuse very slowly, whereas uncharged lipophilic (‘lipid-loving’) molecules such as fatty acids and steroids diffuse rapidly. Ions and other polar molecules generally diffuse across cellular membranes more slowly than lipid-soluble substances. Water readily diffuses through cell membranes because water molecules are small and uncharged. The structure of water allows it to rapidly cross the regions of the bilayer containing the lipid head groups. Their groups constitute the two outer regions of the lipid bilayer. FACILITATED DIFFUSION
Facilitated diffusion occurs when substances such as electrolytes and glucose cannot pass directly through the cell membrane but are required to enter or exit the cell with active ‘facilitated’ assistance. The integral proteins transport the substances via a specific channel or carry them through the cell membrane. Importantly, despite the substances moving through specific channels or ports, facilitated diffusion does not require any energy, as the
Osmosis is the movement of water ‘down’ a concentration gradient — that is, across a semi-permeable membrane from a region of higher water concentration to one of lower concentration (see Fig. 3.15). For osmosis to occur: (1) the membrane must be more permeable to water than to solutes; and (2) the concentration of solutes must be greater so that water moves more easily. Osmosis controls the distribution and movement of water between body compartments and is vital to maintaining normal fluid balance. Osmolality controls the distribution and movement of water between the body compartments. It can be measured by the number of milliosmoles per kilogram of water (mOsm/kg) or the concentration of molecules per weight of water. In addition, osmosis is directly related to both hydrostatic pressure and solute concentration, but not to particle size or weight. The amount of hydrostatic pressure required to oppose the osmotic movement of water is called the osmotic pressure of the solution. Factors that determine osmotic pressure are the type and thickness of the cell membrane, the size of the molecules, the concentration of molecules, or the concentration gradient, and the solubility of molecules within the membrane. Tonicity is related to the osmotic pressure of a solution, because it relates to how a solution will affect the fluid volume inside the cell. Solutions have relative degrees of tonicity. The normal osmolality of body fluids is approximately 290 mOsm/kg and solutions are classified according to body fluids: an isotonic solution has the same concentration of solute as body fluids (iso refers to equal); a hypotonic solution has a lower concentration of solutes and is thus more dilute than body fluids (hypo meaning below); and a hypertonic solution has a greater concentration than body fluids (hyper meaning above). The concept of tonicity is important in patients when administering intravenous fluids to correct water and solute imbalances.
Active transport
In active transport, the protein transporter moves molecules against, or up, the concentration gradient. Unlike passive and facilitated transport, active transport requires energy. Many active transport systems or pumps have ATP as their primary energy source (see Fig. 3.16).
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FIGURE 3.14
Facilitated diffusion. Carrier proteins change shape when a substance binds to the receptor. The protein ‘opens’ and allows the substance to pass the cell membrane. Channel proteins are selective for a particular substance and facilitate movement of this substance.
available the pump works, but when ATP is depleted, such as during disease, the pump will not be as efficient.
Endocytosis and exocytosis
FIGURE 3.15
Osmosis. A Water is present in both sides of the chamber. The right side has large molecules that cannot pass through the semi-permeable membrane. B After time water diffuses across the membrane into the right side of the chamber via osmosis.
A carrier mechanism in the cell membrane mediates the transport of ions and nutrients. The best-known pump is the sodium–potassium ATP pump, which continuously pumps sodium and potassium against their concentration gradient to maintain ionic concentration gradients vital for nerve conduction and homeostasis. The important aspect is that ATP is required, which means that when energy is
The active transport mechanisms by which cells move large proteins or polysaccharides (macromolecules) across the cell membrane are very different from those that mediate small solute and ion transport. Transport of macromolecules involves the sequential formation and fusion of membrane-bound vesicles. In endocytosis, a section of the cell membrane enfolds substances from outside the cell, invaginates (folds inward) and separates from the cell membrane, forming a vesicle that moves into the cell. Two types of endocytosis are designated based on the size of the vesicle formed (see Fig. 3.17): • Pinocytosis (meaning cell-drinking) involves the ingestion of fluids and solute molecules through the formation of small vesicles. • Phagocytosis (literally cell-eating) involves the ingestion of large particles, such as bacteria, through the formation of large vesicles (vacuoles). Because most cells continually ingest fluid and solutes by pinocytosis, the terms pinocytosis and endocytosis are often used interchangeably. In pinocytosis, the vesicle containing fluids, solutes or both fuses with a lysosome and lysosomal enzymes digest them for use by the cell. In phagocytosis, the large molecular substances are engulfed by the cell membrane and enter the cell so that they can
CHAPTER 3 Cellular structure and function
Sodium–potassium ATP pump
Na + Na+
Na +
K+
K+
ATP
Na+
Na+
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be isolated and destroyed by lysosomal enzymes. Substances that are not degraded by lysosomes are isolated in residual bodies and released by exocytosis. Both pinocytosis and phagocytosis require metabolic energy and often involve binding of the substance with cell membrane receptors before membrane invagination and fusion with lysosomes in the cell. Secretion of macromolecules almost always occurs by exocytosis (see Fig. 3.18). Exocytosis has two main functions: 1 replacement of portions of the cell membrane that have been removed by endocytosis 2 release of molecules that have been produced by the cell into the extracellular space.
Na + FOCU S ON L EA RN IN G
1 Describe the difference between filtration, diffusion and osmosis. 2 Explain why water and small electrically charged molecules move easily through the cell membrane. FIGURE 3.16
Active transport and the sodium–potassium pump. Three sodium (Na+) ions bind to sodium-binding sites on the carrier’s inner face. At the same time, an energy-containing ATP molecule produced by the cell’s mitochondria binds to the carrier. The ATP breaks apart, transferring its stored energy to the carrier. The carrier then changes shape, releases the three Na+ ions to the outside of the cell, and attracts two potassium (K+) ions to its potassium-binding sites. The carrier then returns to its original shape, releasing the two K+ ions and the remnant of the ATP molecule to the inside of the cell. The carrier is now ready for another pumping cycle.
3 Explain the difference between passive transport systems and active transport systems. 4 Differentiate between endocytosis and exocytosis.
Cellular metabolism Thus far we have looked at the structure and function of the cellular components, how cells communicate with each other and how substances pass through the cell membrane.
FIGURE 3.17
Endocytosis. A Endocytosis and fusion with a lysosome. B An electron micrograph of the steps in endocytosis.
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B
understand these processes. Accordingly, we focus on those processes that are vital to your understanding of the metabolism. All the chemical tasks of maintaining essential cellular functions are referred to as cellular metabolism. The energy-using process of metabolism is called anabolism (ana meaning upward) and the energy-releasing process is known as catabolism (kata meaning downward). Cellular respiration refers to the catabolic reactions that break down nutrients to ATP. This metabolic process provides cells with the energy they need to produce cellular structures. Dietary proteins, fats and starches are broken down in the digestive system into amino acids, fatty acids and glucose, respectively. These constituents are then absorbed into the blood, circulated and taken up by the cells, where they are used for various vital cellular processes, including ATP production. The process by which ATP is produced is one example of a series of reactions called a metabolic pathway. A metabolic pathway involves several steps whose end products are not always detectable. A key feature of cellular metabolism is the directing of biological reactions by protein catalysts or enzymes. Each enzyme has a high affinity (strong attraction) for a substrate, which is a specific substance converted to a product of the reaction.
The role of ATP
FIGURE 3.18
Exocytosis. A The process of exocytosis, where a vesicle is released out through the cell membrane to the extracellular space. B An electron micrograph of exocytosis.
Many of these functions require energy. While we may think that we consume food for enjoyment and hunger, the real reason that we eat is to provide nutrients for our cells. By far the most important function of the body is the conversion of foods to ATP, the energy-rich substance that powers the cells. Many chemical reactions are involved in the various stages of ATP production; however, only a rudimentary understanding of chemistry is required to
For a cell to function it must be able to extract and use the chemical energy in organic molecules — that is, molecules that contain carbon, with the most important organic molecules essential for life being carbohydrates, proteins, lipids and nucleic acids (see Chapter 1). Basically, chemical energy lost by one molecule is transferred to the chemical structure of another molecule by an energy-carrying or transferring molecule such as ATP. The energy stored in ATP can be used in various energy-requiring reactions and in the process is generally converted to adenosine diphosphate (ADP) and an inorganic phosphate. ATP not only stores energy but also transfers it from one molecule to another. The chemical energy stored by carbohydrates, lipids and proteins in food is metabolically broken down to simple smaller molecules through the process of catabolism and then transferred to ATP (see Fig. 3.19). In this description, we focus on the breakdown of glucose (a carbohydrate) to provide ATP, but lipids and proteins can also be used for cell energy, although these result in some differences to the description here. As long as ATP is present, cells can perform their functions. The majority of ATP is quickly used by the cells after it is produced. Since the body does not have large reserves of stored ATP it continually produces ATP through cellular respiration. This process can occur with or without oxygen present: • Aerobic respiration refers to the production of ATP in the presence of oxygen — this process produces large amounts of ATP, with water and carbon dioxide as byproducts.
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FIGURE 3.19
ATP production from macromolecules. Food is ingested, broken down into micronutrients in the digestive system and transported to the cells. The nutrients, water and oxygen move through the cell membrane and into the cytoplasm and different organelles. In this example, in the mitochondria energy is transferred by breaking down organic compounds from the nutrients to form ATP. The structure of ATP consists of three phosphate groups that have high-energy bonds that can release chemical energy when required by the cell. The ATP is used for cellular metabolism and energy is released to enable movement. Note: (1) this is only one example of ATP use; and (2) energy is neither created nor destroyed, but is transferred from one form to another.
• Anaerobic respiration produces small amounts of ATP without oxygen by breaking down carbohydrate, with lactic acid as the byproduct. Where possible, the body uses aerobic respiration to produce ATP as it is more efficient than anaerobic respiration. Briefly, there are three main phases in the production of ATP: glycolysis (the initial breakdown of glucose into pyruvate), the citric acid cycle (also known as the Krebs or tri-carboxylic acid cycle; this cycle uses the pyruvate which was formed from glycolysis) and the electron transport chain. Glycolysis occurs with or without the presence of oxygen, and breaks down glucose into pyruvate. The processes that occur next depend on the presence of adequate oxygen – the presence of oxygen results in the pyruvate entering the aerobic processes within the mitochondria,
namely the citric acid cycle and then the electron transport chain. The citric acid cycle produces only relatively small amounts of ATP, and after the citric acid cycle produces the large majority of the ATP required for the cell’s needs. Importantly, the electron transport chain will only function in the presence of oxygen. Therefore the presence of adequate oxygen in the body is absolutely essential for the adequate production of ATP for the body’s needs. In the absence of oxygen, the pyruvate which was formed during glycolysis the body enters anaerobic processes, which results in the production of only limited quantities of ATP, and the production of lactic acid. As a result the body will fatigue easily due to the scant quantity of ATP produced, and the muscles will cramp due to the accumulation of lactic acid from the anaerobic respiration process. The necessity for adequate oxygen delivery to the tissues for
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ongoing peak performance is one of the many reasons that some elite athletes have turned to performance enhancing drugs such as erythropoietin (or EPO), to increase the delivery of oxygen to tissues by increasing the number of red cells in the blood stream. F OC US O N L E ARN IN G
1 Describe the difference between catabolism and anabolism. 2 Explain the difference between aerobic and anaerobic respiration.
Tissues Groups of cells are organised into tissues; different types of tissues compose organs; and organs are integrated to perform complex functions as tracts or systems. All cells are in contact with a network of extracellular macromolecules known as the extracellular matrix. This matrix not only holds cells and tissues together, but also provides an organised latticework within which cells can migrate and interact with one another. The process by which differentiated cells create tissues and organs is called pattern formation.4 To form tissues, cells must exhibit intercellular recognition and communication, adhesion and memory. Specialised cells sense their environment through signals, such as growth factors, from other cells. This type of communication ensures that new cells are produced only when and where they are required. Different cell types have different adhesion molecules in their cell membranes, sticking selectively to other cells of the same type. They can also adhere to extracellular matrix components.
Types of tissues
There are four primary types of tissues: epithelial, connective, muscle and nervous. The structure and function of these four types underlie the structure and function of each organ system.
Epithelial tissue
Epithelial tissue, also called epithelium, is a protective lining tissue for both inside and outside the body. It lines cavities, forms a lining for organs (such as the heart, lungs and digestive tract) and is the primary tissue of the skin covering our bodies. The cells are typically tightly packed and have no blood supply, relying on the capillaries in the underlying connective tissue to supply oxygen and nutrients and to remove wastes. Epithelial tissue has several functions, including: 1 protection, such as the epidermis of the skin 2 absorption, which occurs when nutrients are absorbed from the digestion of food in the digestive system 3 secretion of substances, such as enzymes and hormones
4
excretion of waste products 5 diffusion of substances, such as oxygen and carbon dioxide, through the tissues across the capillary wall. The classification of epithelial tissue is based on the shape and layer arrangement of the cells. There are three basic shapes: squamous, cuboidal and columnar. Another type, transitional, refers to cells that can change shape. There are two major divisions based on layers: simple and stratified. Pseudostratified epithelium is a special type of simple epithelium, with the tissue appearing to have multiple layers (stratified) but in fact this is false (hence pseudo). The shapes and arrangements of the different epithelial tissues is strongly linked to their function, such as the stratified squamous epithelial tissue acting as a barrier (e.g. in the skin) and the simple epithelial tissue that is a single layer to facilitate the movement of gases and other small molecules from one compartment or tissue to another. Examples of this type of tissue and some of their respective locations are provided in Fig. 3.20.
Connective tissue
Connective tissue is widely distributed throughout the body. In contrast to epithelium, the cells are loosely arranged and are not in contact with each other — an extracellular matrix fills the spaces between the cells. Its functions include protection, fat storage, support, transport and, as the name suggests, connecting or binding other tissues and organs so that they are held in place. The various tissues that are classified as connective tissue often cause considerable confusion for students. The classification is based on exclusion, with tissues that do not conform to epithelial, muscle or nervous tissues being classified as connective. Accordingly, connective tissue is the most varied of the tissues and its appearance varies considerably. The different types include loose connective tissue, dense fibrous tissue, cartilage, bone, blood and bone marrow. Basically, loose connective tissue includes adipose (fat) and reticular tissue (resembling a net-like formation). Reticular tissue is situated in organs such as the spleen and liver where it forms a frame or scaffold for other cells in these organs. Dense fibrous tissue can be regular or irregular (referring to the appearance of the tissue): regular dense tissue is located in tendons and ligaments; and irregular dense tissue is located in the dermis of the skin and the capsules around the liver, kidneys and spleen. Blood, cartilage and bone are referred to in the haematological and musculoskeletal systems in Chapters 16 and 20, respectively. Connective tissue types are summarised in Fig. 3.21.
Muscle tissue
Muscle tissue has long, thin cells that contract and shorten when stimulated, resulting in movement. The other defining characteristic is that the cells are densely packed with proteins, which are responsible for muscle contraction. There are three main types of muscle tissue: skeletal, cardiac and smooth muscle. Briefly: • Skeletal muscle tissue consists of muscle fibres that are arranged attached to bones (hence the name ‘skeletal’)
CHAPTER 3 Cellular structure and function
Epithelial tissue Mouth and skin: stratified squamous
Ovary surface: simple cuboidal
CELL SHAPES Squamous
Respiratory airways: pseudostratified columnar
Air sacs in lungs: simple squamous
Bladder: transitional Digestive tract: simple columnar
Cuboidal
Columnar
FIGURE 3.20
Classification and locations of epithelial tissue. The tissues are classified according to the shape and arrangement of the cells.
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Connective tissue Dense fibrous Bone
Ligaments
Reticular
Cartilage
Bone marrow
Loose connective (areolar)
Adipose Skin
Basement membrane
FIGURE 3.21
Types and locations of connective tissue. Connective tissues are the most diverse tissues throughout the body.
CHAPTER 3 Cellular structure and function
and are responsible for voluntary movement. More details of skeletal muscle tissue are provided in Chapter 20. • Cardiac muscle tissue is similar to skeletal muscle tissue, but it is limited to the heart. The tissue contracts involuntarily, which means that it is not under conscious control, and contracts continually throughout your entire life. Further details can be found in Chapter 22. • Smooth muscle tissue is found in a variety of locations, such as the digestive system, the airways of the lungs and the blood vessels. The name derives from its appearance and its functions are connected with the organ where it is located. For instance, smooth muscle tissue can change the diameter of blood vessels and so is vitally important in maintaining normal blood pressure.
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Nervous tissue
Nervous tissue is composed of highly specialised cells called neurons, which receive and transmit electrical impulses rapidly across junctions called synapses. Different types of neurons have special characteristics that depend on their distribution and function within the nervous system and are explored in Chapter 6. FOCU S ON L EA RN IN G
1 Differentiate between epithelial, connective, muscle and nervous tissue. 2 Provide examples of locations for each of these four primary tissue types.
Ageing and cellular structure and function
Cellular, tissue and systemic ageing The maximal life span of humans is between 80 and 100 years. In Western societies, many individuals attain the maximal life span, which is primarily due to improvements in nutrition, housing, water quality, hygiene, sanitation and, importantly and relevant to you as a
student of health science, healthcare. The average life span, or life expectancy, has increased gradually in Western countries over the last 100 years. However, while it was anticipated that this trend will continue,5 this has been disputed due to increasing obesity and diabetes mellitus epidemics in Western cultures.6 In addition, the death rate in the elderly population — those 65 years of age and older — has declined significantly, largely as a result of decreased incidence and improved management of cardiovascular disease. Cellular changes characteristic of ageing include atrophy, decreased function and loss of cells, possibly caused by apoptosis. Loss of cellular function from any of these causes initiates the compensatory mechanisms of hypertrophy and hyperplasia of remaining cells, which can lead to metaplasia, dysplasia (terms are described in Chapter 4) and cancers. In the aged cell, DNA, RNA, cellular proteins and membranes are most susceptible to injurious stimuli. DNA is particularly vulnerable to such injuries, which can cause breaks, deletions and additions in the DNA code. Lack of DNA repair increases the cell’s susceptibility to mutations that may be lethal or promote the development of cancer (see Chapters 37 and 38). There is a gradual decline in most physiological processes with increasing age. The most characteristic tissue change with age is a progressive stiffness or rigidity that affects many systems, including the arterial, pulmonary (lungs) and musculoskeletal systems. A consequence of blood vessel and organ stiffness is a progressive increase in the resistance to blood flow, which means that cells and tissues may not receive enough blood supply. Changes in the endocrine and immune systems affect the elderly individual’s ability to combat invasions of foreign substances, like bacteria. In women, the reproductive system loses oocytes, and in men sperm production decreases. The stomach experiences decreases in the rate Continued
AGEING
Ageing usually is defined as a normal physiological process that is both universal and inevitable — that means all of us will get older. Ageing traditionally has not been considered a disease because it is ‘normal’; and disease is usually considered ‘abnormal’. Conceptually, this distinction seems clear until the concept of injury is introduced. Some pathologists have defined disease as the result of injury. Ageing has been defined as the timedependent loss of structure and function that proceeds slowly and in such small increments that it appears to be the result of the accumulation of small, imperceptible injuries — a gradual result of ‘wear and tear’. However, lifelong exposure to harmful environmental factors, or abnormalities hidden amongst a person’s DNA, could also influence the rate at which each of us age. These conceptual distinctions have given rise to two general categories of theories of ageing. The first category proposes that ageing is the result of the accumulation of random injuries and events — general ‘wear and tear’. The second category proposes that ageing is the result of a genetically controlled developmental program or built-in self-destructive processes. There is an ongoing debate in the scientific community as to which is more likely or if there is another reason or possibly a combination of both theories. To date, evidence exists both for and against any particular theory of ageing. This chapter focuses on what are considered to be ‘normal’ processes and rates of ageing, while Chapter 4 gives more detail on the factors that may accelerate this process.
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of emptying and secretion of hormones and acid. Muscular atrophy diminishes mobility by decreasing motor tone and contractility. Sarcopenia, loss of muscle mass and strength, can occur into old age. The skin of the aged individual is affected by atrophy and wrinkling of the epidermis and alterations in the underlying dermis, fat and muscle. We consider each of these changes as we progress through the chapters on individual body systems. Total body changes include a decrease in height; a reduction in circumference of the neck, thighs and arms; widening of the pelvis; and lengthening of the nose and ears. Several of these changes are the result of tissue atrophy and decreased bone mass. Body composition changes with age. With middle age, there is an increase in body weight (men gain weight until about 50 years of age and women until 70 years) and fat mass, followed by a decrease in stature, weight, fat-free mass (which includes all minerals, proteins and water plus all other constituents except lipids) and body cell mass at older ages. As fat increases, total body water decreases, so older individuals have less body water and are more prone to dehydration. Increased body fat and centralised fat distribution (abdominal) are associated with diabetes mellitus and heart disease. Some of these changes are summarised in Fig. 3.22. Advanced age increases susceptibility to disease, and death occurs after an injury or insult because of diminished cellular, tissue and organic function. As we meet the challenges of present day health issues and an elderly population is prominent in Australia and New Zealand, the issues that impact on our wellbeing as we advance into older age continue to confront us.
85%
Brain weight
Citric 80% acid cycle Basal metabolic rate 50%
Liver blood flow
63% Liver weight
65%
Cardiac output at rest 55%
Respiratory capacity of lungs 65%
Kidney mass
85% Conduction velocity of nerve fibre
FIGURE 3.22
Biological changes associated with ageing. Insets show the proportion of remaining function in the organs of an elderly person compared with that of a 20-year-old. These data are for illustration only; individuals exhibit highly variable changes over the life span.
chapter SUMMARY Cellular structure and function
Cellular components
• There are more than 200 different cell types of different shapes and sizes and each performs quite different functions. • Cells become specialised through the process of differentiation, or maturation. • The four common characteristics of all cells are: cell metabolism, excretion, communication and reproduction.
• Cells consist of three general components: the cell membrane, the cytoplasm and organelles. • The organelles (little organs) are suspended in the cytoplasm and the majority are enclosed in membranes, except for the ribosomes, centrioles and cytoskeleton. • The nucleus is the largest membrane-bound organelle and is found usually in the cell’s centre. The chief
•
•
•
•
• • • • •
CHAPTER 3 Cellular structure and function
functions of the nucleus are cell division and control of genetic information. Ribosomes are composed of ribonucleic acid (RNA) and protein and are located in the cytoplasm and endoplasmic reticulum. They are primarily responsible for protein production. The endoplasmic reticulum is a network of tubular channels (cisternae) that extends throughout the outer nuclear membrane. It specialises in the production and transport of the protein and lipid components of most of the organelles. The Golgi apparatus is a network of smooth membranes and vesicles located near the nucleus. It is responsible for processing and packaging proteins into secretory vesicles. These vesicles break away from the Golgi apparatus and migrate to a variety of intracellular and extracellular destinations, including the cell membrane. Lysosomes are sac-like structures that originate from the Golgi apparatus and contain digestive enzymes. These enzymes are responsible for digesting most cellular substances down to their basic form, such as amino acids, fatty acids and sugars. Cellular injury leads to a release of the lysosomal enzymes, causing cellular self-digestion. Peroxisomes are similar to lysosomes but contain several enzymes that either produce or use hydrogen peroxide. Mitochondria contain the metabolic machinery necessary for cellular energy metabolism. The mitochondria generate most of the cell’s ATP. The cytoskeleton is the ‘bone and muscle’ of the cell. Cytoplasm, or the cytoplasmic matrix, is an aqueous solution that fills the space between the nucleus and the cell membrane.
The cell membrane • The cell membrane encloses the cell and, by controlling the movement of substances across it, exerts a powerful influence on metabolic pathways. • The cell membrane is a bilayer of lipids (phospholipids) and cholesterol, which gives the membrane its structural integrity. • Membrane functions are determined largely by proteins. These functions include recognition by protein receptors and transport of substances into and out of the cell. • The fluid mosaic model accounts for the fluidity of the lipid bilayer and the flexibility, self-sealing properties and selective impermeability of the cell membrane.
Cellular receptors and communication • Cellular receptors are protein molecules on the cell membrane, in the cytoplasm or in the nucleus that are capable of recognising and binding to various substances, such as hormones. • Protein receptors on the cell membrane enable the cell to interact with other cells and with extracellular substances. • Cells communicate in a variety of ways: they form protein channels, called gap junctions, which directly coordinate the activities of adjacent cells; and they have
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receptors on the cell membrane that respond to signals that affect the cell itself and other cells in direct physical contact. • The primary modes of cellular signalling are hormonal and neural signalling.
Membrane transport • Two types of solute exist in body fluids: electrolytes and non-electrolytes. Electrolytes are electrically charged and dissociate into constituent ions when placed in solution. Non-electrolytes do not dissociate when placed in solution. • Water and small electrically uncharged molecules move through pores in the cell membrane’s lipid bilayer in the process called passive transport. • Passive transport does not require the expenditure of energy; rather, it is driven by the physical effects of osmosis, hydrostatic pressure and diffusion. • Filtration is the measurement of water and solutes through a membrane because of a greater pushing pressure. • Diffusion is the passive movement of a solute from an area of higher solute concentration to an area of lower solute concentration. • Hydrostatic pressure is the mechanical force of water pushing against cellular membranes. • Facilitated diffusion does not require energy: substances are transported across the cell membrane via an integral membrane, through either a channel or a carrier protein. • Osmosis is the movement of water across a semipermeable membrane from a region of lower solute concentration to a region of higher solute concentration. • The amount of hydrostatic pressure required to oppose the osmotic movement of water is called the osmotic pressure of the solution. • Active transport requires metabolic energy (ATP) to move molecules against the concentration gradient. • Larger molecules and molecular complexes are moved into the cell by active transport, which requires the cell to expend energy (by means of ATP). • Active transport occurs also by endocytosis or vesicle formation, in which the substance to be transported is engulfed by a segment of the cell membrane, forming a vesicle that moves into the cell. • The largest molecules (macromolecules) and fluids are transported by the processes of endocytosis (ingestion) and exocytosis (expulsion). • Pinocytosis is a type of endocytosis in which fluids and solute molecules are ingested through the formation of small vesicles. • Phagocytosis is a type of endocytosis in which large particles, such as bacteria, are ingested through the formation of large vesicles, called vacuoles. • Endocytosis occurs when a section of the cell membrane enfolds substances from outside the cell and invaginates, internalising the substances in coated vesicles. • Inside the cell, lysosomal enzymes process and digest material ingested by endocytosis. Continued
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Cellular metabolism • The chemical tasks of maintaining essential cellular functions are referred to as cellular metabolism. Anabolism is the energy-using process of metabolism, whereas catabolism is the energy-releasing process. • Adenosine triphosphate (ATP) functions as an energytransferring molecule. Energy is stored by molecules of carbohydrate, lipid and protein, which, when catabolised, transfer energy to ATP. • Cellular respiration can be either aerobic or anaerobic; aerobic respiration is both more efficient and yields more molecules of ATP.
Tissues • Cells of one or more types are organised into tissues; different types of tissues compose organs; and organs are organised to function as tracts or systems. • The four basic types of tissues are epithelial, connective, muscle and nervous. • Epithelial tissue covers most internal and external surfaces of the body. The functions of epithelial tissue include protection, absorption, secretion and excretion.
• Connective tissue binds various tissues and organs together, supporting them in their locations and serving as storage sites for excess nutrients. • Muscle tissue is composed of long, thin, highly contractile cells or fibres. Muscle tissue that is attached to bones enables voluntary movement. Muscle tissue in internal organs enables involuntary movement. • Nervous tissue is composed of highly specialised cells called neurons that receive and transmit electrical impulses rapidly across junctions called synapses.
Ageing and cellular structure and function • It is difficult to differentiate the normal physiological changes of ageing from the pathological changes of ageing. • Humans have an inherent maximal life span (80 to 100 years) that is dictated by currently unknown intrinsic mechanisms. • Although the maximal life span has not changed significantly over time, the average life span, or life expectancy, has increased. • The physiological mechanisms of ageing are mainly associated with cellular changes produced by genetic and environmental/lifestyle factors.
CASE STUDY
AD ULT Emma and Amelie are in the laboratory doing an introductory practical on cells. Their tutor has asked them to look at slides of different types of cells under the microscope. They have been told to look at the various structures and to compare them with the illustrations of cells in their textbook. Emma and Amelie notice that parts of the cell look different from the textbook illustrations and that the shapes vary according to the type of cell. Answer the following questions as though you were participating in the lab session with Emma and Amelie. 1 Discuss why the cells look different under the microscope compared to the textbook illustrations.
2
Explain why cells are different shapes. (Hint: think about their functions.) 3 Explain why some cells have more organelles than others. In your answer, compare cells with many mitochondria and multiple nuclei. 4 Cells survive for different lengths of time. Explain why some cells reproduce rapidly and others stay the same for the life of the person. 5 Cells require nutrients, oxygen and water to survive. Explain how oxygen and nutrients enter the cell and wastes leave the cell.
CHAPTER 3 Cellular structure and function
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CASE STUDY
ADULT Rebecca is an avid runner outside of her nursing studies. She is considering changing her specialty from sprints to long distance running and achieving her lifelong goal of running the City to Surf in Sydney. This will require a considerable change in her training and nutrition, and she has been investigating the differences in how the metabolism of body behaves at the early, middle and late stages of a distance race. Answer the following questions to help Rebecca understand how her body will be coping with a longer race. 1 Which organelles are responsible for the energy generated for cell activity, and what is this energy known as?
2
At the start of the race a runner would be using aerobic respiration. Explain the conditions, materials and waste products that are included in this process. 3 As the race continues the body’s glucose stores are depleted, and the oxygen delivery to the tissues becomes inadequate. What energy production process will become active, and what waste products will be produced? 4 As Rebecca undergoes further training, her skeletal muscle cells will contain a greater number of mitochondria. Explain how this is going to sustain her performance level while racing. 5 Other than carbohydrates, what other substances can the body use for energy production during times of need?
REVIEW QUESTIONS 1 List and explain the 4 characteristic functions of all cells in the body. 2 Describe how the structure and function of a cell can be compared to the structure and function of a factory. 3 Explain the function of the nucleus and why it has a surrounding membrane. 4 The mitochondria are often described as the powerhouse of the cell. Explain the meaning of this statement. 5 Describe the arrangement of phospholipids in the cell membrane and how this protects the cell.
6 The cell membrane is a semi-permeable membrane. What does this mean? 7 Describe the difference between passive and active transport, and provide examples of each. 8 Discuss how adenosine triphosphate (ATP) is formed and why is it essential for life. 9 Describe 5 components related to ageing and how they impact on normal functioning. 10 List the 4 primary tissue types and provide examples of locations of each tissue type in the body.
Key terms algor mortis, 75 anoxia, 59 apoptosis, 71 atrophy, 66 dysplasia, 68 free radicals, 64 hyperplasia, 67 hypertrophy, 67 hypoxia, 59 irreversible cell injury, 69 ischaemia, 59 metaplasia, 68 necrosis, 72 poisons, 61 reactive oxygen species, 64 reperfusion injury, 64 reversible cell injury, 69 rigor mortis, 75 somatic death, 75
CHAPTER
4
Altered cellular function Sarah List
Chapter outline Introduction, 59 Causes of cellular injury, 59 Hypoxia, 59 Chemical agents, 59 Physical agents, 61 Infectious agents, 61 Genetic causes, 62 Mechanisms of cellular injury, 62 Hypoxic injury, 62 The impact of oxygen and oxygen-derived free radicals, 64 Alteration to calcium homeostasis, 65
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Cellular adaptation, 66 Atrophy, 66 Hypertrophy, 67 Hyperplasia, 67 Metaplasia, 68 Dysplasia, 68 Reversible and irreversible cell injury, 69 Reversible cell injury, 69 Irreversible cell injury, 70 Ageing and altered cellular function, 74 Death, 75
Introduction Knowledge of the structural and functional reactions of cells to injurious agents is key to understanding disease processes. Altered cellular biology can result from adaptation, injury, disease, cancer or ageing. Adaptation occurs in response to both normal (or physiological) conditions and adverse (or pathophysiological) conditions. For example, the uterus adapts to pregnancy, which is clearly a normal physiological state, by enlarging to accommodate the growing fetus. Enlargement occurs because of an increase in the size and number of uterine cells. In contrast, when an adverse condition such as high blood pressure arises, heart cells are stimulated to enlarge because of the increased pressure. However, unlike most of the body’s adaptive mechanisms, cellular adaptations to adverse conditions are usually successful for only a short period of time. If the stress on the cell is severe or long term it will eventually overwhelm the adaptive processes, and cellular injury or death ensues. Cellular injury may be reversible or irreversible. Cellular injuries from various causes have different clinical and pathophysiological manifestations. Cellular death is confirmed by structural changes seen when cells are examined under a microscope. Cellular ageing causes structural and functional changes that eventually may lead to cellular death or a decreased capacity to recover from injury. Mechanisms explaining how and why cells age are currently not fully understood, and distinguishing between pathophysiological changes and physiological changes that occur with ageing is often difficult. Ageing clearly causes alterations in cellular structure and function, yet growing old is both inevitable and normal. Furthermore, many older people are able to maintain a remarkable state of health, with little or no apparent disease.
Causes of cellular injury Most diseases begin with cell injury. Cellular injury occurs if the cell is unable to maintain homeostasis, which is a normal or adaptive steady state, in the face of injurious stimuli. Injured cells may recover or die. Stimuli that can cause damage to the cell include a lack of adequate oxygen supply (hypoxia), chemical agents, physical agents, infectious agents, genetic factors and nutritional imbalances (see Fig. 4.1). All of these noxious stimuli (noxious meaning that they can cause harm) may contribute to cell injury, depending on a number of factors. If cellular injury does occur, the extent of injury depends on the type, state (i.e. if the cell is dividing or fully matured) and adaptive processes of the cell. In addition, it is also influenced by the type, severity and duration of the injurious stimulus. Moreover, two individuals exposed to an identical stimulus may incur different degrees of cellular injury, as modifying factors, such as nutritional status, can profoundly influence the extent of injury. While the scientific community has a good knowledge of the types and effects of these
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stimuli on cells, the precise ‘point of no return’ that leads to cellular death remains a biochemical puzzle and the exact mechanisms responsible for the transition from reversible to irreversible cellular damage are not fully understood. Some of the different causes of cellular injury are summarised in Table 4.1.
Hypoxia
Hypoxia, or lack of sufficient oxygen, is the single most common cause of cellular injury. Hypoxia can result for many reasons, but these can be broadly classified into problems with oxygen entering the blood and problems with transporting oxygen around the body to the cells (see Fig. 4.2). Conditions that cause inadequate oxygen delivery to the blood include: • diseases of the respiratory system, such as asthma • blockage of the upper airways in the lungs, whereby air cannot get into the lungs • a lower concentration of oxygen in the atmosphere, which occurs only with increasing altitude. Hypoxia due to insufficient transport of oxygen through the body can occur because of: • a decrease in haemoglobin (which is the molecule inside red blood cells that carries oxygen around the blood) • decreased production of red blood cells (which means a decreased oxygen-carrying capacity) • diseases of the cardiovascular system (where the pumping ability of the heart is insufficient). But by far the most common cause of hypoxia in the body is a reduction in blood supply to the cells. This is termed ischaemia, which literally means a restriction in blood flow. This may be observed in many hospital patients and contributes significantly to mortality. For instance, patients with ischaemia of the heart and brain often die because these organs need a constant supply of oxygen. Ischaemic injury is often caused by the gradual narrowing of arteries (termed arteriosclerosis; see Chapter 23) and complete blockage by blood clots (thrombosis). Progressive hypoxia caused by gradual arterial obstruction is better tolerated than the sudden acute anoxia (total lack of oxygen) caused by a sudden obstruction, as with a blood clot or other plug in the circulation. An acute obstruction in a coronary artery can cause cell death within minutes if the blood supply is not restored.
Chemical agents
Chemical injury to the cell begins with a biochemical interaction between a toxic substance and the cell membrane, which is ultimately damaged, leading to increased permeability. This means that more substances, both harmful and non-harmful, can pass through the cell membrane. There are two general mechanisms: 1 direct toxicity caused by combination of a chemical with a part of the cell membrane or organelles
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CONCEPT MAP
Cell death without reversal results in
e.g. Hyperlipidaemia Deposition of lipids in blood vessels = atherosclerosis
Cell swelling Due to failure of ATP powered Na+/K+ pump
can lead to
causes Cellular injury Homeostasis not maintained
Hypoxia—lack of O2 e.g. lung and heart disease
Sunlight: UV exposure Strongly linked to cancer e.g. melanoma
Physical agents Mechanical cell injury
Hypothermic injury: chilling or freezing of cells e.g. frostbite triggers Vasoconstriction and increased blood viscosity Ischaemic injury causing
Atmospheric pressure: waves of air or fluid pressure e.g. decompression sickness with scuba diving (‘the bends’) defined as Increased followed by decreased pressure Diverse effects
Necrotic death of tissue
results in Lung collapse
Organ rupture
Nutritional imbalance e.g. deficient or excessive nutrients in diet Trauma: physical impact or irritation e.g. strains and sprains
Hyperthermic injury: excessive heat exposure e.g. burns, heat stroke can Vary in severity Due to intensity/ extent of heat may cause Cell death
Gases (CO2 and O2) coming out of solution
Bleeding
all lead to Hypoxia injury and pain and ultimately Cell death
FIGURE 4.1
Concept map of cellular injury alterations leading to cell death. Main causes of cell injury include hypoxia, and chemical, physical and infectious agents. Hypoxic cell injury is a main cause of cell death.
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TABLE 4.1 Some causes of cellular injury CAUSE
CHARACTERISTICS
EXAMPLES
Hypoxia
Lack of cellular oxygen causes an increase in anaerobic respiration leading to a lack of sodium and potassium transport across the cell membrane. Eventually, the cells swell due to fluid accumulation and die
• Lung and heart disease
Pathophysiological cellular effects develop when nutrients are not consumed in the diet and so are not transported to the body’s cells, or when excessive amounts of nutrients are consumed and transported to the body’s cells
• Protein deficiency
Nutritional imbalances
• Critical illness with respiratory failure • High altitude • Glucose deficiency • Lipid deficiency (hypolipidaemia) • Hyperlipidaemia (increased lipoproteins in the blood causing deposits of fat in the heart, liver, and muscle) • Vitamin deficiencies
Physical agents Hypothermic injury
Caused by chilling or freezing of cells, creating high intracellular sodium concentrations; or abrupt drops in temperature leading to vasoconstriction and increased viscosity of the blood, and causing ischaemic injury, infarction and necrosis
• Frostbite
Hyperthermic injury
Caused by excessive heat; varies in severity according to the nature, intensity and extent of the heat
• Burns
• Prolonged exposure to cold conditions
• Burn blisters • Heat cramps • Heat exhaustion • Heat stroke
Atmospheric pressure
Tissue injury caused by compressive waves of air or fluid impinging on the body, followed by a sudden wave of decreased pressure. Changes may collapse the lungs, rupture internal solid organs and cause widespread haemorrhage (bleeding). Also, carbon dioxide and nitrogen, which are normally dissolved in the blood, come out of solution and form small bubbles (called gas emboli), causing hypoxic injury and pain
• Decompression sickness with scuba diving
Sunlight
Prolonged exposure to sunlight has been strongly linked to skin cancers
• Melanoma
Trauma
Injury is caused by physical impact or irritation; injuries may be overt or cumulative
• Musculoskeletal sprains and strains
2
the formation of substances that cause the lipids in the cell membrane to be damaged.
Many chemical agents cause cellular injury. Highly toxic substances are known as poisons. Minute amounts of some agents, such as cyanide, can rapidly destroy enough cells to cause the death of the individual in a very short period of time after exposure. Chronic exposure to air pollutants, insecticides and herbicides can also cause cellular injury. Carbon monoxide (in the exhaust of car fumes) and social drugs such as alcohol can significantly alter cellular function and injure cellular structures. Recreational, over-the-counter and prescribed drugs also may cause cellular injury, sometimes leading to death. Accidental or suicidal poisonings by chemical agents cause numerous deaths.
• Sunburn
Physical agents
Physical agents that lead to cell injury include blunt trauma to the body resulting in damage to the tissues and penetrating wounds that pass the skin and enter the body, such as surgical incisions. Other forms of physical agents include environmental stressors such as high and low temperatures and sunlight.
Infectious agents
Infectious microorganisms can enter the body and multiply rapidly to cause disease. They may enter the cell, like viruses, or release toxins that are harmful to the cell. Infections in hospital patients are one of the most common clinical presentations and, accordingly, Chapter 14 examines the effects of infection.
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TABLE 4.2 Mechanisms of cell injury MECHANISM
EFFECTS ON THE CELL
ATP depletion
Loss of mitochondrial ATP and decreased ATP production. Results include cellular swelling, decreased protein production and decreased membrane transport — all changes that contribute to loss of integrity of the cell membrane
Oxygen and oxygen-derived free radicals
Lack of oxygen is key in the progression of cell injury in ischaemia (reduced blood supply); reactive oxygen species cause destruction of the cell membrane and cell structure
Intracellular calcium increased
Normally, intracellular calcium concentrations in the cytoplasm are very low. Ischaemia causes an increase in cytoplasmic calcium concentrations; sustained levels of calcium continue to increase with damage to the cell membrane
Defects in cell membrane permeability
Early loss of selective membrane permeability is found in all forms of cell injury
O2 The mouth and nose serve to inhale air
1
Lungs oxygenate blood
2
Veins
Heart pumps the blood
Arteries transport oxygenated blood
3 Red blood cells carry oxygen
FIGURE 4.2
The different causes of hypoxia. 1 Interruption of oxygen supply to the lungs. 2 Inadequate oxygen entering the blood in the lungs. 3 Inadequate transport of oxygen in the circulation.
Genetic causes
Genetic abnormalities can produce defects in cellular metabolism, alter the structure and function of cells and make cells more susceptible to injury. Genetic abnormalities and environmental influences on genes are discussed in Chapter 38.
F OC US O N L E ARN IN G
1 List and discuss the different forms of hypoxia. 2 Name at least 3 other causes of cellular injury and state why they can damage the cell.
Mechanisms of cellular injury There are four common biochemical themes that are important in understanding cell injury and cell death regardless of the injurious agent. These are ATP depletion, oxygen and oxygen-derived free radicals, increased intracellular calcium and loss of calcium steady state, and defects in cell membrane permeability (see Table 4.2).
However, the mechanisms that drive cellular damage can be grouped under three main areas: • hypoxic injury • the impact of oxygen and oxygen-derived free radicals • alterations to calcium homeostasis. We start with hypoxic injury, which can be relatively common in patients in hospital settings.
Hypoxic injury
Cellular responses to hypoxic injury (insufficient oxygen at the cells) caused by ischaemia (insufficient blood supply to the cells) have been demonstrated in studies of the heart muscle. Within 1 minute of blood supply to the heart muscle (myocardium) being interrupted, the heart becomes pale and has difficulty contracting normally. Within 3–5 minutes, the ischaemic portion of the myocardium ceases to contract because of a rapid decrease in the ability of the mitochondria to produce ATP (refer to Chapter 3 for details of how glucose is used to generate ATP, with maximal ATP being generated by aerobic processes). However, in the case of ischaemia causing hypoxia, lack of ATP leads to increased reliance on anaerobic metabolism, which can only generate limited quantities of ATP. In the case of persistent ischaemia leading to persistent hypoxia, the cell suffers from severe lack of ATP. A reduction in ATP levels causes the cell membrane’s sodium–potassium (Na+–K+) pump and sodium–calcium exchange to fail, which leads to an intracellular accumulation of sodium and calcium and diffusion of potassium out of the cell. The sodium–potassium pump uses ATP to actively pump sodium out of the cell and potassium into the cell,
CHAPTER 4 Altered cellular function
which is vital to cell homeostasis. Sodium and water then can enter the cell freely causing cellular swelling; as well, early dilation of the endoplasmic reticulum results. Dilation causes the ribosomes to detach from the rough endoplasmic reticulum, reducing production of protein (protein synthesis). With continued hypoxia, the entire cell becomes markedly swollen, with increased concentrations of sodium, water and chloride, and decreased concentrations of potassium. It should be noted that these disruptions will be reversed if oxygen is made available and restored. However, if oxygen is not restored, swelling of lysosomes and marked mitochondrial swelling occurs. Continued hypoxic injury
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with accumulation of calcium subsequently activates multiple enzyme systems, resulting in membrane damage, cytoskeleton disruption, activation of inflammation, DNA degradation and eventual cell death (see Fig. 4.3). Structurally, with plasma membrane damage, calcium from outside the cell readily moves into the cell and intracellular calcium stores are released. Intracellular calcium activates enzymes that can further damage cell membrane proteins, ATP and nucleic acids. Irreversible damage is characterised by two events: • lack of ATP generation because of mitochondrial damage • major disturbances and damage in membrane function.
Loss of aerobic respiration
More reliance on anaerobic respiration depends on glycogen stores, and leads to
Ischaemia
Depletion of glycogen
leads to
leads to
Decreased oxygen at the cell
OUTSIDE
K+
Decreased ATP via aerobic metabolism lack of ATP to pump Na+/K+ and Na+/Ca2+
Na+ Ca2+
Hypoxia causes
Excess water leads to enters cell
ATP production from anaerobic metabolism
ATP production ceases
When glycogen stores depleted
Cell swelling
ER, lysosome and mitochondria swelling
INSIDE
Intracellular accumulation of Na and Ca
Insufficient ATP
causing
Detached ribosomes
Cell membrane damage Cell death FIGURE 4.3
ATP depletion. Ischaemia causing hypoxia which leads to reduction in ATP production. If the hypoxic insult continues, a series of intracellular changes occur leading to cell death.
CONCEPT MAP
Hypoxia
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Thrombus
Swollen cell
CONCEPT MAP
A Anoxia
Blood vessel O2
B
Reperfusion
O2
Cell death
Reactive oxygen species Radicals
FIGURE 4.4
Reperfusion injury. A Without oxygen, or anoxia, the cells display hypoxic injury and become swollen. B With reoxygenation, reperfusion injury increases because of the formation of reactive oxygen radicals that can cause cell necrosis.
Restoration of oxygen, however, can cause additional injury called reperfusion injury (see Fig. 4.4). Briefly, this occurs during the process of ATP production in the mitochondria, where oxygen is transformed to water and small amounts of partially reduced oxygen are formed, called free radicals. Reperfusion injury results from the generation of free radicals, which are chemically highly unstable and can cause damage to the cell membrane by undergoing destructive chemical reactions. This process is sometimes referred to as oxidative stress and is discussed in the next section.
The impact of oxygen and oxygen-derived free radicals
Although we require oxygen to survive, oxygen can actually be particularly harmful to cells — which is extremely surprising! To understand how this occurs, we need to delve into some chemistry. Free radicals are formed during ATP production from partially reduced oxygen molecules called reactive oxygen species. A free radical is an atom that is electrically uncharged yet is unstable; this means that it is prone to stealing or donating a charge from another molecule. When a molecule has its charge stolen, it becomes a free radical. Therefore, it is capable of injurious chemical bonding with proteins, lipids and carbohydrates, which are the key molecules in membranes and nucleic acids (see Chapter 2). Free radicals are highly reactive and can react with most molecules close by. Normally, this is not an issue, as the body produces only a small amount of free radicals. Furthermore, very efficient scavengers, called antioxidants, clean up these molecules before they can undergo chemical
FIGURE 4.5
An overview of reactive oxygen species formation and the effects on the cell. In response to the stress that leads to production of reactive oxygen species, the cell undergoes disruption to the mitochondria, DNA and cell membrane, which can cause cell death.
reactions. However, during periods of stress, more reactive oxygen species are produced and free radicals become more difficult to control. They accumulate when cells are injured and initiate many chain reactions, causing damage. The large numbers of reactive oxygen species overwhelm the balance by antioxidants. This inefficiency of antioxidants is even more serious in mitochondria because mitochondria are unable to remove high amounts of free radicals.1 Consequently, excessive production of reactive oxygen species in mitochondria will damage lipids, proteins and mitochondrial DNA (mDNA), leading to irreversible cell death (see Fig. 4.5).2 Mitochondrial oxidative stress has been implicated in heart disease, Alzheimer’s disease and Parkinson’s disease, as well as ageing itself.3 Free radicals cause several damaging effects by: (1) lipid peroxidation, which is the destruction of lipids leading to membrane damage and increased permeability; (2) attacking
CHAPTER 4 Altered cellular function
Ca2+
Injurious agent
Alteration to calcium homeostasis
2+
Activation of cellular enzymes Intracellular enzymes are activated
DAMAGE TO DAMAGE TO CELL MEMBRANE NUCLEUS
Mitochondrial damage
ATP
FIGURE 4.6
The mechanism by which increases in intracellular calcium cause cellular damage. Calcium enters the cell and is released from the stores in the mitochondria and endoplasmic reticulum. This activates enzymes that cause a decrease in ATP production and damage the cell membrane and nucleus.
1 Describe how a cell affected by hypoxia can lead to ATP depletion and cell damage. 2 Differentiate between free radicals and antioxidants. 3 Discuss how calcium can cause cellular damage.
Diseases and disorders linked to oxygen-derived free radicals
Alzheimer’s disease Atherosclerosis Cancer Deterioration noted in ageing Diabetes mellitus Eye disorders Macular degeneration Cataracts
Ca2+
Phospho- Disruption lipids of membrane and cytoskeletal proteins
F O CUS O N L E A R N IN G
• • • • • • • •
Ca2+
Ca2+
Increased cytosolic Ca
The concentration of calcium inside the cell is quite low compared with the concentration in the extracellular fluid. Also, it tends to be stored in the mitochondria and endoplasmic reticulum and is released only when needed, so the amount of calcium actually in the cytoplasm is low. The role of calcium is to activate enzymes in the cell and it is intricately involved in muscle contraction. Therefore, like the sodium–potassium pump, calcium too is pumped out of the cell to keep the concentration low. However, if the cell membrane is damaged, such as occurs when the cell is hypoxic, calcium enters the cell and the concentration in the cytoplasm increases. Stored calcium is also released, further increasing the cytoplasmic concentration. Unfortunately, this increased intracellular calcium causes cell injury by: • damaging the mitochondria, which reduces the capacity to produce ATP • activating enzymes, which are destructive to the cell • breaking down the cell membrane and cytoskeleton, so that the cell loses its barrier (see Fig. 4.6).
Smooth endoplasmic reticulum
Mitochondrion Ca2+
BOX 4.1
Extracellular Ca2+
• • • • • • • •
Inflammatory disorders Lung disorders Asbestosis Emphysema Nutritional deficiencies Reperfusion injury Rheumatoid arthritis Skin disorders
CONCEPT MAP
critical proteins that affect ion pumps and transport mechanisms; (3) fragmenting DNA, causing decreased protein production; and (4) damaging mitochondria, causing the liberation of calcium into the cytoplasm. Because of the increased understanding of free radicals, a growing number of diseases and disorders have been linked either directly or indirectly to these oxygen reactive species (see Box 4.1).
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RESEARCH IN F
CUS
Hypoxia and oxidative stress injury to the brain in the infant and adult brain Arterial hypoxic–ischaemic stroke occurs when the supply of blood is temporarily blocked from supply via one of the cerebral arteries to the brain tissues. The brain is highly sensitive to oxygen deprivation, and irreversible damage may result after just minutes of a reduced supply. Inflammatory cells and products are attracted to the site of damage and are thought to work in assisting the repair and recovery of tissues, although studies have found that excessive inflammation and the production of reactive oxygen species (ROS, otherwise known as free radicals) are tightly linked and may impair the repair process, rather than enhance it. Interestingly, arterial stroke rates in newborns (1 in 4000) are similar to that in the elderly; however, the injury and response to that injury appear to be distinctly different in these two groups. In adults, tissue death appears to be necrotic, whereas neuronal apoptosis appears to be more dominant in the postnatal infant. However in both age groups, the inflammatory and oxidative responses are major contributors to ischaemic injury and a reduction in the production of ROS provides a significant protective effect in animal stroke models. The immature neonatal brain appears particularly vulnerable to these effects which are therefore more likely to have a greater long-term effect on the function of the brain tissue affected. The immune cells known as neutrophils and macrophages appear to have a substantial role in the effects on the tissue, while the immune protein complement system is also considered to be influential. Interestingly, a reduction in these components in animal stroke models shows a reduction in tissue damage, and a greater chance of tissue recovery. There is evidence that inflammation in the neonatal brain can reprogram the adult brain’s sensitivity to ischaemia, and therefore research is ongoing in this area, and towards the balance of helpful vs harmful levels of inflammation and ROS production posthypoxic stroke.
RESEARCH IN F Natural antioxidants
Nutrient antioxidants, namely vitamin C, vitamin E and betacarotene (a precursor to vitamin A), work by inactivating free radicals. Especially important is the prevention of oxidative damage to mitochondrial DNA. Vitamin C, found in citrus fruits, broccoli and potatoes, is probably the most notable of the antioxidant nutrients. A water-soluble vitamin, it is the first line of defence, scavenging free radicals before they enter cell membranes. Vitamin C promotes wound healing, growth and tissue repair. It also enhances the effect of vitamin E. It is known to lower the risk of heart disease and cataracts. Vitamin E, which is fat-soluble and available in unprocessed oils, wheat germ, hazelnuts, almonds, egg yolk and butter, does much of its protective antioxidant work within the lipid-rich cell membrane. It is an anticoagulant and important in the formation of blood cells. It also helps to utilise vitamin K, and it reduces the risk of cataracts. Betacarotene, found in carrots, dark green and yellow–orange vegetables and fruits, leafy vegetables, tomatoes, spinach, squash and broccoli, is converted to vitamin A in the small intestine and may be associated with reduced risk of cancer, cataracts and heart disease.
it is hard to know whether the response is pathological or an extreme adaptation to an excessive functional demand. The most significant adaptive changes in cells are: • atrophy, where the cells decrease in size and function • hypertrophy, where individual cells increase in size • hyperplasia, where the number of cells increases • metaplasia, where the cells change from one mature cell type into another less mature cell type (see Fig. 4.7). Another change, which is not truly adaptive, is dysplasia. This involves abnormal change in the size, shape and arrangement of mature cells.
Atrophy
Cellular adaptation We have looked at the causes of cellular injury and how these agents affect cell structure and function. Now we need to explore what cells do in response to these insults. A number of factors determine cellular function and structure; these include genetics, the type of surrounding cells and whether the cell can readily obtain nutrients and oxygen. However, if cells are placed under continual stress, they have the ability to adapt. Cells adapt to their environment to escape and protect themselves from injury. An adapted cell is neither normal nor injured — its condition lies somewhere between these two states. Cellular adaptations are a common and central part of many disease states. In the early stages of a successful adaptive response, cells may have enhanced function; thus,
CUS
Atrophy is a decrease or shrinkage in cellular size. If atrophy occurs in a sufficient number of an organ’s cells, the entire organ shrinks and becomes smaller. Atrophy can affect any organ, but it is most common in skeletal muscle, the heart, secondary sex organs and the brain, and is especially related to ageing (see Fig. 4.8). Atrophy can be classified as physiological or pathological. Physiological atrophy occurs with early development. For example, the thymus gland, a gland involved in immune system function, undergoes the normal process of physiological atrophy during childhood. The reasons for this are unknown. Pathological atrophy occurs as a result of decreases in workload, pressure, use, blood supply, nutrition and hormonal and nervous system stimulation. Individuals immobilised in bed for a prolonged time exhibit a type of skeletal muscle atrophy called disuse atrophy. This is prevalent in hospitalised patients who cannot be mobilised; for instance, patients with multiple bone
CHAPTER 4 Altered cellular function
uptake is reduced. The biochemical changes of atrophy are just beginning to be understood. The mechanisms probably include decreased protein production, increased protein catabolism (breakdown), or both.4
Nucleus
Normal
Basement membrane
Atrophy
Hypertrophy
Hyperplasia FIGURE 4.7
Adaptive cell changes. Adaptive cell changes include atrophy (decrease in cell size), hypertrophy (increase in cell size), and hyperplasia (increase in cell number).
A
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B
Hypertrophy
Hypertrophy is an increase in the size of cells and consequently in the size of the affected organ. The cells of the heart and kidneys are particularly prone to enlargement. The increased cellular size is associated with an increased accumulation of protein in the cellular components (the cell membrane, endoplasmic reticulum and mitochondria) and not with an increase in cellular fluid. Hypertrophy, like atrophy, can be physiological or pathological and is caused by specific hormone stimulation or by increased functional demand. The triggers for hypertrophy include two types of signals: (1) mechanical signals, such as stretch; and (2) chemical signals, such as growth factors, which stimulate growth. For example, in skeletal muscles (the ones you contract to move bones), physiological hypertrophy occurs in response to heavy work. Hypertrophy is the mechanism that occurs in body builders who lift heavy weights repeatedly, as the size of their muscles increases. Muscular hypertrophy tends to diminish if the excessive workload diminishes. Another example of normal or physiological hypertrophy is the increased growth of the uterus and mammary glands in response to pregnancy. A pathological example is pathophysiological hypertrophy of the heart, secondary to mechanical problems, such as faulty heart valves (see Fig. 4.9).
Hyperplasia
FIGURE 4.8
Atrophy of the brain. A Normal brain of a young adult. B Atrophy of the brain of an 82-year-old male with cerebrovascular disease, resulting in reduced blood supply. Note: the meninges (a vascular layer of the brain) have been stripped from the right half of each specimen to reveal the surface of the brain. Viewed from the top of the brain.
fractures or significant obesity. Ageing causes brain cells to become atrophic and endocrine-dependent organs, such as the gonads (testes or ovaries), to shrink as hormonal stimulation decreases. Whether atrophy is caused by normal physiological conditions or by pathological conditions, atrophic cells exhibit the same basic changes. Cells that have atrophied contain less endoplasmic reticulum and fewer mitochondria than normal cells. These cells also reduce their oxygen consumption and amino acid
Hyperplasia is an increase in the number of cells resulting from an increased rate of cellular division. Hyperplasia, as a response to injury, occurs when the injury has been severe and prolonged enough to have caused cell death. Loss of epithelial cells and cells of the liver and kidneys triggers DNA production and mitotic division (discussed in Chapter 5). Increased cell growth is a multistep process involving the production of growth factors, which stimulate the remaining cells to produce new cell components and, ultimately, to divide. Hyperplasia and hypertrophy often occur together and both take place if the cells can produce DNA; however, in non-dividing cells only hypertrophy occurs. Two types of normal, or physiological, hyperplasia are (1) compensatory and (2) hormonal. Compensatory hyperplasia is an adaptive mechanism that enables certain organs to regenerate. For example, removal of part of the liver leads to hyperplasia of the remaining liver cells (hepatocytes) to compensate for the loss. Even with removal of 70% of the liver, regeneration of the liver occurs over time. Hormonal hyperplasia occurs in response to release of a hormone. The most common example of this is enlargement of the uterus in the female when pregnancy occurs. Pathological hyperplasia is the abnormal proliferation of normal cells, usually in response to excessive hormonal stimulation or growth factors on target cells. One of the
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most common examples of pathological hyperplasia in males is enlargement of the prostate, which occurs in a significant proportion of males over the age of 60 years.5
A A
Metaplasia
Left ventricle
B B
Left ventricle
FIGURE 4.9
Hypertrophy. A Hypertrophy of heart muscle in the left ventricle (the major chamber of the heart). B Normal left ventricle size. Arrows indicate thickness of the muscle wall and demonstrate the large increase that occurs with hypertrophy. Images show a transverse slice through the heart.
Metaplasia is the reversible replacement of one mature cell type by another, sometimes less differentiated, cell type. It is thought to develop from a reprogramming of stem cells (cells that replicate and can turn into one of many different types of cells) in epithelial or connective tissue. These precursor cells mature along a new pathway because of chemical signals in the cells’ environment. This may be precipitated by a persistent irritant to the cells, such as cigarette smoking. Metaplasia occurs when normal epithelial cells lining the upper airways in the lungs (columnar cells) are replaced by stratified squamous epithelial cells (see Fig. 4.10). The newly formed cells do not secrete mucus or have cilia (projections that protect the lining of the airway), causing loss of a vital protective mechanism. Metaplasia can be reversed if the inducing stimulus, cigarette smoking in this example, is removed. With prolonged exposure to the inducing stimulus, however, dysplasia and cancerous transformation may occur.
Dysplasia
Dysplasia refers to abnormal changes in the size, shape and organisation of mature cells (see Fig. 4.10). Dysplasia is not considered a true adaptive process but is related to metaplasia. Dysplastic changes are often encountered in epithelial tissue of the cervix and respiratory tract, where they are strongly associated with cancer development. However, it should be noted that dysplastic cell changes are likely to be adaptive in nature, but have gone off course, meaning that if the inciting stimulus is removed early enough, dysplastic changes are often reversible.
Normal epithelium
Metaplasia FIGURE 4.10
Metaplasia and dysplasia of cells in the upper airway of the lungs. These cell changes are reversible if the irritant stimulus is removed.
Dysplasia
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Hyperfunction
FO CUS O N L E A R N IN G
1 Describe the cellular changes that occur with atrophy.
69
Removal of stimulus (revert to normal)
2 Provide examples of hypertrophy and explain why it occurs. 3 Differentiate between hypertrophy and hyperplasia. 4 Describe how dysplasia is different from metaplasia.
Reversible injury
Point of no return Hypofunction
Reversible and irreversible cell injury
Reversal to normal Normal cell
Reversible swelling
FIGURE 4.11
Changes in cellular function that can lead to reversible and irreversible cell damage. The blue line refers to changes that are reversible, whereas the red line has extended to the extremes of cell function and leads to irreversible injury.
REVERSIBLE INJURY
NORMAL CELL (homeostasis) Injurious stimulus
Stress
ADAPTATION
Inability to adapt
Reversible cell injury
Cellular injury occurs if the cell is unable to maintain homeostasis (see Fig. 4.12). However, not all injured cells die, as some may recover. The exact mechanisms for why some cells survive and recover and others progress to cell death is not fully understood. This feature has been termed the ‘point of no return’ and is the defining feature of reversible cell injury. If this point is not passed, the cell can recover. Intracellular accumulations, also known as infiltrations, occur not only when injury is sub-lethal and sustained in injured cells, but also in normal cells. Such accumulations may or may not be toxic to the cell and consist of substances that are normally present, such as fluids and electrolytes, lipids,
Necrotic cell
Mild, transient CELL INJURY Severe, progressive
IRREVERSIBLE INJURY
NECROSIS
CELL DEATH
APOPTOSIS
FIGURE 4.12
Stages of cellular response to stress and injurious stimuli. In response to cell stress, cells can either adapt, or result in cell injury. If the cell injury is reversible, the cell may be able to then return to normal. However, if the injury is more severe, the injury may be irreversible, leading to cell death.
CONCEPT MAP
All cells in the body require oxygen and nutrients to provide fuel for cellular metabolism. There must be a constant flow of blood with oxygen and the necessary molecules that cells use as raw materials to be able to produce ATP, as well as for other chemical reactions. In addition, cells produce waste products, such as carbon dioxide, that need to be removed from the cell, the space surrounding the cell and ultimately out of the body. To achieve these processes, the intracellular and extracellular fluids interact in a homeostatic balance to facilitate cellular function. This is considered to be the normal state and it operates using a steady state — that is, slight variations in function are allowed, but essentially homeostasis is maintained. However, we have seen that a decrease in blood flow (ischaemia) or hypoxia severely affects the cell’s normal functions. In fact, any alteration to the extracellular environment will eventually affect inside the cell and possibly lead to a disruption in cell function. If the noxious stimulus is severe and is not removed, the cell may undergo adaptations in an attempt to cope with the change in environmental conditions. If the stimulus ceases, over time the cell will return to a normal state, thereby reversing its injury; this is known as reversible cell injury. However, if the insult continues, it is very likely that a critical point will be reached and irreversible cell injury will occur. This is shown in Fig. 4.11. In the following sections we explore these two concepts in more detail.
Irreversible injury Necrosis
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glycogen, calcium and proteins. Abnormal accumulations of these substances can occur in the cytoplasm (often in the lysosomes) or in the nucleus if: (1) the normal, endogenous substance is produced in excess or at an increased rate; (2) a substance (normal or abnormal) is not effectively catabolised, usually because of a lack of a vital lysosomal enzyme; or (3) harmful exogenous materials, such as heavy metals or microorganisms, accumulate because of inhalation, ingestion or infection. Two types of intracellular accumulation are commonly associated with reversible cell injury: • Water swelling. Cellular swelling, the most common degenerative change, is caused by the shift of extracellular water into the cells. In hypoxic injury, movement of fluid and ions into the cell is associated with acute failure of metabolism and loss of ATP production. Normally, the pump that transports sodium ions out of the cell is maintained by the presence of ATP (the sodium–potassium pump). In metabolic failure caused by hypoxia, reduced ATP allows sodium to accumulate in the cell while potassium diffuses outwards. This is not normal, as sodium should be in greater concentrations outside the cell and potassium greater inside the cell. The increased intracellular sodium increases osmotic pressure, drawing more water into the cell. The endoplasmic reticulum becomes distended, ruptures and forms large vacuoles (enclosed compartments) that isolate the water from the cytoplasm. If cellular swelling affects all the cells in an organ, the organ increases in weight and becomes distended (stretched) and pale.
A
• Increased deposition of lipids. Although lipids some times accumulate in heart and kidney cells, the most common site of intracellular lipid accumulation, or fatty change, is liver cells. Because hepatic (liver) metabolism and secretion of lipids are crucial to proper body function, imbalances and deficiencies in these processes lead to major pathological changes. Lipid accumulation in liver cells causes fatty liver or fatty change (see Fig. 4.13). As lipids fill the cells, vacuolation pushes the nucleus and other organelles aside. Lipid accumulation in liver cells occurs after cellular injury. Grossly, the liver looks yellowish and greasy.
Irreversible cell injury
If the stimulus is severe and sustained and the ‘point of no return’ is passed, irreversible cell injury ensues and the cell dies. However, there are two types of irreversible cell injury and their mechanisms are quite different (see Fig. 4.12): • Apoptosis is programmed cell death that causes self-destruction of the cell. • Necrosis is a common form of cellular death with severe cellular swelling and breakdown of the organelles in response to sustained, severe, noxious stimuli. The defining feature between these two forms is that apoptosis is usually a normal cellular function that is not necessarily associated with any form of cellular insult, whereas necrosis always arises in response to pathophysiological processes.
B
FIGURE 4.13
Fatty liver. A Normal liver in the upper abdomen (dashed black line). It has a shiny, smooth appearance and is a deep red colour. B Fatty liver due to accumulation of lipid intracellularly. The liver is pale yellow and smooth (the front or anterior part of the liver has been removed).
CHAPTER 4 Altered cellular function
Apoptosis
Apoptosis (‘dropping off ’) is an important, distinct type of cell death that differs from necrosis in several ways (see Fig. 4.14). Apoptosis is an active process of cellular self-destruction called programmed cell death. Why would cells be programmed to die after a set amount of time? The answer is very simple: cells need to die otherwise endless proliferation would lead to gigantic bodies. In addition, cells become ‘worn out’ and need to be replaced. Every day the average adult may create 10 billion new cells, and kill off the same number.6 A specific set of enzymes and genes are activated to cause apoptosis. These genes are sometimes called suicide genes because their activation by the nucleus inactivates so-called life-sustaining genes and promotes pathways leading to killer genes. Apoptosis affects scattered, single cells; however, there are examples of it occurring in widespread areas. The process
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of apoptosis consists of nuclear and cytoplasmic shrinkage of a cell. This is followed by fragmentation into membrane-bound fragments and subsequent phagocytosis (literally cell eating, as specialised cells (phagocytes) perform this task, and these are discussed in detail in Chapter 12) by neighbouring healthy cells. As a controlled process in normal development, apoptosis determines the size, patterning and function of many tissues.7 Apoptosis occurs throughout the life span, from birth to old age. It can be activated by outside factors — for example, a long-lasting viral infection — or triggered internally by the absence of certain growth factors (these normally stimulate tissues to grow). Accordingly, apoptosis can be classified as physiological or pathological: • Physiological apoptosis is important in the development of body tissue. It is responsible for local deletion of cells during tissue turnover and normal embryonic
A
B NORMAL CELL
Reversible injury
Recovery Condensation of chromatin
Swelling of endoplasmic reticulum and mitochondria
Myelin figure
Progressive injury Myelin figures
Inflammation
NORMAL CELL
Membrane blebs (bulges in the membrane that break off)
Membrane blebs (bulges in the membrane that break off) Breakdown of plasma membrane, organelles and nucleus; leakage of contents
Cellular fragmentation Apoptotic body
NECROSIS Phagocyte
APOPTOSIS
Phagocytosis of apoptotic cells and fragments
FIGURE 4.14
Schematic illustration of the changes in cell injury causing necrosis and apoptosis. A If the cellular injury is reversible, the cell may recover and return to normal. If the injury is irreversible, the cell progresses through to necrosis. B On the other hand, apoptosis is an intentional program to cause cell suicide.
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development. One important example of widespread areas of apoptosis is in the central nervous system during childhood and adolescence. We are born with far more neurons than are required in the adult brain and apoptosis in the early years of life removes the unnecessary neurons. • Pathological apoptosis is the result of intracellular events or adverse external stimuli. For example, deficiencies of specific enzymes can lead to diseases where cells have undergone apoptosis. Liver cells infected with viral hepatitis C, for example, can undergo apoptosis.
Necrosis
Cellular death eventually leads to cellular dissolution or necrosis. Necrosis is the sum of cellular changes after local cell death and the process of cellular self-digestion known as autodigestion, or autolysis (see Fig. 4.14). Cells die long before any necrotic changes are noted by light microscopy.6 The structural signs that indicate irreversible injury and progression to necrosis are dense clumping and progressive disruption of genetic material, and disruption of the cellular and organelle membranes. In later stages of necrosis, most organelles are disrupted and karyolysis (dissolving of the nucleus due to enzymes) is under way. In some cells, the nucleus shrinks and becomes a small, dense mass of genetic material (pyknosis). The pyknotic nucleus eventually dissolves by karyolysis as a result of the action of lysosomal enzymes on DNA. These processes are shown in Fig. 4.15. Different types of necroses tend to occur in different organs or tissues and sometimes can indicate the mechanism or cause of cellular injury. The four major types of necroses are coagulative, liquefactive, caseous and fatty. Another type, gangrenous necrosis, is not a distinctive type of cell death but refers instead to larger areas of tissue death. These necroses are summarised as follows: • Coagulative necrosis. Occurs in almost all tissues (except the brain), and primarily in the kidneys, heart and
Nucleus
Endoplasmic reticulum
Normal cell
Clumping of chromatin
General swelling of cell
Pyknosis
adrenal glands. It commonly results from hypoxia caused by severe ischaemia. Coagulation is caused by protein denaturation (a process that modifies the molecular structure of protein), which causes the protein albumin to change from a gelatinous, transparent state to a firm, opaque state (see Fig. 4.16). • Liquefactive necrosis. Commonly results from ischaemic injury to nerve cells in the brain (see Fig. 4.17), or from microbial infections. Dead brain tissue is readily affected by liquefactive necrosis because brain cells are rich in digestive enzymes and lipids and the brain contains little connective tissue. Cells are digested by their own enzymes, so the tissue becomes soft, liquefies and is walled off from healthy tissue. • Caseous necrosis. Usually results from a lung infection that caused tuberculosis (see Fig. 4.18). It is a combination
FIGURE 4.16
Coagulative necrosis. This picture of a kidney shows a wedge shape of dead cells (yellow).
Dissolution of nuclear structure
Rupture of cell membrane
Karyolysis
FIGURE 4.15
Different stages of necrosis — pyknosis and karyolysis. Pyknosis refers to the process by which the nucleus shrinks, whilst karyolysis occurs when the cell swells and the membrane ruptures.
FIGURE 4.17
Liquefactive necrosis. An area in the brain of necrosis, showing dissolution of the tissue (dashed line). The arrow indicates a blood clot that caused the cell death.
CHAPTER 4 Altered cellular function
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FIGURE 4.19
Fat necrosis. The areas of white chalky deposits throughout the tissue represent fat necrosis with soap formation (saponification) at sites of lipid breakdown.
FIGURE 4.20 FIGURE 4.18
Gangrenous necrosis. Dry gangrene of the toe from severe ischaemia to the lower leg.
Caseous necrosis. Tuberculosis of the lung, with a large area of caseous necrosis containing yellow–white and cheesy debris.
of coagulative and liquefactive necroses. The dead cells disintegrate, but the debris is not completely digested by enzymes. Tissues resemble clumped cheese — hence the name caseous, in that they are soft and granular. • Fat necrosis. Fat necrosis is cellular dissolution caused by powerful enzymes, called lipases, that occur in the pancreas and other abdominal structures (see Fig. 4.19). Lipases break down triglycerides, releasing
free fatty acids, which then combine with calcium, magnesium and sodium ions, creating soaps (called saponification). The necrotic tissue appears opaque and chalk-white. • Gangrenous necrosis. Refers to the death of tissue and results from severe hypoxic injury. This commonly occurs because of blockages of arteries, particularly those in the lower leg (see Fig. 4.20). With hypoxia and subsequent bacterial invasion, the tissues can
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undergo necrosis. In dry gangrene the skin becomes very dry and shrinks, resulting in wrinkles, and its colour changes to dark brown or black. Wet gangrene develops when the main white blood cells of the body, neutrophils, invade the site, causing liquefactive necrosis. This usually occurs in internal organs, causing the site to become cold, swollen and black. A foul odour is present, and if systemic symptoms become severe, death can ensue.
FOCU S ON L EA RN IN G
1 Distinguish between reversible and irreversible cell injury. 2 Explain the mechanisms for the most common forms of intracellular accumulations associated with reversible cell injury. 3 Differentiate between necrosis and apoptosis, and explain the different mechanisms. 4 List 4 types of necrosis and the tissues that are likely to be affected in each case.
Ageing and altered cellular function
Genetic and environmental factors Cellular ageing results from wear and tear that causes functional changes and eventual cellular death. Cells may become damaged during replication as a result of factors within the cell, such as DNA and protein mechanisms, or factors outside the cell. Cells may already be programmed at birth or injured during life so as to cause errors in mitosis and in the replication of genetic material, eventually leading to either cellular atrophy or death. Atrophy is common in the testes, ovaries, uterus and breasts of aged individuals, although these organs age differently. One genetic mechanism of ageing is programmed ageing. An example of influence of our genetic
programming on the ageing process is evidenced by the ages at which females may undergo menopause. For example, a daughter whose mother has undergone early menopause is more likely to undergo the same early menopause herself. Regardless of damaging environmental factors, some investigators think that each normal cell may have a finite life span during which it can replicate. This may be in the form of a genetic program that progressively slows or shuts down physiological mechanisms, including mitosis, and so cells are not replaced. Extracellular factors (those outside of the cell) that affect the ageing process include the binding of connective tissue, which makes it stiffer; the increase in free radicals’ effects on cells; the structural alterations of tendons, ligaments, bones and joints; and diseases of the blood vessels, particularly atherosclerosis (see Chapter 23). Many of these issues have been linked to our changes in lifestyle and diet, and the increase of stress in our lives. These issues are summarised in Chapters 33, 34, 35, 36 and 37. Reactive oxygen species, produced during aerobic metabolism, damage tissues during the ageing process. These oxygen products are extremely reactive and can damage nucleic acids, destroy carbohydrates, damage proteins and fatty acids, and kill cells. Oxidant effects on target cells can also cause DNA damage. Progressive and cumulative damage from oxygen radicals may lead to harmful alterations in cellular function because these oxygen-reactive species not only can permanently damage cells but also may lead to cell death. The damage from these radicals is consistent with alterations during ageing. The combination of genetic and environmental factors on ageing is summarised in Fig. 4.21.
AGEING
As detailed in Chapter 3, ageing is a normal physiological process that is both universal and inevitable. However, as individuals age, they are continually exposed to agents that may cause cellular injury in addition to what is considered to be general ‘wear and tear’. Microinsults (little insults) caused by continuous bombardment by ultraviolet light, environmental temperature changes, infectious agents and chemical reactions in the body that can produce substances like free radicals all may alter cellular structure and function. In this context, the distinction between ageing and disease becomes unclear. For example, some degree of atrophy of the brain is considered normal in old age until it proceeds far enough to cause clinically significant disability and is called a disease. Likewise, all human beings have atherosclerosis (gradual thickening and hardening of the arterial walls due to deposition of fats called plaques) and the plaques progress with age, but at what point in this progression is atherosclerosis considered abnormal?
CHAPTER 4 Altered cellular function
DNA repair defects
Accumulation of mutations
ENVIRONMENTAL FACTORS Environmental insults
Genetic abnormalities
Free radical damage
Reduced enzyme activity
Accumulation of damaged cellular proteins and organelles
Abnormal cellular signalling
Reduced ability to produce new cells
CONCEPT MAP
GENETIC FACTORS
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CELLULAR AGEING FIGURE 4.21
Mechanisms involved in ageing. Genetic and environmental factors combine to produce the characteristic features in cellular structure and function associated with ageing.
Death The word somatic refers to the body, so technically we call the death of an individual somatic death. Unlike the changes that follow cellular death in a live body, postmortem changes after somatic death are widespread. Within minutes after death, postmortem changes appear, eliminating any difficulty in determining that death has occurred. The most notable manifestations are complete cessation of breathing and circulation, meaning there is no heartbeat. The surface of the skin usually becomes pale and yellowish. Body temperature falls gradually immediately after death and then more rapidly until, after 24 hours, body temperature equals that of the environment.8 After death caused by certain infective diseases, body temperature may continue to rise for a short time. Postmortem reduction of body temperature is called algor mortis, from the Latin, meaning coolness of death. The pupils become dilated and do not react to light. The face, nose and chin become sharp or peaked-looking as blood and fluids drain away.9 Gravity causes blood to settle in the lowest tissues, which develop a purple
discolouration. Incisions made at this time usually fail to cause bleeding. The skin loses its elasticity and transparency. Within 6 hours after death, acidic compounds accumulate within the muscles because of the breakdown of carbohydrate and depletion of ATP. This interferes with proteins in the muscle that are responsible for muscle contraction, causing muscle stiffening, or rigor mortis. The smaller muscles are usually affected first, particularly the muscles of the jaw. Within 12–14 hours, rigor mortis usually affects the entire body. Rigor mortis gradually diminishes and the body becomes flaccid at 36–62 hours. FOCU S ON L EA RN IN G
1 Differentiate between environmental and genetic factors associated with ageing. 2 Discuss the body composition changes that occur with ageing. 3 Describe anatomical and physiological events that occur following somatic death.
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chapter SUMMARY Causes of cellular injury • Cellular injury may be caused by: a lack of oxygen (hypoxia), free radicals, toxic chemicals, infectious agents, inflammatory and immune responses, genetic factors, insufficient nutrients or physical trauma from many causes. • The initial insult in chemical injury is damage or destruction of the cell membrane. • Injurious physical agents include temperature extremes and changes in atmospheric pressure.
Mechanisms of cellular injury • Biochemical changes that are important to cell injury are: (a) ATP depletion; (b) oxygen and oxygen-derived free radicals; and (c) intracellular calcium and loss of calcium steady state. • The sequence of events leading to cell death is commonly decreased ATP production, failure of active transport mechanisms (the sodium–potassium pump), cellular swelling, detachment of ribosomes from the endoplasmic reticulum, cessation of protein production, mitochondrial swelling as a result of calcium accumulation, vacuolation, leakage of digestive enzymes from lysosomes, autodigestion of intracellular structures, lysis of the cell membrane and death. • The initial insult in hypoxic injury is usually ischaemia (the cessation of blood flow into vessels that supply the cell with oxygen and nutrients). • Free radicals cause cell injury because they have an unpaired electron that makes the molecule unstable. To stabilise itself, the molecule gives up an electron to another molecule or steals one. In so doing it forms injurious chemical bonds with proteins, lipids and carbohydrates — key molecules in membranes and nucleic acids. • The damaging effects of free radicals include: (a) damage to lipids in the cell membrane; (b) alteration of sodium– potassium and sodium–calcium pumps and transport mechanisms; (c) fragmentation of DNA; and (d) damage to mitochondria-releasing calcium into the cytoplasm. • Restoration of oxygen can cause additional injury, called reperfusion injury. • Cell membrane damage can lead to increases in calcium inside the cell, leading to mitochondrial damage, activation of enzymes that are destructive to the cell and further breakdown of the cell membrane and cytoskeleton.
Cellular adaptation • Cellular adaptation is an alteration that enables the cell to maintain a steady state despite adverse conditions.
• Atrophy is a decrease in cellular size caused by ageing, disuse or lack of blood supply, hormonal stimulation or neural stimulation. The amounts of endoplasmic reticulum and mitochondria decrease. • Hypertrophy is an increase in the size of cells caused by increased work demands or hormonal stimulation. The amounts of protein in the cell membrane, endoplasmic reticulum and mitochondria increase. • Hyperplasia is an increase in the number of cells caused by an increased rate of cellular division. Normal hyperplasia is stimulated by hormones or the need to replace lost tissues. • Metaplasia is the reversible replacement of one mature cell type by another less mature cell type. • Dysplasia refers to an abnormal change in the size, shape and organisation of mature tissue cells. Dysplastic changes can lead to the formation of cancerous cells.
Reversible and irreversible cell injury • Cell injury occurs if the cell is unable to maintain homeostasis. Injured cells may recover (reversible injury) or die (irreversible injury). • The reasons why some cells recover and others do not are not well understood. • Reversible cell injury is usually associated with cellular swelling. This occurs when there is an accumulation of excessive water in the cell caused by the failure of transport mechanisms. • Increases in intracellular lipid content are associated with reversible cell injury. • Irreversible cell injury occurs when the ‘point of no return’ is passed and the cell dies. There are two types — apoptosis and necrosis — which are physiologically different. • Apoptosis is a process of selective cellular selfdestruction that occurs in both normal and pathological tissue changes. • Cellular death is manifested as cellular dissolution, or necrosis. Necrosis is the sum of the changes after local cell death and includes the process of autolysis, or cellular self-destruction. • There are four major types of necroses: coagulative, liquefactive, caseous and fat necroses. Different types of necroses occur in different tissues. • Structural signs that indicate irreversible injury and progression to necrosis are dense clumping and disruption of genetic material, and disruption of the cell and organelle membranes. • Gangrenous necrosis, or gangrene, is tissue necrosis caused by hypoxia and the subsequent bacterial invasion.
Ageing and altered cellular function • It is difficult to differentiate the normal physiological changes of ageing from the pathological changes of ageing. • Genetic factors and lifestyle choices can have a significant impact and the rate at which a person ages.
CHAPTER 4 Altered cellular function
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• Manifestations of somatic death include cessation of breathing and circulation, gradual lowering of body temperature, pupil dilation, loss of elasticity and transparency in the skin, muscle stiffening (rigor mortis) and skin discolouration.
Death • Somatic death is death of the entire organism. Postmortem changes are diffuse and occur over several hours to days.
CASE STUDY
ADU LT/A GEING Jonathon, who is 20 years old, and his 71-year-old father, Terry, are discussing ageing. Jonathon has an active lifestyle, including playing sport, but his diet is poor — he frequently eats fast food from take-away restaurants. He has had no major illnesses. Jonathon notices that his dad’s skin contains many wrinkles and is stiff looking, and that he has lost muscle mass from his legs and arms but gained weight around his abdomen. In contrast, Terry, although remaining active, developed colon cancer when he was 67 and has recently been diagnosed with diabetes mellitus. Terry observes that his son’s skin contains few wrinkles, he is taller than him and his energy levels are high.
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Describe some of the environmental and genetic factors that may account for the physical differences between Jonathon and Terry. Discuss whether Terry’s active lifestyle has been of any benefit to his health, given that he now has diabetes mellitus and colon cancer. Was his exercise a waste of time? How can Jonathon have a poor diet, yet have no major illnesses? At what age should Jonathon think about improving his lifestyle to prevent chronic disease? Terry suggests that Jonathon should drink tea because he’s heard that it contains antioxidants. Jonathon thinks his father has strange ideas sometimes. What might be the potential benefit of consuming antioxidants?
CASE STUDY
P AEDIATR IC S Brian is the infant son of Mary (33 years old) and Bruce (31 years old). Both parents have smoked 20 cigarettes per day since the age of 17. Since his birth, Brian has been exposed to second-hand smoke from his mother, and he has developed a persistent cough with thick mucus, in response to the ongoing irritation by the smoke. 1 Describe some of the mechanisms that would be affecting Brian’s respiratory epithelial tissues and how they will cause injury. 2 Describe the early changes that will occur to his respiratory tissues with prolonged exposure to
the cigarette smoke, and why such adaptations occur. 3 If Brian continues to be exposed to second-hand smoke for a period of years, or takes up the smoking habit himself, what advanced changes would you expect to see in his epithelial tissues, and what risks will be associated with these changes? 4 Describe what it means if a tissue sample is taken from Brian’s airways and the tissue shows dysplasia. 5 Is dysplasia considered to be a reversible or irreversible change? Explain your answer.
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REVIEW QUESTIONS 1 Explain the differences between hypoxia, anoxia and ischaemia. 2 Discuss why hypoxia can be so damaging to cells. 3 Describe how ATP depletion occurs and discuss methods to prevent it. 4 Define free radical and explain why free radicals accumulate in large amounts and how they can be destructive to cells. 5 Discuss why long-term hospitalised patients who are immobile may develop atrophy of skeletal muscles.
6 Discuss why dysplasia is not considered a ‘true’ adaptive process. 7 Irreversible cell injury means that the cell dies. Explain how this occurs and what processes can lead to cell death. 8 Explain how apoptosis is involved in regulation of body tissues and contributes to cellular repair. 9 Describe anatomical and physiological changes associated with ageing. 10 Explain how rigor mortis arises.
Key terms adenine, 83 allele, 86 amino acids, 83 anaphase, 82 apoptosis, 83 autosomal, 88 autosomal trait, 89 autosomes, 80 carrier, 89 cell cycle, 81 chromatin, 80 chromosomes, 80 codominance, 87 codons, 84 complementary base pairing, 83 cytokinesis, 81 cytosine, 83 daughter cells, 81 dominant, 87 double helix, 83 gametes, 80 gene expression, 84 genotype, 86 guanine, 83 heterozygous, 87 homozygous, 87 interphase, 81 karyotype, 80 meiosis, 81 metaphase, 82 messenger RNA (mRNA), 84 mitosis, 81 mode of inheritance, 88 monozygotic twins, 86 multiple alleles, 89 mutations, 86 nucleotide, 83 phenotype, 86 polypeptides, 83 prophase, 82 Punnett square, 88 purines, 83 pyrimidines, 83 recessive, 87 replication, 83 ribonucleic acid (RNA), 84 ribosomal RNA (rRNA), 84 ribosome, 84 RNA polymerase, 84 telophase, 82 template, 83 termination sequence, 84 thymine, 83 trait, 86 transcription, 84 transfer RNA (tRNA), 84 translation, 84
CHAPTER
Genes
5
Sarah List
Chapter outline Introduction, 80 The nucleus, 80 Cell proliferation, 81 The cell cycle, 81 Control of cell division, 82 DNA, RNA and proteins: heredity at the molecular level, 83 Chemical composition of DNA, 83 From genes to proteins, 84
Elements of genetics, 85 Genes, alleles and mutations, 85 Phenotype and genotype, 86 Dominance and recessiveness, 87 Inheritance of traits, 88 Autosomal and X-linked inheritance, 89 Codominance and multiple alleles, 89 Newborn screening, 90
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Introduction Look at a family photo. Do you look more like your mother or your father? Do your children have your eyes or your partners? Can you see aspects of your grandmother’s smile in your own? These similarities between family members represent the activity of genes that pass unchanged through multiple generations of a family. But despite the similarities, you are a unique individual. Each of us begins our lives as a single cell, the fertilised egg, which is formed through the fusion of our father’s sperm and our mother’s ovum. This cell and its descendants undergo thousands of cell divisions to produce hundreds of different types of cells, organised into tissues, organs and organ systems. The blueprint of the human body is encoded in the genetic information tucked away in each cell’s nucleus. However, the genetic information in virtually every body cell, whether it is a neuron, an epithelial cell, a hepatocyte or a cardiac muscle cell, is identical. In this chapter, you will learn how this genetic blueprint is used to control events within cells and to generate the raw material for producing new and different cells. You will learn how our parents and grandparents contribute to the range of traits that make each one of us unique and how this information is passed from generation to generation. Later in this text, we will explore how genetic diseases arise and, importantly, how the link between genes and an individual’s environment is related to many diseases and disorders that are prevalent in Australia and New Zealand. FIGURE 5.1
The nucleus The nucleus is a membrane-bound organelle, typically the largest structure within a cell. The nucleus acts as the control centre for the cell. It directs activities of the cell and determines how that cell interacts with other body cells. The genetic information for each cell is contained within the nucleus and within this information are the instructions for constructing approximately 100 000 different proteins. The nucleus is critical for cell growth, repair and proliferation. A cell lacking a nucleus cannot repair itself or divide and will typically be destroyed within 3 to 4 months. For example, erythrocytes (red blood cells) have no nucleus and have a life span of about 120 days before they are removed from circulation. The nuclear membrane is similar in structure to the cell membrane. It is a double-layered membrane studded with nuclear pores which allow the transport of certain proteins and other macromolecules into and out of the nucleus. The nucleus is fluid filled and also contains various ions and electrolytes, enzymes, structural proteins and nucleic acids. The latter component serves as the genetic information for the cell. Two similar nucleic acids, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) play distinct but related roles in the production of proteins. The nuclear DNA is organised as chromosomes (Fig. 5.1). Chromosomes are very long, extremely thin molecules of DNA (deoxyribonucleic
The cell’s genetic information. The genetic information of the cell is stored within the nucleus as DNA. DNA is packaged into chromosomes. Note that histone proteins assist in coiling DNA, forming chromosomes that are found in the nucleus.
acid) and structural histone proteins. Except for gametes (egg and sperm), each human cell contains 46 chromosomes, consisting of 22 paired chromosomes (referred to as autosomes) and two sex chromosomes (X or Y). Throughout most of the cell cycle, chromosomes are arranged as a tangle of DNA and associated proteins referred to as chromatin. However, during one phase of mitosis, chromosomes are arranged as discrete units. This can be visualised as a karyotype (Fig. 5.2). It can be produced by obtaining a blood sample and staining the blood cells during the stages of cell division when individual chromosomes are paired and therefore visible. The chromosomes are arranged in order of size and are numbered sequentially from largest to smallest. Karyotyping is routinely used in antenatal testing, when a significant birth defect is suspected. It can readily detect abnormal chromosome numbers, for example, Down syndrome (also known as trisomy 21) or significant chromosomal rearrangements, such as the so-called ‘Philadelphia translocation’ which is associated with leukaemia.
CHAPTER 5 Genes
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19
20
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15
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12
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X
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FIGURE 5.2
Karyotype of a normal human male. There are 22 paired chromosomes, numbered from 1–22, and two sex chromosomes, X and Y. Note that chromosomes 1, 2 and 3 are the largest, and 21 and 22 are the smallest.
FO CUS O N L E A R N IN G
1 Discuss the role of the nucleus. 2 Explain the differences between DNA and chromosomes.
Cell proliferation Every cell in the body originates from the fertilised egg. This cell and its descendants then undergo thousands of rounds of ordered cell division to generate the approximately 50 to 100 trillion cells that make up the adult human body. Cells divide even after maturity as a means of continued growth and to replenish damaged cells. Generally a cell divides to produce two new daughter cells. Before cell division, cellular components multiply, the genetic information in the nucleus is copied and the cytoplasm expands. When cell division takes place, these components are distributed to each daughter cell. These events occur in a predictable rhythm known as the cell cycle. Some cells live only for a short period of time; for instance, many epithelial cells are constantly being replaced because they are exposed to a wide variety of damaging agents. However, in most tissues, new cells are created as fast as old cells die. Cellular reproduction is therefore necessary for the maintenance of life. There are two types of cell division used in the body. Cell division to produce the gametes (sperm and egg cells)
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occurs through a process called meiosis. In this form of cell division, there are gamete progenitors which undergo two rounds of cell division. In the first round, the chromosomes are copied and two diploid cells, which have two copies of each chromosome pair, are generated. In the second round, cell division occurs without the chromosomes being copied. The product of this division is four haploid gametes, each of which only has one of each chromosome pair. This type of division is critical in sexual reproduction. If gametes were not haploid, our number of chromosomes would double every generation. Meiosis and sexual reproduction are discussed in more detail in Chapter 31. The reproduction, or division, of other body cells (somatic cells) involves two sequential steps: mitosis, or nuclear division; and cytokinesis, or cytoplasmic division. Somatic cells spend most of their lives in interphase, in which cells perform their normal functions and prepare for cell division. When a cell is prepared for division, it enters the cell cycle.
The cell cycle
The cell cycle is divided into four discrete phases (Fig. 5.3): 1 First gap phase (G1) 2 Synthesis phase (S) 3 Second gap phase (G2) 4 Mitosis. The cell cycle begins immediately after a cell division has been completed. G1, S and G2 make up interphase, the longest phase of the cell cycle. Another gap phase (G0) is often used to describe cells that are not preparing for cell division, but performing all their normal functions. Some cell types, including skeletal muscle cells and many neurons, never leave G0 and never undergo cell division. Other cells that divide almost continuously, such as many epithelial cells and some types of stem cells, never enter G0. A cell that is ready to divide enters G1. During this phase the cell makes enough mitochondria, other organelles and cytoplasm for two cells. G1 is typically the longest phase of the cell cycle and may last for months in cells that divide slowly. In cells that divide continuously, G1 lasts for approximately 8–12 hours. During the S phase, synthesis or replication of DNA and associated structural proteins takes place. DNA replication will be discussed in more detail below. S phase is completed in 6–8 hours. Once DNA replication has been completed, there is a brief G2 phase in which enzymes that control cell division are produced and mitochondria are replicated so that they can be shared between the new daughter cells. This phase takes between 2–5 hours, after which the cell has completed interphase and is ready to enter mitosis. Mitosis is the phase in which the cell nucleus is duplicated and it takes less than an hour to complete (Fig. 5.4). At the beginning of mitosis, the chromosomes are a tangled mass of DNA and histone proteins in the nucleus known as chromatin. Mitosis is subdivided into four phases:
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FIGURE 5.3
The cell cycle. The figure shows the cell cycle phases (G0, G1, G2, S and M) and the G1/S, G2/M and M cell cycle checkpoints. Skin cells cycle continuously but liver cells spend much of their time in G0 and nerve cells rarely (if ever) enter the cell cycle.
prophase, the chromatin condenses, or untangles and separates into compact X-shaped chromosomes. The nuclear membrane breaks down. Very thin fibres attach to the centromere, a region of each chromosome, pulling them towards the midline of the cell. 2 In metaphase, the centromeres line up along the midline of the cell, so that all the chromosomes are arranged side by side. The chromosomes are stretched out and often clearly visible at this stage (using a microscope). 3 In anaphase, each pair of chromosomes separates and moves towards opposite ends of the cell. By the end of this stage, half of the original chromosomes has moved to each end of the cell. 4 During telophase, a nucleus begins to reform on each side of the cell, and the chromosomes return to the random coil structure of chromatin. To generate two separate cells cytokinesis occurs. This involves the pinching of the cell membrane directly between the two nuclei to generate a cleavage furrow that gradually becomes deeper until the cell eventually undergoes cleavage, whereby it splits into two daughter cells. Now the original cell has been copied and divided into two identical cells, each with the same genetic information as seen in the original cell. 1 In
Control of cell division
Cell division is a tightly regulated process to ensure that the cells which are produced do not have defects. In extreme cases cells that have suffered extreme damage to their DNA
divide and proliferate, and this can lead to cancer. The timing and rate of cell division in different parts of the body are critical for normal growth, development and maintenance. Different types of cells have different patterns of division: skin cells divide frequently to replace the outer layer of cells that are constantly being removed, whereas liver cells do not divide unless it becomes necessary to repair damaged tissue. Nerve cells and muscle cells do not divide at all in adult humans. All types of cells undergo mitosis during formation of the embryo, but this ability to undergo cell division becomes gradually lost in some cell types in the progression from embryo to adulthood. An internal clock that responds to internal and environmental signals that either push the cell towards division or prevent it from dividing regulates the control of cell division. An example within the body is the hormone erythropoietin, which stimulates the production of red blood cells through cell division. If the level of erythropoietin is increased, the number of red blood cells that are produced is also increased. In this way, the process of cell division can be influenced or stimulated by substances external to the cell. Once the cell enters G1 there are several critical checkpoints at which progression of the cell cycle can be halted. For the cycle to continue past these points, signals must be present which override the halt on the cycle. Most of these signals come from systems that check that the state of the cell is appropriate to continue. The first of these, the G1/S checkpoint, is a point of no return. The onset of the S phase commits the cell to continue through the cell cycle
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FOCU S ON L EA RN IN G
1 Briefly describe the benefits of meiosis. 2 Outline the main process that occurs during each stage of the cell cycle. 3 Discuss the control of cell division, including what happens if abnormalities are detected.
DNA, RNA and proteins: heredity at the molecular level Chemical composition of DNA
FIGURE 5.4
Mitosis. During mitosis, the DNA is replicated and chromosomes condense, eventually leading to the formation of two genetically identical daughter cells.
to divide, regardless of external conditions such as nutrient supply. This does not mean that the cell is out of control. The precise sequence of events required for successful division seems to depend on the completion of each task before the cell can progress to the next stage. If the G1/S checkpoint is not overcome, the cell will return to G0. A second G2/M checkpoint ensures that the chromosomes have been replicated and are intact before allowing the cycle to proceed to mitosis. A final M phase checkpoint determines whether the chromosomes have been properly distributed before cell cleavage occurs. Failure of these checkpoints to halt the cell cycle is associated with cancer. In a normal cell, abnormalities that are detected at the checkpoints are either repaired or the cell cycle is halted and the cell undergoes apoptosis, a form of programmed cell death. Cancerous cells, which typically have a number of genetic and other abnormalities, are able to overcome these checkpoints, meaning these abnormal cells survive and divide. Drugs such as chemotherapeutic agents that control the cell cycle have the potential to control the progression and/or spread of tumour cells, and are discussed further in Chapter 37.
DNA has three basic components: deoxyribose, a five-carbon monosaccharide; a phosphate molecule; and four types of nitrogenous bases. Two of the bases, cytosine and thymine, are single carbon-nitrogen rings called pyrimidines. The other two bases, adenine and guanine, are double carbon-nitrogen rings called purines. The four bases are commonly represented by their first letters: A, C, T and G. In the cell, DNA exists as double helix, in which DNA appears like a twisted ladder with chemical bonds as its rungs (Fig. 5.5). The two sides of the ladder consist of the sugar and phosphate molecules. Projecting from each side of the ladder, at regular intervals, are the nitrogenous bases. The base projecting from one side is bound to the base projecting from the other by a weak hydrogen bond. Therefore the nitrogenous bases form the rungs of the ladder; adenine pairs with thymine, and guanine pairs with cytosine. Each DNA subunit — consisting of one deoxyribose molecule, one phosphate group, and one base — is called a nucleotide. DNA acts as the blueprint for all the body’s proteins. Proteins are composed of one or more polypeptides (intermediate protein compounds), which in turn consist of sequences of amino acids. The body contains 20 different types of amino acids; they are specified by the four nitrogenous bases. To specify (code for) 20 different amino acids with only 4 bases, different combinations of bases, occurring in groups of 3, are used. This genetic code is universal: all living organisms use precisely the same DNA codes to specify proteins. Copying or replication of DNA, which occurs in the S phase of the cell cycle, consists of breaking the weak hydrogen bonds between the bases, leaving a single strand with each base unpaired. The consistent pairing of adenine with thymine and of guanine with cytosine, known as complementary base pairing, is the key to accurate replication. The unpaired base attracts a free nucleotide only if the nucleotide has the proper complementary base. When replication is complete, a new double-stranded molecule identical to the original is formed (Fig. 5.6). The single strand is said to be a template, or molecule on which
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Sugar Sugar Phosphate Cytosine
Guanine
Adenine
Thymine
Hydrogen bonds
FIGURE 5.5
The structure of DNA. The DNA structure, which shows that each side of the DNA molecule consists of alternating sugar and phosphate groups. Each sugar group is united to the sugar group opposite it by a pair of nitrogenous bases (adenine-thymine or cytosine-guanine). The sequence of these pairs constitutes a genetic code that determines the structure and function of a cell.
a complementary molecule is built, and is the basis for producing the new double strand.
From genes to proteins
Genes are small, discrete sections of chromosomal DNA arrayed along the length of the chromosome in single file, without overlap. Spaces between genes also have important regulatory roles; for example, they may determine whether a given gene is active or silent in a particular cell. This means that, although every cell has a complete set of genetic instructions, each cell reads only those instructions that are relevant to the activities of that individual cell. Most genes code for a specific protein, whose actions determine particular characteristics. We refer to the process by which a gene directs the production of a protein as gene expression. Genes acts as blueprints for the construction of proteins in much the same way as we use letters to construct words that we organise into sentences. As discussed earlier, DNA is made up of four different bases (A, G, C and T). These bases (letters) are arranged in different three-letter words, known as codons, each of which corresponds to a particular
amino acid. Different combinations of amino acids make different proteins (sentences). As genes can be very long, containing thousands of bases, the number of different combinations is vast. Changing a base, or the order of bases, can change an amino acid, or the order of amino acids, and therefore make a protein with a different function. Again, we are familiar with this from simple language, such as: • First sentence contains particular information: The cat ate the rat. • Changing a letter (base) changes the meaning: The cat ate the mat. • Changing the order also changes the meaning: The rat ate the cat. DNA is housed in the cell nucleus, but protein production (synthesis) takes place in the cytoplasm. The information encoded in the DNA needs to be accurately transmitted from the nucleus to the cytoplasm in order for production of proteins to occur correctly (Fig. 5.7). There are two steps involved in the transmission of this message: transcription, the copying of DNA into a message that can leave the nucleus; and translation, the conversion of the nucleic acid code into the amino acid code. These processes are mediated by ribonucleic acid (RNA), which is chemically similar to DNA except that the sugar molecule is ribose rather than deoxyribose, RNA usually occurs as a single-stranded rather than a double stranded molecule, and uracil replaces thymine as one of the four bases. Uracil is structurally similar to thymine, so it also can pair with adenine. Transcription is the copying of the DNA template into a message that can leave the nucleus, which is an RNA molecule known as messenger RNA (mRNA) by RNA polymerase. The sequence of bases in the mRNA is complementary to the template DNA strand, and except for the presence of uracil instead of thymine, the mRNA sequence is identical to the other DNA strand. Transcription continues until a termination sequence, codons that act as signals for the termination of the protein production, is reached. Then the RNA polymerase detaches from the DNA, and the transcribed mRNA is freed to move out of the nucleus and into the cytoplasm (Fig. 5.8). In translation, the nucleic acid code is converted into an amino acid code: RNA directs the production of a polypeptide (Fig. 5.9), interacting with transfer RNA (tRNA), a cloverleaf-shaped strand of about 80 nucleotides. The tRNA molecule has a site where an amino acid attaches. The three-nucleotide sequence at the opposite side of the cloverleaf is called the anticodon. It undergoes complementary base pairing with an appropriate codon in the mRNA, which specifies the sequence of amino acids through tRNA. The site of actual production of proteins is in the ribosome, which consists of approximately equal parts of protein and ribosomal RNA (rRNA). During translation, the ribosome first binds to an initiation site on the mRNA sequence and then binds to its surface, so that base pairing can occur between tRNA and mRNA. The ribosome then moves along the mRNA sequence, processing each codon
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DNA polymerase T
A T
C
G C
C
A
A
DNA nucleotides
G
A
A
C
T
C
G T
C G
C A
C G
T
G
C
G
C
G G
C
A
T
A
C
C
Supercoiled DNA
T
G
A
T
New DNA strands forming Old DNA strand
A
C
Cytosine
A
Adenine
G
Guanine
T
Thymine
FIGURE 5.6
DNA replication. The two chains of the double helix separate, and each chain serves as the template for a new complementary chain.
and translating an amino acid by way of the interaction of mRNA and tRNA. The ribosome provides an enzyme that catalyses the formation of covalent peptide bonds between the adjacent amino acids, resulting in a growing polypeptide. When the ribosome arrives at a termination signal on the mRNA sequence, translation and polypeptide formation cease; the mRNA, ribosome, and polypeptide separate from one another; and the polypeptide is released into the cytoplasm to perform its required function. Once the polypeptide strand is formed, this new protein undergoes a number of changes before it is functional. For example, the polypeptide has to be folded in particular ways (similar to origami), needs to be transported to the appropriate part of the cell or out of the cell, and it may need to bind other proteins or factors. FOCU S ON L EA RN IN G
1 Discuss the composition of DNA. 2 Describe how genes are converted into proteins, including transcription and translation.
FIGURE 5.7
General overview of protein synthesis (production of proteins). DNA in the nucleus is transcribed into mRNA, which moves through the nuclear envelope before it is translated into protein.
Elements of genetics Genes, alleles and mutations
As discussed above, a gene is a discrete stretch of DNA on a chromosome that usually codes for a particular protein.
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DNA double helix
mRNA strand
C
G
C
G
C
G
A
T
A
C
G
C
A
A
T
A
A
T C
C T
U
A
C
C
G
T
U
A
G
G
C
C
C
RNA nucleotide
T A
Phenotype and genotype
G A
U
RNA polymerase
T
A A
T
U G
C
G
C
G
C A
T C
G T C G
A G C
to DNA (such as breaking the strand), by adding or removing bases or by altering the chemical structure of the bases. The effects of mutations are unpredictable and highly variable. Some have no effect at all, some may have beneficial effects and others have pathological or even lethal consequences. Because DNA damage has potentially severe outcomes, the nucleus contains proofreading systems that continually check and, if necessary, repair the DNA base sequence. Although these repair systems are very efficient, if the damage is extensive mutations may escape detection and repair. For example, prolonged exposure to the UV radiation in sunlight damages some bases; this can result in skin cancer. Australia has one of the highest incidences of skin cancer in the world: two-thirds of Australians will have been diagnosed with skin cancer by the time they reach 70 years of age.1
C A G U T
Cytosine Adenine Guanine Uracil Thymine
FIGURE 5.8
A closer look at ribonucleic acid (RNA) transcription. The template DNA strand is copied into messenger RNA (mRNA) in the nucleus. The primary enzyme involved in transcription is RNA polymerase.
An allele is an alternative form of a gene. Because cells contain paired chromosomes, every cell contains two alleles for each gene, one whose origin is paternal and one whose origin is maternal. A cell may contain two identical alleles, or two different alleles. Alternative alleles for a particular gene sometimes direct production of slightly different proteins. These differences can produce alternative forms of a trait or characteristic, such as straight, wavy or curly hair. In genes that are associated with disease, the alternative allele may produce nonfunctional or harmful proteins, leading to a genetic disease (Chapter 38). Changes in the DNA base sequence are known as mutations. Mutations can be caused by physical damage
The genotype is the genetic composition of an individual, represented by the alleles that the individual possesses. The combination of alleles that each individual possesses results in that person being genetically unique. This is important to understand, because it provides reasons why we are all different despite being human. The combination also determines much about how we will turn out as individuals for traits such as height, musical ability and susceptibility to disease. Recent research has revealed more about how genes can influence the likelihood of our developing particular diseases and, in the future, increased understanding of the genetic processes in diseases may even lead the way to improved treatment options (genetic diseases are discussed in Chapter 38). The genotype is fixed at conception and remains largely constant throughout life though mutations that we acquire over the course of our lives may lead to changes in some cells or tissues. The phenotype comprises the characteristics and physical features displayed by the individual, which may change throughout life and may be affected by environment. For example, weight may be affected by diet, skin colour is affected by sun exposure, and diseases such as asthma and cancer may develop if an individual is exposed to particular environmental factors. This means that, while the phenotype is determined by the genotype, the genotype cannot be accurately predicted from the phenotype. The relationships between genetic information from chromosomes, through to genotype and phenotype, are shown in Fig. 5.10. A good example of the effect of environment on phenotype is monozygotic, or identical, twins. Monozygotic twins arise from the union of one ovum and one sperm — one fertilised egg divides in the very early stages to develop into two embryos. Thus, identical twins have the same combination of alleles. They therefore have the same genotype. However, as identical twins age, they are rarely phenotypically identical. They often develop subtle differences in appearance and typically have different personalities. Thus, lifestyle and environmental influences prevent them from having identical phenotypes.
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87
FIGURE 5.9
A closer look at protein translation. Note that each set of three nucleotides specifies one particular amino acid. ALA = alanine, CYS=cysteine, SER= serine, TYR = tyrosine, VA = valine.
Dominance and recessiveness
If an individual receives two identical copies of an allele, one from each parent, they are described as being homozygous for that particular allele (homo meaning same). If an individual receives a different allele from each parent, they are said to be heterozygous for the allele (hetero meaning different). In many genes, the effects of one allele mask those of the second when the two are found together in a heterozygote. The allele whose effects are observable is said to be dominant. The allele whose effects are hidden is said to be recessive (from the Latin for ‘hiding’). Traditionally, for loci having two alleles, the dominant allele is denoted by an uppercase letter and the recessive allele is denoted by a lowercase letter. When one allele is dominant over another, the heterozygote genotype A/a has the same phenotype as the dominant homozygote AA. For the recessive allele to be expressed, it must exist in the homozygote form, a/a. When the heterozygote is distinguishable from both homozygotes, the locus is said to exhibit codominance. A simple example of how dominance and recessiveness and homozygosity and heterozygosity work in human
genetics is freckles. The presence of freckles is determined by a dominant allele (F) of a gene that codes for a protein that is important in the pattern of melanin production in the skin. The recessive f allele leads to an even distribution of melanin, or no freckles. A person who is homozygous for F (F/F) will have freckles. A person who is homozygous for f (f/f) will not have freckles. Finally a heterozygous individual (F/f) will have freckles because the dominant F allele will mask the expression of the recessive f allele. Although there is an effect of sun exposure in the appearance of more freckles, the underlying alleles for this trait determine the genetic role.
FOCU S ON L EA RN IN G
1 Define genes, alleles, traits and mutations. 2 Define the terms genotype and phenotype. 3 Compare homozygous with heterozygous. 4 Compare dominant with recessive.
Part 1 Essential concepts of pathophysiology
Chromosomes contain long molecules of
contain thousands of
Alleles combinations represent Genotype
DNA transcription mRNA translation
may produce different forms of
determines
Protein
Father (homozygous f/f ) structure and activity represents
Trait (Phenotype)
FIGURE 5.10
Chromosomes, DNA and genes from the code that results in the production of proteins. Combinations of genetic factors result in the genotype, or genetic makeup of the person. The unique combinations of proteins are a main contributor to this individual’s phenotype, the actual expression of individual characteristics.
Inheritance of traits The pattern by which a particular trait is inherited through generations is termed the mode of inheritance. Knowing the mode of inheritance of a trait of a genetic disease can reveal much about the gene itself. Most traits can be classified into four major modes of inheritance: autosomal dominant, autosomal recessive, X-linked recessive and co- or incompletely dominant. The inheritance of traits can be predicted by determining whether a trait is dominant or recessive, whether the gene responsible for that trait lies on one of the 22 autosomes or the X or Y chromosome, and the phenotype and genotype of parents. The Punnett square is a simple tool that can be used to predict the inheritance of particular traits based on parental phenotypes and genotypes. We can use the example of freckles to demonstrate the utility of the Punnett square. As discussed above, the dominant F allele leads to freckles, whereas the recessive f allele results in no freckles. The F gene is an autosomal gene, meaning that it is found on one of the 22 autosomes. Therefore, the inheritance of freckles is an example of autosomal dominant/recessive inheritance. A young couple
Mother (homozygous F/F)
alternative forms are
genes are short stretches of DNA
f
f
F F
Now, we fill in the squares taking one paternal gamete from the top and one from the side until we have four potential children’s genotypes. Father (homozygous f/f ) Mother (homozygous F/F)
Genes
is contemplating having children. The woman has freckles; the man does not. This couple would like to know the probability of their children having freckles. The first step in predicting the inheritance of freckles is to draw a two by two square. We next need to predict the genotype of each parent. The man has no freckles; as this state is recessive, we can say with confidence that his genotype is f/f. The woman is expressing the dominant trait, which means that we know she has at least one F allele. For the sake of simplicity, we will assume she is homozygous F/F. Then, write the parental genotypes on the top and sides of the square, one allele of the pair above or beside each square. This reflects each potential gamete that can be generated by each parent.
f
f
F
F/f
F/f
F
F/f
F/f
In this case, any child of these parents would be heterozygous F/f and freckled. Now, if we repeat the steps above, but assume that the woman is heterozygous herself, how does that change the probability of having a freckled child? Father (homozygous f/f ) Mother (heterozygous (F/f)
CONCEPT MAP
88
f
f
F
F/f
F/f
f
f/f
f/f
In this case, any child that this couple has will have a 50% chance of being F/f and freckled or f/f and unfreckled. The Punnett square can also be used to predict parental genotypes based on the children’s phenotype. Again using freckles as an example, the same couple from above has two children — one freckled (F/f) and one without freckles (f/f). We know that the father does not have freckles, and thus his genotype is f/f. We know that the mother is freckled, so her genotype is F/?. By using the Punnett squares above, we can state with certainty that the ? in this case is f, in other words she is heterozygous. If she were homozygous, it is not possible for her to bear a child without freckles.
CHAPTER 5 Genes
Autosomal and X-linked inheritance
Mother (XCB/Xcb)
Father (XCB/Y)
XCB
Y
XCB Xcb
Then, pair one allele from each parent to determine the possible genotypes of any children.
Father (XCB/Y) Mother (XCB/Xcb)
The presence or absence of freckles is one example of an autosomal trait, a trait that is caused by a gene found on one of the 22 autosomes. About 23 000 of the 25 000 genes in the human genome are carried on one of the autosomes. Each individual, regardless of gender, has two copies of each of these genes in most of the body cells. Approximately 2000 genes are carried on the X chromosome. Recall that the X chromosome is different from the autosomes in that women carry two copies of the X chromosome whereas men carry only one. The Y chromosome, present only in men, carries only a few genes, most of which are important in sex determination. Due to this gender imbalance, inheritance of genes on the X chromosome is different from inheritance of genes on autosomes. As an example, we can look at the inheritance of red–green colour blindness. This form of colour blindness, in which people have difficulty distinguishing red from green, is caused by a recessive mutation of a gene on the X chromosome that codes for a component of one of the photoreceptors in the eye. About 1 in 10 men have some form of colour blindness. There are very few women who are colour blind. This demonstrates an important point about X-linked inheritance — there is a gender bias in traits that are X linked. This is because men carry only one X chromosome. Therefore, recessive traits on the X are unmasked in men that lack a balancing dominant allele. A man with normal colour vision and a woman with normal colour vision, but whose father was colour blind, are planning to have children. Can we determine the likelihood that they will have colour-blind children? First, let’s define our terms: let XCB represent the allele for normal colour vision, Xcb represent the allele for colour blindness and Y represent the Y chromosome. The man with normal colour vision’s genotype would be XCB/Y. He has a single X chromosome, and therefore must have the normal allele. The woman’s case is a bit more complicated. We know that she has normal colour vision, so has at least one copy of XCB. We know that her father was colour blind, so that his genotype had to be Xcb/Y. As females inherit one X chromosome from their mother and one from their father, she has inherited the colour blindness allele from her father. Therefore, her genotype must be XCB/Xcb. Now, to determine the likelihood that children of this marriage will be colour blind, we use a Punnett square as above. First, write the father’s alleles along the top and the mother’s along the side:
89
XCB
Y
XCB
XCB/XCB
XCB/Y
Xcb
XCB/Xcb
Xcb/Y
There are two important things to notice. First, there is a 50% chance of having a male child (XY) and a 50% chance of having a female child (XX). Of the female (XX) children, none would be colour blind. However, there is a 50% chance that a female child would be a heterozygous carrier of the colour blindness allele like her mother. If the child were male, there would be a 50% chance that he would be colour blind. Overall, there would be a 25% (50% × 50%) of having a colour-blind child.
Codominance and multiple alleles
There are a number of traits that exhibit more complex inheritance patterns. In some situations, two forms of an allele each produce a slightly different protein. When an individual is heterozygous, they express both forms of the allele, which is referred to as codominance. A common example of codominance is the A/B/O blood groups. There are four blood groups and these have been designated the letters A, B, AB and O. They differ according to the presence or absence of antigenic sugar molecules on the surface of red blood cells (see Chapter 16). When a patient requires a blood transfusion, a sample of their blood is tested to determine the particular blood group, because incompatible blood administered to a patient can cause life-threatening immune reactions (see Chapter 15). Compared to determining sex in offspring, determining blood groups is more complicated. The ABO blood groups are determined by three alleles on chromosome 9, designated IA, IB and iO. These alleles direct the production of enzymes that are responsible for the production of surface antigens on red blood cells. Allele IA results in the production of the A antigen (a protein on the surface of the cell that identifies the cell; see Chapter 12); allele IB results in the production of the B antigen; and allele iO does not cause antigen production. Thus, there are multiple alleles involved in determination of blood group. IA and IB are each dominant to iO, but are codominant to one another. In other words, for an individual to have type A blood, they are either homozygous for IA (IA/IA) or heterozygous (IA/iO). Similarly, for an individual to have type B blood, they are either homozygous for IB (IB/IB) or heterozygous (IB/iO). The codominant state, IA/IB, leads to type AB blood. The only way that an individual will have type O blood is to be homozygous for the recessive state (iO/iO, Table 5.1). Punnett squares can also be used to predict the blood groups of offspring. Consider the case of a father with type AB blood and a mother with type O blood; their respective genotypes are IA/IB and iO/iO, respectively. The Punnett square below shows that their children are equally likely to have type A blood (IA/iO) or type B blood (IB/iO). Interestingly,
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Part 1 Essential concepts of pathophysiology
none of the children will have the same blood group as either parent (type O or type AB). Mother, type O (iO/iO)
Father, type AB (IA/IB)
IA
IB
iO
IA/iO
IB/iO
iO
IA/iO
IB/iO
Now consider the case of a father with type O blood and a mother with type A blood. Can we state, with certainty, the likely blood groups of their offspring? In this case, we know the genotype of the father (iO/iO) but we are not certain of the genotype of the mother (she could be IA/IA or IA/iO; refer to Table 5.1). If you construct Punnett squares, you will see that the blood groups of their children can be either A or O. If the mother has genotype IA/IA, all offspring will have type A blood. However, if she has genotype IA/iO, her offspring are equally likely to have type A or type O blood.
allele in a population. The frequency of the ABO blood groups varies between populations (see Table 5.2) because the distribution of Ia, Ib and io alleles in different ethnic groups is variable. In general, the homozygous recessive group O is common and the codominant group AB is rare. Group O (49%) and Group A (38%) are common in Australia; in fact type A is quite common in Indigenous Australian populations.2 Group B is more common among individuals of Asian descent (such as the Cantonese from China, or Malaysian people) than among individuals of European descent.3
FOCU S ON L EA RN IN G
1 Discuss how a Punnett square is used and use examples to describe inheritance of freckles, colour blindness, and blood groups. 2 Compare autosomal inheritance with X-linked inheritance.
Mother, type A (IA/?)
Father, type O (iO/iO)
iO
iO
IA
IA/iO
IA/iO
?
?/iO
?/iO
Newborn screening
The case with ABO blood groups illustrates an important point. The dominant allele is not always the predominant
TABLE 5.1 Relationships between ABO blood groups alleles, red blood cell antigens and blood groups ALLELES o o
i /i
SURFACE ANTIGEN
BLOOD GROUP
nil
O
a a
a o
A
A
b b
b o
B
B
A and B
AB
I /I or I /i
I /I or I /i a b
I /I
Note that individuals with Ia/Ia or Ia/io genotypes have the same phenotype (blood group A); similarly, both Ib/Ib or Ib/io genotypes produce the blood group B phenotype.
Around the time of pregnancy and childbirth, parents and healthcare professionals become increasingly interested in the genetic possibilities for the offspring. This is perhaps the one time when the theory on genetics just discussed seems particularly relevant for most people in our community. Each unique combination of ovum and sperm can result in genetic possibilities that may actually be detrimental for the offspring. Even newborns that appear healthy may have inherited a genetic defect that, if left untreated, can become life threatening. For some genetic conditions, early detection allows the condition to be managed more effectively. Blood testing of newborn babies for treatable disorders was introduced in Australia and New Zealand in the late 1960s.4 National newborn screening in Australia is performed by laboratories in the different states. Initially this testing was aimed to identify PKU (phenylketonuria), a disease that can cause severe and irreversible mental retardation in untreated children. However, with early identification of affected children brain damage can be easily averted.
TABLE 5.2 The relative frequency of ABO blood groups in selected populations POPULATION GROUP
Blood group (%)
AUSTRALIAN
AUSTRALIAN ABORIGINAL
CANTONESE
ENGLISH
GREEK
MALAYSIAN
A
38
61
23
42
42
18
B
10
0
25
9
14
20
AB
3
0
6
3
5
0
O
49
39
46
47
40
62
Percentages may not total 100%, due to rounding.
Dr Robert Guthrie developed a test for PKU that requires a very small amount of blood, usually obtained by pricking the baby’s heel, and spotting the blood onto a specially prepared absorbent card (often known as a Guthrie card) that is sent to the laboratory for testing. This allows for isolation of DNA from nucleated blood cells and analysis of the gene that, when mutated, causes PKU.5 In recent years the Guthrie test has been expanded into the Newborn Screening Test to test for more than 30 inherited disorders, including sickle-cell anaemia, galactosaemia, and congenital hypothyroidism among others.6 All the disorders tested in newborn genetic screening programs cause severe, often life-threatening disease and can be treated by dietary management or medication. A single heel-prick blood sample, ideally obtained 48–72 hours after birth, is used to provide three blood spots on a specially prepared card; lab results are available within 24 hours. Positive results are followed up by more detailed testing to confirm the diagnosis. While each of the individual disorders is very rare, the importance of screening is highlighted by data from the South Australian Newborn Screening Centre, which indicate that one in every 800 babies screened has one of these
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91
treatable disorders.7 This study also investigated the efficiency of screening programs in South Australia and found that only 98% of newborn babies are screened — meaning that, on average, one baby with a treatable disorder will escape early detection programs in South Australia each year. If we assume that similar screening rates apply Australia-wide, this equates to seven affected babies per year. Nationally, only one in every 1000 babies is actually diagnosed with a condition through this testing process.8 This particular study from South Australia also found that babies less likely to be screened include those born at home, those born to an Aboriginal mother and those born to a mother from interstate. Special strategies may be needed to improve screening efficiency within these groups. It is also important that babies who die in utero or soon after birth are screened to detect inherited disorders, so that strategies can be put into place to ensure a better outcome in subsequent pregnancies. FOCU S ON L EA RN IN G
1 Discuss the purpose of newborn screening programs.
chapter SUMMARY The nucleus • Chromosomes contain long thin molecules of DNA and store genetic information in the cell nucleus.
Cell proliferation • Cellular reproduction in body tissues involves mitosis (nuclear division) and cytokinesis (cytoplasmic division). • Only mature cells are capable of division. Maturation occurs during a stage of cellular life called interphase (the growth phase). • The cell cycle is the reproductive process that begins after interphase in all tissues with cellular turnover. There are four phases of the cell cycle: G1 phase, S phase, G2 phase and M phase. • The M phase (mitosis) involves both nuclear (mitotic) and cytoplasmic (cytokinetic) division. The four nuclear stages are prophase, metaphase, anaphase and telophase. • There are three checkpoints involved in controlling cell division: G1/S, G2/M and a checkpoint during M. A checkpoint arrest leads to apoptosis (programmed cell death) of the cell. Failure of the cell cycle to be arrested at checkpoints may result in abnormalities, including cancer.
DNA, RNA and proteins: heredity at the molecular level • DNA is made up of four nitrogenous bases; the sequence of bases forms the genetic code. • DNA is transcribed in the nucleus to mRNA, which is then translated in the cytoplasm to protein. • Genetic information is organised as a series of genes positioned at specific loci on the DNA molecule. • Alternative forms of genes, known as alleles, have slightly different DNA sequences. • Genes serve as the blueprint for the production of specific proteins. • DNA is transcribed in the nucleus to mRNA, which is then translated in the cytoplasm to protein.
Elements of genetics • A specific gene sequence encodes a particular protein. • Alternative forms of genes, known as alleles, have slightly different DNA sequences. • The genotype represents the combination of alleles possessed by an individual. • An individual’s phenotype reflects interaction between the genotype and the environment. Continued
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• A cell may contain two identical alleles at a particular locus, rendering the individual homozygous. • If the alleles are different at a genetic locus, the individual is heterozygous. • Many genes have alternative alleles that can be described as dominant or recessive. If a single copy of an allele enables its effect to be seen, the allele is dominant; if two copies of the allele are required for its effect to be seen, the allele is recessive.
• An individual’s phenotype (appearance) reflects interactions between the genotype and the environment. • Different patterns of inheritance occur depending on whether a gene is found on one of the 22 autosomes (non-sex chromosomes) or on the X or Y chromosome. • Some alleles do not have true dominance but instead are codominant, for example blood groups. Some traits are governed by multiple alleles of the same gene.
Inheritance of traits
Newborn screening
• A cell may contain two identical alleles or two different alleles at a particular genetic locus; an individual is described as homozygous or heterozygous at that locus. • The genotype represents the combination of alleles possessed by an individual.
• Newborn babies are routinely screened to detect a panel of genetic disorders for which early intervention can prevent or ameliorate symptoms.
CASE STUDY
A DULT/PA ED IA T R IC S Two days ago, Miriam, who is 32 years old, gave birth to her first child, Beth, at home. The pregnancy was carefully planned and Miriam took great care to ensure a healthy pregnancy. Her diet was well balanced and she minimised use of potential toxins (e.g. strong cleaners) in her home. She stopped work quite early in her pregnancy (24 weeks gestation) because she believes that a calm, happy mother is essential for a calm, happy baby. However, she maintained a moderate exercise program (walking and swimming) and is quite fit. The birth was uncomplicated and Beth is contented. The midwife has requested Miriam’s permission to perform a heel-prick test to collect a blood sample from Beth for genetic screening. Miriam is reluctant to agree to this testing, as she believes that
it will upset her baby and is not necessary, given that she did ‘all the right things’ throughout her pregnancy. 1 Discuss how a blood test can be used to determine whether a baby has a genetic condition. 2 Define the terms genes, chromosomes and DNA. 3 Explain why genetic screening is performed soon after birth. What types of disorders might be included in this screening process? 4 Would Miriam’s behaviour during pregnancy affect the likelihood that Beth would have a genetic disorder? 5 What advice would you give Miriam? Would you change that advice if this were Miriam’s fourth child and none of her other children had tested positive for a genetic disorder?
CASE STUDY
A DULT/PA ED IA T R IC S Questions of paternity can often be resolved quite simply by determining the blood type of the child in question and the potential parents. As ABO blood type is genetically determined, it is possible to rule out paternity. Zoe, a 19-yearold woman, has recently given birth to a healthy daughter. Zoe is unsure of the paternity of her child. During the time she has determined that she became pregnant, she was with two men — Robert and Benjamin. Now that the child has been born, she wishes to know which of the men is the likely father.
Zoe has type A blood and the child type O blood. Robert is type AB, while Ben is type B. 1 Discuss how ABO blood groups are determined genetically. 2 Define the terms allele, dominance and codominance. 3 Can either of the men be ruled out as the father? Why or why not? 4 If either man cannot be ruled out as the father does this mean that he is definitely the father of the child?
CHAPTER 5 Genes
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REVIEW QUESTIONS 1 Describe the chromosomes that you would expect to find in a skin cell collected from a human male. 2 Briefly describe the steps involved in cell division (the cell cycle). 3 Explain the structure of a DNA molecule. 4 Outline how chromosomes are packed into the nucleus. 5 Discuss how alternative alleles produce different genetic outcomes. 6 Will two individuals with the same phenotype have the same genotype? Explain. 7 A normal man and his normal wife have three children. Each child is an albino. What is the most likely genetic explanation for the children’s albinism? Assume that one of the three children marries a normal carrier for albinism. What percentage of this couple’s offspring would be expected to be albino?
8 A young couple, neither of whom has the disease in question, is devastated when they learn that their newborn daughter has cystic fibrosis (an autosomal recessive disorder). You are one of the registered nurses who is helping to explain that parents who do not have cystic fibrosis can still have a child who has the disease. How would you explain this in terms which they can understand? What is the likelihood that any subsequent children will have the disease? 9 Tina has blood group A. Her mother also had blood group A, while her father had blood group O. Can you state Tina’s genotype? 10 Tina marries Louis, who has blood group AB. They plan to have four children. Can you predict the most likely blood groups of these four children? (Hint: a Punnett square will be useful.)
Key terms afferent pathways, 98 arachnoid layer, 119 autonomic nervous system, 98 axon, 99 basal nuclei, 108 basilar artery, 122 blood–brain barrier, 120 brainstem, 112 central nervous system, 98 cerebellum, 114 cerebral cortex, 109 cerebral hemispheres, 108 cerebrospinal fluid (CSF), 120 chemoreceptors, 134 choroid, 134 circle of Willis, 122 commissural fibre, 111 corpus callosum, 111 cranial nerves, 124 decussate, 109 dendrites, 99 depolarisation, 104 diencephalon, 111 dura mater, 117 effector organs, 98 efferent pathways, 98 eustachian tube, 136 external auditory canal, 135 fontanels, 140 frontal lobe, 110 ganglion, 108 grey matter, 108 hyperpolarisation, 105 hypothalamus, 111 internal carotid arteries, 121 maculae, 136 mechanoreceptors, 134 medulla oblongata, 113 meninges, 117 midbrain, 112 myelin, 99 neuroglia, 101 neurotransmitters, 105 non-rapid eye movement (NREM) sleep, 113 nuclei, 108 occipital lobe, 110 oval window, 136 parasympathetic nervous system, 128 parietal lobe, 110 peripheral nervous system, 98 pia mater, 119 pinna, 136 pons, 112 posterior cerebral arteries, 122 postganglionic neurons, 127 postsynaptic neurons, 105 prefrontal cortex, 110 preganglionic neurons, 127 premotor cortex, 110 presynaptic neurons, 105 primary motor cortex, 110 proprioceptors, 134 pruritus, 139
CHAPTER
The structure and function of the neurological system
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Amy Nicole Burne Johnston Chapter outline Introduction, 98 Organisation of the nervous system, 98 Cells of the nervous system, 98 Neurons, 98 Neuroglia, 101 Nerve injury and regeneration, 101 The nerve impulse, 102 Membrane potentials, 104 Action potential, 104 Synapses, 105 Neurotransmitters, 106 Myelin, 106 The central nervous system, 108 The brain, 108 The spinal cord, 114 Protective structures of the central nervous system, 117 Blood supply of the central nervous system, 120
The peripheral nervous system, 124 The autonomic nervous system, 127 Anatomy of the sympathetic nervous system, 127 Anatomy of the parasympathetic nervous system, 128 Neurotransmitters and receptors, 128 Physiology of the autonomic nervous system, 132 Sensory function, 133 Somatosensory function, 134 Vision, 134 Hearing, 135 Olfaction and taste, 137 Alterations of sensory function, 138 Ageing and the nervous system, 141
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Key terms continued rapid eye movement (REM) sleep, 113 reflex arcs, 115 repolarisation, 105 resting membrane potential, 103 reticular activating system, 113 retina, 134 saltatory conduction, 106 Schwann cells, 101 sclera, 134 somatic nervous system, 98 spinal cord, 114 sympathetic nervous system, 127 synapse, 103 synaptic cleft, 105 temporal lobe, 110 thalamus, 111 thermoreceptors, 100 tympanic cavity, 136 tympanic membrane, 136 vertebral arteries, 122 white matter, 108
Introduction The human nervous system is a remarkable structure, responsible for the body’s ability to interact with the environment and for monitoring and controlling activities of the internal organs. The nervous system regulates, coordinates and drives the other systems of the body. It oversees the functions of the body, while constantly receiving and processing input to assess performance across every body structure and function within the context of a changing external environment. There is a constant flow of information towards the central nervous system that is processed in the spinal cord and brain and then, if required, is acted on to bring about a change in function. The nervous system achieves this remarkable feat through a network of complex structures that transmit signals — both electrically and chemically — between the body’s many organs and tissues and the brain and spinal cord. In Chapter 2 we considered that homeostasis can often be maintained locally if only small changes occur; however, changes detected by the nervous system enable regulation and homeostatic maintenance of the body in the face of larger changes.
Organisation of the nervous system The nervous system functions as a unified whole; however, it can be divided according to structure and function. It is a complex system and so division into its component parts often makes it easier to understand. Structurally, the nervous system is divided into the central nervous system (CNS) and the peripheral nervous system
(see Fig. 6.1). The central nervous system (commonly abbreviated to CNS) consists of the brain and spinal cord, enclosed within the protective skull or cranium (cranial vault) and vertebrae, respectively. The peripheral nervous system (abbreviated to PNS) is composed of all the cranial and spinal nerves, the nervous tissues that move out of or into the CNS from the rest of the body. The central nervous system receives afferent information from sensory neurons, and sends information in an efferent or outward direction using motor neurons (see Fig. 6.2). So the peripheral nerve pathways are differentiated into afferent pathways (ascending pathways), which carry sensory impulses inwards or towards the central nervous system, and efferent pathways (descending pathways), which innervate skeletal muscle or effector organs, and transmit motor impulses outwards or away from the central nervous system. Functionally, the peripheral nervous system can be divided into the somatic nervous system and the autonomic nervous system. The somatic nervous system (somatic meaning body) consists of pathways that regulate voluntary motor control (namely, skeletal muscle). The autonomic nervous system (autonomic meaning automatic or involuntary) is primarily involved with regulation of the body’s internal environment typically through involuntary control of organ systems. For instance, heart rate is primarily controlled by the autonomic nervous system as we cannot usually consciously control our heart rate. In contrast, breathing is controlled by both the autonomic and somatic nervous systems. We can consciously change our breathing, such as taking deep breaths when trying to relax, but at most other times the regulation of breathing is entirely under the influence of the autonomic nervous system so we don’t have to remember to think about breathing. The autonomic nervous system is further divided into the sympathetic and parasympathetic divisions. Organs innervated by specific components of the nervous system are called effector organs as they ‘effect’ the changes required to maintain physiological homeostasis.
Cells of the nervous system Two basic classes of cells constitute true nervous tissue: neurons and neuroglia (supporting cells). The neuron is the primary cell of the nervous system, whereas neuroglial cells such as astrocytes (in the central nervous system) and Schwann cells (in the peripheral nervous system) provide structural support and nutrition for the neurons.1 The complex role of neuroglia in maintaining CNS homeostasis is an increasingly active area of research in light of the recognition of abnormality of neuroglia, rather than neurons, in many neurological conditions.
Neurons
Neurons, also referred to as nerve cells, are the functional units of the nervous system. They are complex structures that may be anatomically very different, yet have a common function — to transmit nerve (electrical) impulses. They
CHAPTER 6 The structure and function of the neurological system
information into central nervous system
CONCEPT MAP
Central nervous system (brain and spinal cord) information out of central nervous system
Peripheral nervous system (cranial and spinal nerves) information inwards
information outwards
Sensory or afferent signals (sensory receptors)
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Motor or efferent signals (motor neurons) signals to
signals to
Autonomic nervous system (to smooth muscle, glands and internal organs)
Somatic nervous system (to skeletal muscles)
signals to Sympathetic nervous system (fight or flight)
signals to Parasympathetic nervous system (rest and digest)
FIGURE 6.1
Functional divisions of the nervous system. The central nervous system is composed of the brain and spinal cord. All other nerves belong to the peripheral nervous system. The divisions of the peripheral nervous system are divided into sensory and motor, with further divisions in the motor neurons.
can send nerve impulses individually or work in units. Neurons and their associated receptors detect environmental and internal body changes and initiate body responses to maintain homeostasis.
The structure of neurons
A neuron has three basic components: a cell body (soma) and two sets of thin processes extending from the cell; the ‘signal receiving’ processes, the dendrites; and the ‘signal transmitting’ process, the axon (see Fig. 6.3). The cell body includes the nucleus, cytoplasm and other normal organelles of a cell. Neurofibrils are collections of neurofilaments within the cell that extend away from the cell body to assist with carrying substances produced in the cell body along the cell projections towards the axon and the dendrites. The dendrites are branching extensions that receive signals and carry them towards the cell body. Axons are long projections from the cell body that conduct nerve impulses away from the cell towards the next neurons in the nervous pathway. When a signal reaches a dendrite, it typically travels through it, to the cell body and is then transmitted along the axon so that it can reach another neuron or another cell. In this way nerve impulses
can be sent along nerve pathways to various parts of the body. Neurons can be classified according to the number of dendrites that branch from the cell body. Some neurons have only one dendrite, which is typical of sensory neurons in the cranial and spinal nerves. Others have two dendrites. The most common type of neurons is the multipolar neuron, which has multiple dendrites and one axon, typical of motor neurons (nerves that innervate a muscle). The single axon of a typical neuron may be covered with a segmented multi-layered wrapping of fatty cell membrane called myelin, an insulating substance. It typically wraps the axon in sections along its length. This entire membranous wrapping is referred to as the myelin sheath (see Fig. 6.3). The myelin sheaths are interrupted at regular intervals by the nodes of Ranvier. Axons can branch extensively at the nodes of Ranvier. Myelin is an extremely important component of the nervous system as it increases the conduction speed of neural impulses and helps to prevent ‘short circuiting’ in the nervous system, ensuring the ability of neurons to send signals to one discrete area is not impeded or disrupted. We examine the function of myelin later in the chapter when discussing the nerve impulse.
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A Central nervous system
Dendrites
Cell body
AFFERENTS sensory pathways
EFFERENTS motor pathways
Nucleus Red arrows = direction of signal Axon Myelin sheath Node of Ranvier
Body (All other organ systems)
FIGURE 6.2
Axon terminal
Peripheral nerve pathways. The central nervous system receives afferent or inward information from sensory neurons in all body systems, and sends information in an efferent or outward direction back to the systems using motor neurons. These motor neurons regulate all of the body’s functions.
The function of neurons
Functionally, there are three types of neurons: (1) sensory neurons, which send afferent information towards the central nervous system; (2) interneurons, which sit between sensory and motor neurons and appear to integrate information before initiating an efferent signal; and (3) motor neurons, which transmit efferent signals outwards from the central nervous system. • Sensory neurons and their receptors transduce (translate) physical and chemical signals into electrical signals (action potentials) and then carry impulses from the peripheral sensory receptors into the central nervous system. There are a range of different sensory neurons, each being capable of sensing (transducing) a different type of stimulus (see Table 6.1). For example, ther moreceptors located throughout the skin monitor temperature, while a chemoreceptor in the mouth (taste bud) can detect a particular chemical such as acid or sour. Other chemoreceptors located in the walls of blood vessels can sense the amount of oxygen in the blood. Some body regions have more sensory neurons than others; for example, the fingertips and lips have more sensory receptors and associated neurons than the legs and arms. Nerve impulses are continually being sent to the central nervous system with information about the external environment and, equally importantly,
B
FIGURE 6.3
The general structure of a neuron. A A neuron consists of dendrites (receive signals), a cell body (or soma) and an axon (send signals). B A photomicrograph of a neuron.
CHAPTER 6 The structure and function of the neurological system
TABLE 6.1 Types of sensory neurons TYPE OF SENSORY RECEPTOR
LOCATION
DETECTS
Thermoreceptor
Skin
Temperature (e.g. cool, hot)
Nociceptor
Skin, viscera, muscle
Pain (damage)
Mechanoreceptor
Skin, viscera, muscle, ear
Touch, pressure, stretch, vibration (hearing)
Chemoreceptor
Blood vessels, brain, mouth, nose
Chemicals (e.g. acid, sour), taste, smell
Proprioceptor
Muscle
Body positioning
Photoreceptors
Eye
Light (vision)
the condition of the internal environment. The central nervous system controls bodily functions in response to this constant supply of sensory information. • Interneurons transmit impulses from neuron to neuron — that is, they assist in the transmission between sensory and motor neurons. They are located solely within the central nervous system and provide the billions of connections between neurons in the brain. They often connect neural signals between sensory neurons enabling sensory information from multiple systems to be integrated and coordinated. • Motor neurons transmit impulses away from the central nervous system to an effector (i.e. skeletal muscle or organ). In skeletal muscle, the innervation of the muscle by the neuron forms the neuromuscular junction. The function of the neuromuscular junction is discussed in Chapter 20.
Neuroglia
Neuroglia (from the Greek glia meaning glue — so the neuroglia were thought to be a ‘nerve glue’) are the cells that support neurons of the central nervous system. They comprise approximately half of the total brain and spinal cord volume, and are many times more numerous than neurons. There are five different types of neuroglia that are responsible for many different functions in the central and peripheral nervous system. They assist the neurons, by helping to maintain an optimal working environment; otherwise body functions may be affected. Within the central nervous system there are typically four types of neuroglia: • Astrocytes have a star-like appearance (hence the name astro) and fill the spaces between the neurons, as well as filling the spaces left by dead neurons. They scaffold and physically support the many dendritic and axonal projections from neurons. They also surround blood vessels to provide them with structural support and to assist with supplying nutrients to the neurons.
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• Oligodendrocytes deposit myelin around the neuronal axons to electrically insulate the neurons within the central nervous system and speed electrical transmission. • Microglia assist the immune system to protect brain tissues using phagocytosis to engulf cell debris such as dead and dying cells (see Chapter 12 for details of phagocytosis). • Ependymal cells line the cerebrospinal fluid-filled cavities and are involved in the production of cerebrospinal fluid, which circulates around the brain and spinal cord (see the later discussion on protective structures of the central nervous system). They can have filaments that project into the fluid-filled ventricle cavities and contract, ‘beating’ or helping to circulate cerebrospinal fluid through the central nervous system. In the peripheral nervous system, the Schwann cells undertake myelination of axons, performing similar functions to those of oligodendrocytes in the central nervous system. The appearance and characteristics of the neuroglia are shown in Fig. 6.4 and Table 6.2. These cells are clinically important as they are most commonly the basis of brain tumours (see Chapter 9).
A
B
C
D
FIGURE 6.4
Types of neuroglial cells. A Astrocyte. B Oligondendrocytes. C Microglia. D Ependymal cells.
Nerve injury and regeneration Mature neurons do not divide to form new cells or regenerate, like most other body cells. As a result, injury to nervous tissue can cause permanent loss of that tissue and often loss of the function that tissue performed. This is very important for clinical practice as patients who have nerve tissue damage, such as occurs with a stroke, will lose the ability to perform some function/s due to death of the neurons that supply that part of the body. If neurons in the central nervous system are damaged, there will typically be no regeneration or cell repair. The regeneration of axonal constituents in the central nervous
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TABLE 6.2 Neuroglial cells of the nervous system CELL TYPE
PRIMARY FUNCTION
Central nervous system Astrocytes
• Believed to form an essential component of the blood–brain barrier
Neuron cell body Axon Schwann cells
• Form specialised contacts between neuronal surfaces and blood vessels
Cut
• Provide rapid transport for nutrients and metabolites • Appear to be the scar-forming cells of the central nervous system, which may be the foci for seizures • Appear to work with neurons in processing information and memory storage Ependymal cells
• Serve as a lining for ventricles and choroid plexuses involved in the production of cerebrospinal fluid
Microglia
• Responsible for clearing cellular debris (phagocytic properties)
Oligodendrocytes
• Formation of myelin sheath in central nervous system
Peripheral nervous system Schwann cells
• Formation of myelin sheath in peripheral nervous system
system is limited by an increased incidence of scar formation and the different nature of myelin formed by the oligodendrocytes. These actively inhibit the development of new axonal projections from central nervous system cells. However, neurons in the peripheral nervous system do have the ability to repair, although this depends on a number of factors (see Fig. 6.5). When an axon is severed in the peripheral nervous system, degeneration occurs in the distal part of the axon: (1) a characteristic swelling appears within the portion of the axon distal to the cut; (2) the neurofilaments hypertrophy (cell size increases); (3) the myelin sheath shrinks and disintegrates; and (4) the distal axon degenerates and disappears. The myelin sheaths reform into entire Schwann cells that line up in a column between the axonal cut and the effector organ. At the proximal end of the injured axon (towards its cell body), similar changes occur but only back to the next node of Ranvier. During the repair process, the cell increases its metabolic activity, production of protein (protein synthesis) and mitochondrial activity. Approximately 7–14 days after the injury, new terminal sprouts project from the proximal axonal segment and may enter the remaining Schwann cell ‘pathway’. Fig. 6.5 contains a more detailed representation of these events. This process is typically limited to myelinated fibres. Nerve regeneration depends on many factors, such as the location of the injury, the type and severity of injury,
Muscle cell
FIGURE 6.5
Repair of a peripheral nerve fibre. When cut, a damaged motor axon can regrow to its distal connection only if the Schwann cells remain intact (to form a guiding tunnel) and if scar tissue does not block its way.
the inflammatory responses and the development of scarring. The closer the injury to the cell body of the nerve cell, the greater the chance that the nerve cell will die and so will not regenerate. In the peripheral nervous system, a crushing injury allows recovery more fully than does a cut injury. Crushed nerve cells sometimes recover fully, whereas cut nerves can form connective tissue scars that block or slow regenerating axonal branches. FOCU S ON L EA RN IN G
1 Outline the broad divisions of the nervous system. 2 Define the terms afferent and efferent. 3 Describe the general structure of the neuron. Explain the different functions of sensory and motor neurons. 4 Briefly describe the different types of neuroglia. 5 Discuss what happens to the neuron following injury.
The nerve impulse Neurons typically release chemicals to generate and conduct electrical impulses to facilitate communication. Electrical impulses are transmitted through nerves cells by moving electrolytes, predominately sodium and potassium, through the nerve cell membrane. The change in the concentration of these electrolytes inside compared to outside the neuron causes a change in electrical charge across the cell membrane,
CHAPTER 6 The structure and function of the neurological system
and this permits the propagation of an electrical impulse. An unexcited neuron, a nerve cell in its resting state, maintains a resting membrane potential. The contribution of ions to neuronal cell resting membrane potential is shown diagrammatically in Fig. 6.6. In this state the inside of the
FIGURE 6.6
Normal concentration gradient of sodium, potassium and calcium ions between the intracellular fluid of a neuron at rest and the surrounding extracellular fluid. These differences in ion concentrations between inside and outside of the cell produce changes in membrane voltage, which can be measured using a voltmeter.
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cell contains fewer positively charged ions than are found in the extracellular fluid surrounding the cell, so that there is a charge split across the cell membrane. When the neuron is stimulated, the permeability of the cell membrane to ions is altered so that they can move into and out of the cell, and thus the potential is altered and a nerve impulse, or more correctly an action potential, is generated. This is shown diagrammatically in Fig. 6.7B. This ion movement into neurons occurs over all parts of the neuron in a systematic ‘wave’ as shown with red arrows in Fig. 6.3A. The action potential response occurs only when the initial stimulus is strong enough; if it is too weak, the membrane remains unexcited. This property is termed the all-or-none response, as all action potentials of the neuron are of the same size and so they either happen or they don’t. The ions that move across the cell membrane are typically sodium, potassium and calcium ions, hence their importance to overall physiological wellbeing. In this section, we also consider how a neuron is able to communicate with another cell using synaptic transmission, whereby the nerve signal travels from one neuron, across a small space separating neurons known as a synapse, to the next neuron in the nerve pathway and initiates a response in the next cell. This process of neuron-to-neuron communication is shown diagrammatically in Fig. 6.7 and summarised in Fig. 6.8.
FIGURE 6.7
The action potential. A Opening and closing of sodium and potassium ion channels occurs throughout the action potential. B Changes in membrane potential with the action potential. Stages: 1 Rest — resting membrane potential; a few potassium channels open. 2 Depolarisation — sodium channels open; sodium enters the cell. 3 Repolarisation — potassium channels open; potassium exits the cell (sodium channels are shut). 4 Return to resting membrane position.
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are often supplemented in acute and critical care nursing. If the concentration of sodium, potassium or calcium in the body is altered, it can be detrimental to the function of neurons and so induce life-threatening situations for the patient. The different ion concentrations across the cell membrane (inside compared to outside a cell), ensure that there is a difference in electrical potential across the cell membrane. This is referred to as the membrane potential and it can be measured in millivolts (mV) as shown in Fig. 6.6. It can also change as ions move into and out of nerve cells.
Resting membrane potential
FIGURE 6.8
The synapse. 1 The action potential arrives at the axon terminal. 2 Rather than sodium entry, calcium channels open and calcium enters the axon. 3 The increase in calcium causes the synaptic vesicles to move to the presynaptic membrane. 4 The neurotransmitter is released using exocytosis. 5 The neurotransmitter diffuses across the synapse and binds with receptors on the postsynaptic neuron.
As you read through the details of these processes, you may be wondering why this information is so important for someone working with patients in the healthcare system. Having a good understanding of how neurons communicate using action potentials and synaptic transmission will assist you in clinical practice as it will allow you to: • understand why it is so critical that sodium and potassium are kept at normal levels • understand how many drugs work to modify nerve transmission • appreciate why drugs might have side effects that interact with nerve transmission — a mistake here may be fatal for the patient, so you should be able to think critically about the potential effects of drugs, based on your knowledge of normal neuron function.
Membrane potentials
When a neuron is at rest (unexcited or not signalling), there are differences between the intracellular and extracellular concentrations of ions (or electrolytes), such that there is a concentration gradient of ions across the cell membrane. Important ions involved in neuronal function are sodium (Na+), potassium (K+) and calcium (Ca2+). The positive charge associated with each of these ions is relevant to how the neurons work, because the movement of each ion means that there is a change in the amount of positive charge in the area. Knowing how these ions contribute to the function of the neuron will give you valuable insight as to why these ions are monitored closely in patients and
In a neuron at rest, ions cannot easily pass through the cell wall membrane. However, using proteins embedded in the cell membrane, sodium ions are actively concentrated in the extracellular fluid, and potassium ions are actively pumped into the intracellular fluid (see Fig. 6.6). When the neuron is resting, a few of the potassium channels in the cell membrane are actually open, which allows small amounts of potassium to diffuse down the potassium concentration gradient and ‘leak out’ or exit the cell. The pump that forces sodium out of the cell and potassium into the cell does so unevenly; two positively charged potassium ions are pushed into the cell cytoplasm in exchange for each of the three positively charged sodium ions forced out of the cell. This pump, known as the sodium–potassium ATPase pump, creates a charge imbalance across the cell membrane which, together with the large strongly negatively charged proteins present in the cell cytoplasm results in a relatively negative charge inside the neuron compared to outside the neuron. Recording the electrical potential across a cell membrane typically results in a negative number; the average value at rest is approximately –70 millivolts (mV; see Fig. 6.7A, stage 1).
Action potential
Neurons are excitable and their resting membrane potential changes in response to stimuli. For example, thermoreceptors in your hand that detect cold will be stimulated when you grasp a cold drink from the fridge. This stimulus is translated into an electrical signal that is transmitted to the central nervous system. The ‘translation’ process (cold stimulus to action potential), known as transduction, involves the generation of an action potential in that sensory neuron. To do this the stimulus causes sodium ion channels in the neuron cell membrane to open. As there is a higher concentration of sodium in the extracellular fluid than in the intracellular fluid, sodium diffuses down its concentration gradient and enters the cell. This entry of sodium into the cell is supported by the attraction the net negative charge inside the cell exerts on the positively charged sodium ions (opposites attract). As more and more positively charged sodium ions enter the neuron the inside of the cell becomes relatively more positive, so that the membrane potential moves from –70 mV towards zero. This is referred to as depolarisation. The membrane potential
CHAPTER 6 The structure and function of the neurological system
actually continues upwards to about +30 mV (see Fig. 6.7A, stage 2). When the membrane potential reaches approximately +30 mV, sodium channels close, so that further sodium entry is prohibited. At the same time, potassium channels also embedded in the neuronal cell membrane open and thus potassium moves down its concentration gradient and exits the cell. Exiting of these positively charged potassium ions is further supported by the relatively positively charged environment now found inside the neuron (like charges repel). Positively-charged potassium ions exit the cell causing the inside of the cell to become less and less positive, so that the membrane potential returns to its starting point of about –70 millivolts. This is known as repolarisation (see Fig. 6.7A, stage 3). The impetus to drive potassium out of the cell is so great that there is often an overshoot, so that the inside of the neuron can become even more negative than at its original resting level (see Fig. 6.7B). This overshoot is known as hyperpolarisation and is usually transient. When the action potential is completed and repolarisation has occurred, the sodium–potassium ATPase pump located in the cell membrane returns the membrane to the resting potential by pumping potassium back into the cell and sodium out of the cell. This restores the normal concentration and electrical gradients present across the cell membrane at rest (see Fig. 6.7A, stage 4). Again, in each cycle of the pump, three molecules of sodium are pumped out of the cell cytoplasm for every two potassium ions returned into the cell. The sodium–potassium ATPase pump requires the use of energy, in the form of ATP, in order that molecules can be transported against their concentration gradients (see Chapter 3 for details). During the action potential, there are two different refractory periods during which the neuron cannot respond to a stimulus in the same way that it could when it was resting: • The absolute refractory period occurs during sodium entry phase (depolarisation). When a neuron is in this stage it is completely unable to respond to another stimulus. Remember that the neuron responded to the initial stimulus by opening the sodium channels, which led to changes in the membrane potential; the neuron is incapable of responding again during the absolute refractory period as the sodium channels are already open. • The relative refractory period occurs after the sodium channels are shut (commencement of repolarisation) and during the latter part of the action potential. During this time it is possible, although more difficult, to restimulate the neuron. The refractory periods are important because they allow the neuron to be ready for the next action potential. They also govern the total number of action potentials a neuron can transmit in a period of time. This limitation is particularly important in places like the heart, where over-stimulation of the cardiac muscle by too many action potentials too fast could cause abnormal heart muscle contraction
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(abnormal rhythms such as atrial or ventricular fibrillation), poor cardiac emptying, decreased circulation and thus, a life-threatening situation. It is clear that this mechanism will only allow an action potential to occur or not occur. Either a cell will depolarise and the potential will reach +30 mV, or it will not. It is not possible to have a small action potential or a large one. The nervous system uses the number (frequency) of action potentials to encode the size of a stimulus. The frequency is directly regulated by the absolute and relative refractory period of each neuron.
Synapses
Neurons do not physically actually touch one another. There is a very small space between the end of one neuron and the beginning of the next neuron in a neuronal chain. The region between adjacent neurons is called a synapse (see Fig. 6.8). These synapses are crucial to the ability of the nervous system to communicate not only within itself, but also with effector organs. Synapses enable information to be spread simultaneously to many different areas of the brain, which aids in the rapid regulation of bodily processes. In addition, they also direct the conversion of electrical signals into chemical signals. Electrical impulses are transmitted across synapses by chemical messengers. The neurons that conduct a nerve impulse across each gap or synapse are named according to whether they relay the impulse towards the synapse; the presynaptic neurons, or away from the synapse; the postsynaptic neurons. The synapse is usually formed by the axon of the presynaptic neuron and the dendrite of the postsynaptic neuron so that the signal can travel in one direction only across the synapse (anterograde transmission). The synaptic cleft, the space or gap between the two neuronal terminals, contains extracellular fluid. Signals are transmitted across the synapse by the release of chemicals usually stored inside small vesicles in the axon terminal. These chemicals are known as neurotransmitters. An action potential originates in a presynaptic neuron, is transmitted along that neuron, travelling down its axon to the presynaptic axonal terminal. As the impulse reaches the axon terminal, rather than opening sodium ion channels and allowing sodium to move into the neuron, the voltage changes here cause calcium ion channels to open (see Fig. 6.8). Calcium moves from the higher concentration outside the cell to lower concentration regions inside the cell and so enters the axon terminal. The entry of calcium into the axon terminal causes vesicles filled with a chemical (neurotransmitter) to move to the cell membrane and, by fusing with the cell membrane at the presynaptic terminal, to release their neurotransmitter by exocytosis into the synaptic cleft (refer to Chapter 3). Once released from the vesicles, the neurotransmitter from the presynaptic neuron diffuses across the synaptic cleft and binds to receptor sites on the cell membrane of the postsynaptic neuron.2 The steps involved in neuron communication are summarised in Table 6.3.
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TABLE 6.3 Signalling functions of neurons STAGE
WHAT THE NEURON IS DOING
WHAT PROCESSES ARE INVOLVED
Rest Resting membrane At rest, not potential signalling
A few potassium ion channels are open
Signalling Action potential
Receiving a signal at the dendrite and then sending it out through the axon
Opening and of the sodium and potassium ion channels
Synaptic transmission
Sending a signal from the axon across the synapse to another cell
Opening of the calcium ion channels; neurotransmitter released by exocytosis
Neurotransmitters
When a neurotransmitter interacts with the receptor, the interaction is referred to as binding. The binding of a neurotransmitter at the receptor site is highly specific — in other words, a neurotransmitter can bind only to the specific receptor for that neurotransmitter. This is often referred to as the ‘lock-and-key’ characteristic of neurotransmitter– receptor interaction; just as only the correct key can open each lock, only the correct neurotransmitter can bind to each specific class of receptor. When the neurotransmitter binds with the receptor, it opens ion channels embedded in the cell membrane, just as the correct key in a lock can enable the opening of a door. These ion channels enable ions such as sodium, potassium or chloride to move into and out of the cell down their electrical and chemical gradients. Such ion movement alters ion concentration gradients and electrical gradients across the cell membrane, altering the charge split across the membrane wall and resulting in a change in that neuron’s membrane potential so that it is no longer at rest. Two possible scenarios may result: 1 the postsynaptic neuron may become excited increasing the chances of an action potential being generated in it; or 2 the postsynaptic neuron may be inhibited, decreasing the chances of an action potential being generated in it. The resulting scenario depends on binding of the neurotransmitter to receptors on the membrane of the postsynaptic neuron and the class of neurotransmitter released. Neurotransmitters that are associated with opening of positive ion channels allow positive ions into the cell and thus ‘excite’ the postsynaptic membrane. These neurotransmitters are called excitatory neurotransmitters. Alternatively, binding of other neurotransmitters onto
receptors on the postsynaptic neuron opens ion channels that allow negatively charged ions to enter the neuron, increasing the charge spilt across the membrane and making it more negative inside the neuron compared to outside the neuron. This makes it harder to ‘fire’ the neuron, delaying or stopping the propagation of the action potential, thereby inhibiting the nerve transmission. Neurotransmitters that inhibit the action potential are known as inhibitory neurotransmitters. A range of substances are neurotransmitters (see Table 6.4), with acetylcholine, adrenaline and noradrenaline being particularly important for the central nervous system, as well as having some specific roles in the peripheral nervous system (see the section on the autonomic nervous system later in the chapter). Other neurotransmitters with important roles within the central nervous system include dopamine, serotonin, gamma (γ)-aminobutyric acid (GABA), glutamate, glycine, aspartate, encephalins, endorphins and substance P. Many of these transmitters have more than one function and can be functionally either excitatory or inhibitory, depending on the receptor site where the neurotransmitter binds.3 For example, noradrenaline (referred to as norepinephrine in the USA) in the brain probably helps regulate mood, functions in dreaming sleep and maintains arousal. It is worth remembering that a substance is classified as a neurotransmitter if it meets a series of criteria including that it is stored in synaptic vesicles and released by a neuron. The same substance may also be considered a hormone when it is released into the bloodstream. Irrespective of its origin it can still bind to receptors and activate neurons.
Myelin
The speed of nerve transmission is greatly influenced by myelin. Where there is a myelin sheath (insulating wrapping) around a neuron, the velocity (speed) of nerve impulses increases. This occurs because myelin acts as an insulator that allows ions to flow between segments of the neuron rather than along the entire length of the neuronal membrane. In this way, an action potential ‘jumps’ between the gaps in myelin, called nodes of Ranvier, increasing the velocity (speed of movement) of the potential along the neuron. This mechanism is referred to as saltatory conduction. For instance, if you place your foot on a sharp object, detection of the stimulus is very rapid and you will quickly move your foot away. In an adult, the nerve transmission has to travel approximately 1 metre from the foot to the central nervous system and back 1 metre again for the nerve impulses to activate the muscles to move your foot. The total distance travelled is about 2 metres and this occurs in seconds due to the presence of myelin around the nerves. In fact, the speed of nerve transmission in myelinated neurons can be up to 50 times faster than in nerves without myelin. The speed action potentials are transmitted at, or conduction velocities, depend not only on the presence of a myelin coating but also on the diameter of the axon. Larger diameter axons transmit impulses at a faster rate, thereby speeding up the nerve impulses even more.
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TABLE 6.4 Neurotransmitters SUBSTANCE
LOCATION
EFFECT
CLINICAL EXAMPLE
Acetylcholine
Many parts of the brain, spinal cord, neuromuscular junction of skeletal muscle and many autonomic nervous system synapses
Excitatory or inhibitory
Alzheimer’s disease (a type of dementia) is associated with a decrease in acetylcholine-secreting neurons.
Noradrenaline
Many areas of the brain and spinal cord; also in some autonomic nervous system synapses
Excitatory or inhibitory
Cocaine and amphetamines, resulting in overstimulation of postsynaptic neurons.
Serotonin
Many areas of the brain and spinal cord
Generally inhibitory
Involved with mood, anxiety and sleep induction. Levels of serotonin are elevated in schizophrenia (delusions, hallucinations, withdrawal).
Dopamine
Some areas of the brain
Generally excitatory
Parkinson’s disease (depression of voluntary motor control) results from destruction of dopamine-secreting neurons. Drugs used to increase dopamine production may induce schizophrenia.
Gamma-aminobutyric acid (GABA)
Most neurons of the central nervous system
Inhibitory
Drugs that increase GABA function have been used to treat epilepsy (excessive discharge of neurons).
Glutamate and aspartate
Widespread in the brain and spinal cord
Excitatory
Drugs that block glutamate or aspartate may prevent seizures and neural degeneration from overexcitation.
Endorphins and encephalin
Widely distributed in the central and peripheral nervous systems
Generally inhibitory
Opiates such as morphine and heroin bind to endorphin and encephalin receptors on presynaptic neurons and reduce pain by blocking the release of neurotransmitters.
Substance P
Spinal cord, brain and sensory neurons associated with pain; digestive tract
Generally excitatory
Substance P is a neurotransmitter in pain transmission pathways. Blocking the release of substance P by morphine reduces pain.
RESEARCH IN F
CUS
Neuroimaging techniques FO CUS O N L E A R N IN G
1 Sketch a diagram of a neuron and write in relative ion concentrations, indicating whether the ions involved in the action potential are in a high or low concentration inside the neuron at rest. 2 Discuss how ion movements into and out of the neuron relate to the action potential. 3 Describe the events that occur when the action potential reaches the synapse. 4 Explain what neurotransmitters are and list some examples of neurotransmitters. 5 Discuss the benefits of myelin.
Functional and structural neuroimaging techniques have reached a level of sophistication where they can be used in diagnosing brain dysfunctions by looking at levels of brain activity in specific areas. The technologies include positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single-photon emission computed tomography (SPECT), magnetoencephalography (MEG) and magnetic resonance spectroscopy (MRS). Researchers are starting to apply these techniques and others to psychiatry and cognitive neuroscience problems. They are evaluating problems such as how brain areas interact in individuals with psychoses or hallucinations, how they recover from neurotrauma and the advancement of neurodegenerative diseases.
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The central nervous system The brain
The human brain enables a person to reason, function intellectually, express personality and mood, and interact with the environment. It enables every person to become a unique individual capable of complex actions that depend on detection, integration and interpretation of multiple sensory stimuli. All of these intricate and complex actions are possible because of the billions of neurons present in the brain and spinal cord. The mass of the brain is approximately 1.5 kilograms. It requires a constant blood supply for the transport of oxygen and nutrients. To maintain this large oxygen supply the brain receives approximately 15% to 20% of the total cardiac output, much more than the approximately 3% it is entitled to on the basis simply of relative weight. This disproportionately large blood supply to the brain is because of the specific metabolic requirements of central nervous system tissue. It is extremely metabolically active and yet relies on aerobic metabolism, having an absolute requirement for an almost uninterrupted supply of oxygen to cells. It also requires a continual supply of glucose. Unlike many other tissues, it cannot easily utilise protein or fat to supply its cells with the chemical energy they require. The major divisions of the brain are: • the cerebral hemispheres • the diencephalon • the brainstem • the cerebellum (see Fig. 6.9). The constituents of these divisions are listed in Table 6.5. The different divisions of the brain are associated with different functions. However attributing specific functions
Cerebral hemispheres
Corpus callosum Ventricles Thalamus
Hypothalamus Pituitary gland
Midbrain
The cerebral hemispheres
The cerebral hemispheres — or cerebrum — comprise the largest portion of the brain. This is the structure that most people would recognise as the brain, and it is divided broadly into the cerebral cortex, cerebral white matter and the basal nuclei. The surface of the cerebral hemispheres, the cerebral cortex, is covered with convolutions. Elevations called gyri (singular = gyrus) and corresponding grooves between
TABLE 6.5 The main divisions of the central nervous system MAIN REGION
CONTAINS
Cerebral hemispheres
Cerebral cortex
Cerebellum
Pons Medulla Brainstem
to defined regions of the brain is not simple, as there is substantial duplication between regional functions, and many functions can be coordinated in several brain areas. Moreover, greater and greater levels of cerebral plasticity (which is the ability to alter and change functionality) are being understood about the CNS. However, for clinical considerations, functional specificity is very useful for localising pathological conditions in different regions of the brain. The general, larger-scale appearance of nervous tissue depends on the presence of cellular structures. The grey matter is actually slightly darker tissue, due to the presence of cell bodies from many neurons within a small volume of tissue. The organelles within the cell body contribute to this grey appearance. White matter consists mainly of axons, and is visibly lighter than the grey matter (see Fig. 6.10). The white matter typically contains myelinated axons, which have a fatty phospholipid sheath surrounding them that contributes to the white appearance. Collections of cell bodies are often organised into a delineated local area, due to a similarity of function between those neurons. Where a group of cell bodies is found within the central nervous system, it is commonly referred to as the nuclei — an example being the basal nuclei. A cluster of cell bodies within the peripheral nervous system is referred to as a ganglion, such as the sympathetic chain ganglion. A collection of axons in the peripheral nervous system is referred to as a nerve while a large collection of axons is referred to as a plexus.
Cerebral white matter Basal nuclei Diencephalon
Spinal cord
Hypothalamus Brainstem
FIGURE 6.9
Schematic of the human brain. Major regions of the brain include the cerebral hemispheres, thalamus, brainstem and cerebellum.
Thalamus Midbrain Pons Medulla oblongata
Cerebellum
Cerebellum
CHAPTER 6 The structure and function of the neurological system
B
A Cerebral cortex, grey matter Corpus callosum Cerebral white matter
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Cerebral cortex, grey matter Cerebral white matter Corpus callosum — connects the right and left sides of the brain
FIGURE 6.10
Coronal imaging through the cerebral cortex, showing grey and white matter. A Brain cut demonstrating the cerebral cortex (grey matter) and corpus callosum (white matter). B Magnetic resonance image (MRI) scan of the brain. The cerebral cortex and corpus callosum are shown, as are the differences in the white and grey matter. (Red = hippocampus; green = parahippocampus.)
adjacent gyri, called sulci, (singular = sulcus) greatly increase the surface area of the cortex. A greater surface area of cortex increases the number of neurons it is possible to fit into this thin layer of tissue that runs across the outermost layer of the cerebrum. It should be stressed that billions of neurons are fitted into this thin cortical layer, typically only six cells deep, which runs across the surface of the brain. Grooves between adjacent gyri are termed sulci, and deeper grooves are known as fissures. The two cerebral hemispheres, left and right, are separated by the longitudinal fissure. The surface of each hemisphere is divided into lobes named similarly to the region of the skull under which it lies — frontal, parietal, occipital and temporal — with each having a left and right (see Fig. 6.11). The fifth cortical region, the insula cortex, runs under the temporal cortex, away from the inner layer of the skull. The principle of contralateral control occurs with the brain, meaning that the left side of the brain receives sensory input from and sends controls to govern the motor activities of the right side of the body, and vice versa. This is because the neurons that communicate with the cerebral cortex actually cross over to the other side of the body (the crossover usually occurs in the spinal cord or brainstem). The crossover site is referred to as the location where neurons decussate. Interestingly, it is common for one side of the brain to be more dominant than the other. This hemispheric dominance varies from person to person. Moreover, specific functions governed by the brain are often localised on one or the other side of the brain, not both; a concept known as cerebral lateralisation. The left side of the brain seems to be dominant in most people for the control of logical and analytical skills, such as mathematics and language.
The left side of the brain specialises in controlling the writing skills of most of our population, as the majority of people are right-handed. The right side is dominant for creative and emotional activities, such as art, music and spatial relationships. Sometimes equivalent areas on each side of the brain manage related functions — for example, the language and speaking areas on the left side of the brain seem to be matched by areas for singing and chanting on the right side of the brain. Although one side of the brain tends to dominate in each individual, it also communicates extensively with the other side. If a function is damaged in the dominant side of the brain, then the non-dominant side may be able to increase its control over that function. THE CEREBRAL CORTEX
The cerebral cortex is the outer or superficial layer of the cerebral hemispheres and contains the cell bodies of neurons (the grey matter). Even though it is only a thin layer, between 2 and 4 millimetres thick, this is the critical part of the brain for conscious control, as sensory information must reach the cerebral cortex for conscious awareness, and conscious control of muscles originates in the cerebral cortex. Many functions do not require conscious thought, and these are located in brain areas other than the cerebral cortex. This may be a way of ‘filtering out’ incoming signals so that the cerebral cortex is not bombarded with information that can be monitored by other brain centres. The cerebral cortex is also referred to as a ‘higher brain’ region, due to its role in conscious thought. Processes that do not require conscious thought or the same degree of integration are coordinated by ‘lower brain’ regions (such as the brainstem) which seem to have developed earlier in evolutionary history.
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FIGURE 6.11
The cerebral hemispheres, lateral surface. A Structural divisions. B Functional areas.
The posterior margin of the frontal lobe (located posterior to the forehead) is on the central sulcus and it borders inferiorly on the lateral sulcus (see Fig. 6.11). The prefrontal cortex is responsible for goal-oriented behaviour (e.g. ability to concentrate), short-term or recall memory, the elaboration of thought and inhibition of the limbic areas of the central nervous system. The premotor cortex
is involved in programming motor movements — the name premotor indicates that this is where movements are thought about, before they actually occur. The frontal eye fields, which are involved in controlling eye movements, are located on the middle frontal gyrus. The primary motor cortex is an important region in the frontal lobe. It is located along the precentral gyrus and is responsible for the conscious control of voluntary muscle activities. It receives information from the premotor cortex. The primary motor cortex then signals down to the skeletal muscles to cause movement. The axons travelling from the cell bodies in and on either side of this gyrus project (send) fibres (axons) that form the corticospinal tracts (discussed in the next section) that descend into the spinal cord and then to the skeletal muscle. The Broca’s speech area is on the inferior frontal gyrus. It is usually on the left hemisphere and is responsible for the motor aspects of speech (movements of muscles that allow words to be formed). The parietal lobe (located posterior to the frontal lobe) lies within the borders of the central, parieto-occipital and lateral sulci (see Fig. 6.11). This lobe contains the major area for somatosensory input, located primarily along the postcentral gyrus, which is adjacent to the primary motor area. The parietal lobe receives sensory information and then integrates and interprets it. For example, you may feel a smooth, round object with your fingers, and sensory integration allows you to recognise it as a ball. The occipital lobe (at the most posterior part of the brain) lies caudal to the parieto-occipital sulcus and is superior to the cerebellum (see Fig. 6.11). The primary visual cortex is located in this region and receives input from the retinas. Most of this lobe is involved in visual association, so that you can interpret and associate structures that you see. The temporal lobe lies inferior to the lateral fissure (inside the skull near the ears; see Fig. 6.11). The primary auditory cortex and its related association area lie deep within the lateral sulcus on the superior temporal gyrus. The Wernicke’s area, along with adjacent portions of the parietal lobe, constitutes a sensory speech area. This area is responsible for reception, understanding and interpretation of speech, which is closely linked with hearing. The temporal lobe is also involved in memory consolidation and smell. The insula cortex is found underneath portions of the temporal, parietal and frontal cortical regions. It runs across the surface of the cerebrum inside the lateral sulcus and forms a part of the base of this structure. It has important roles in sensory processing including gustation (taste). CEREBRAL TRACTS
Inside the cerebral hemispheres are numerous tracts or axons (white matter; see Fig. 6.12). This white matter lies beneath the cerebral cortex and is composed of myelinated nerve fibres. Lying directly beneath the longitudinal fissure is a mass of white matter that creates a set of pathways
CHAPTER 6 The structure and function of the neurological system
A A
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B
Commissural fibres (corpus callosum)
Association fibres
Cerebral cortex Basal nuclei White matter Thalamus Projection fibres
FIGURE 6.12
Cerebral tracts. A Lateral perspective, showing various association fibres. B Frontal (coronal) perspective, showing commissural fibres that make up the corpus callosum and the projection fibres that communicate with lower regions of the nervous system.
called the corpus callosum. This structure is the major connection route between the two cerebral hemispheres, containing millions of nerve cell projections, and is essential in coordinating activities between the hemispheres (see also Fig. 6.10). It is the largest of the commissural fibre connections that link equivalent areas in the left and right side of the brain. Association fibres are a range of fibres that connect regions of the brain within a single hemisphere (side), connecting between gyri and between lobes. There are extensive association fibres that allow effective communication and coordination between brain regions in the same hemisphere of the brain. For example, the communication between the motor and sensory areas allows appropriate motor response to sensory inputs. BASAL NUCLEI
The major cerebral nuclei are called basal nuclei (nuclei referring to a collection of cell bodies in the central nervous system). The basal nuclei are found deep in the white matter and functionally include a number of nuclei that connect to different regions of the brain. The basal nuclei have direct and indirect interconnections with the thalamus, premotor cortex, reticular formation and spinal cord. The exact functions of the basal nuclei are not yet fully understood, but they are believed to influence muscular activity by exerting a fine-tuning effect on motor movements and inhibiting unnecessary movement (see Chapter 9 on Parkinson’s disease). Note that the basal nuclei were previously known as the basal ganglia.
THE LIMBIC SYSTEM
The limbic system is a group of structures, many of which are in the cerebral hemispheres and surround the corpus callosum, which influence emotions. The regions integral to this system include parts of the prefrontal cortex, the hippocampus, amygdala, olfactory bulb, hypothalamus and thalamus. Its principal effects are believed to be involved in basic behavioural responses, visceral reaction to emotions, feeding behaviours, biological rhythms and sense of smell (see Fig. 6.13). This system is powerful and has a great influence on how we interpret our environment and experiences, such as whether something makes us happy or not.
The diencephalon
The diencephalon, surrounded by the cerebrum, consists mainly of the thalamus and hypothalamus (see Fig. 6.9). The thalamus borders and surrounds the third ventricle. It is a major integration centre for afferent impulses to the cerebral cortex. Various sensations are perceived at this level, but processing by the cerebral cortex is required for interpretation. The thalamus serves also as a relay centre for information from the basal nuclei and cerebellum to the appropriate motor area. The hypothalamus forms the base of the diencephalon. The hypothalamus functions to: (1) maintain a constant internal environment; and (2) implement behavioural patterns. Integrative centres control autonomic nervous system function, regulate body temperature, endocrine function, and regulate emotional expression. The hypothalamus exerts
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Cingulate gyrus
Frontal lobe Limbic lobe
Fornix
Corpus callosum Mammillary body
Thalamus
Olfactory bulb Septal nuclei Amygdala Spinal cord
Hippocampus
FIGURE 6.13
The limbic system. The limbic system is composed of a group of structures deep in the brain that are important in memory and emotion. These structures include the limbic lobe, amygdala, fornix, hippocampus, olfactory cortex and portions of the thalamus.
BOX 6.1
• • • • • • • • • •
Functions of the hypothalamus
Visceral and somatic responses Affective responses Production of hormones (hormone synthesis) Sympathetic and parasympathetic activity Temperature regulation Feeding responses Physical expression of emotions Sexual behaviour Pleasure–punishment centres Level of arousal or wakefulness
its influence through the endocrinological system, as well as via neural pathways (see Box 6.1). The hypothalamus is a fairly unique brain region in that it actually produces several hormones including oxytocin and antidiuretic hormone.
The brainstem
The brainstem is the vital centre of the brain. Damage to this area affects functions required for life such as breathing and blood pressure control. It is divided into the midbrain (the superior portion of the brainstem), the pons and the
medulla oblongata (at the most inferior part). The medulla is continuous with the spinal cord (see Fig. 6.9). • The midbrain is composed of several structures, including the superior and inferior colliculi, the red nucleus and substantia nigra, and the cerebral peduncles. The superior colliculi are involved with voluntary and involuntary visual motor movements (e.g. the ability of the eyes to track moving objects in the visual field); while the inferior colliculi accomplish similar motor activities but involve movements affecting the auditory system (e.g. positioning the head to improve hearing). The red nucleus receives ascending sensory information from the cerebellum and projects a minor motor pathway to the cervical part of the spinal cord. The substantia nigra, which produces the neurotransmitter dopamine, may also be considered part of the basal nuclei. Other notable structures of this region are the nuclei of cranial nerves III (called oculomotor) and IV (called trochlear), and the cerebral aqueduct, which carries cerebrospinal fluid. This region is clinically critical as the periaqueductal grey matter, surrounding the cerebral aqueduct, produces chemicals that help the body to manage pain. • The pons is easily recognised by its bulging appearance below the midbrain and above the medulla (see Fig. 6.9). Primarily it transmits information from the cerebellum to the brainstem and between the two cerebellar hemispheres. The nuclei of the cranial nerves
CHAPTER 6 The structure and function of the neurological system
V (trigeminal) to VIII (vestibulocochlear) are located in this structure. It also helps nuclei in the medulla oblongata to maintain respiratory function. • The medulla oblongata forms the lowest portion of the brainstem. Reflex activities, such as heart rate, breathing, blood pressure, coughing, sneezing, swallowing and vomiting, are controlled in this area. The nuclei of cranial nerves IX (glossopharyngeal) to XII (hypoglossal) also are located in this region. This is diagrammatically represented in Fig. 6.27 later in this chapter. The medulla is the most important region of the brain for basic life support. Damage to other areas of the brain may cause alterations in function, yet not be fatal; however, injury to the medulla is likely to damage the neurons that control the vital functions of the cardiovascular and respiratory systems, and this usually results in death. A collection of nerve cell bodies (nuclei) within the brainstem and other higher brain regions makes up the reticular formation (see Fig. 6.14). The reticular formation is a large network of connected tissue that contains portions of vital reflexes, such as those controlling cardiovascular function and ventilation. The reticular formation is essential for maintaining wakefulness or ‘consciousness’; and therefore is sometimes also referred to as the reticular activating system (RAS). It is thought to be the neural tissue targeted by anaesthetic agents during sedation and induction of general anaesthesia. Functioning of the RAS is tested indirectly using clinical assessment systems such as the Radiations to cerebral cortex
Thalamus
Visual impulses Reticular formation Ascending sensory tracts
FIGURE 6.14
The reticular activating system. This system consists of nuclei in the brainstem reticular formation plus fibres that conduct to the nuclei from below and fibres that conduct from the nuclei to widespread areas of the cerebral cortex. Functioning of the reticular activating system is essential for consciousness.
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Glasgow Coma Scale (GCS; see Chapter 8). We now discuss the sleep process and the role of the reticular activating system. THE SLEEP PROCESS
Sleep is a temporary state of relative unconsciousness from which the individual can be aroused either by internal stimuli such as neural impulses signalling a full bladder, or by an external stimulus such as an alarm clock, a baby crying or light in the room. It is distinguished from the unconsciousness of coma, whereby arousal cannot be easily restored (consciousness is discussed in Chapter 8). Even when asleep or ‘unconscious’ the brain remains constantly active. Interestingly, the brain consumes similar amounts of glucose and oxygen whether awake or asleep, indicating that sleep does not reduce the nutrient or energy requirements of the brain. Normal sleep has two phases that alternate through the night, as distinguished by electrooculography (eye movement recordings), electroencephalogram (EEG) (recording of the electrical activity of the cerebral cortex from the skull surface) and submental (chin) electromyography:4 • non-rapid eye movement (NREM) sleep • rapid eye movement (REM) sleep, also known as stage R sleep. Non-rapid eye movement (NREM) sleep is divided into three stages (N1, N2 and N3) from light to deep sleep and based on characteristic EEG wave forms.4 NREM sleep accounts for about 75% of sleep time in adults.4 During NREM sleep, sympathetic tone is decreased and parasympathetic activity is increased, reducing motor activity. The basal metabolic rate falls by 10–15%; the core temperature decreases by 0.5° to 1.0°C; the heart rate decreases by 10–30 beats per minute; and there are also decreases in the breathing rate, blood pressure and muscle tone. During the various stages, cerebral blood flow to the brain and secretion of corticosteroids (such as cortisol and aldosterone) and catecholamines (adrenaline and noradrenaline) decrease, while growth hormone is released. Rapid eye movement (REM) sleep occurs about every 90 minutes beginning 1–2 hours after NREM sleep begins, with each REM period getting longer throughout the sleep block. In total it typically occupies about 25% of an adult’s sleeping episodes. The EEG pattern recorded in REM sleep is similar to the normal awake pattern and the brain is very active. The changes associated with REM sleep include increased parasympathetic activity and variable sympathetic activity associated with rapid eye movement; muscle relaxation; loss of temperature regulation; altered heart rate, blood pressure and breathing rate; penile erection in men and clitoral engorgement in women; release of steroids; and many memorable dreams (although classically nightmares are thought to occur in stage N3 NREM sleep). Respiratory control appears largely independent of metabolic requirements and oxygen variation. Loss of normal voluntary muscle control in the tongue and upper pharynx may produce some partial respiratory obstructions. Cerebral blood flow
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increases. The exact reason for all these changes is not fully understood and researchers are exploring the physiological and pathophysiological implications. However, it is clear that REM sleep is essential for normal behaviour and lack of REM sleep has been linked to negative psychological outcomes. The importance of sleep Sleep is restful and allows restoration of normal body cycles. The essential and unavoidable nature of sleep suggests that there must be distinct advantages to the body. After insufficient sleep, there is an increased amount of sleep at the next opportunity, usually at a higher intensity (seen on the EEG).5 Sleep is an important part of the consolidation of memories,5,6 which makes it critical for students to undertake an appropriate pattern of sleep throughout their studies. In addition, sleep deprivation can result in impaired function of some regions of the brain that are involved in learning, as well as those involved in mood and emotion.7 During the deepest stage of NREM sleep, serotonin is released, which actually maintains the wellbeing of the brain.8 The role of sleep in setting daily rhythms of hormone secretion is discussed in Chapter 34. Disrupted sleep can induce a delirium-like condition as well as significantly altered mood and emotion control.4 Control of the sleep–wake cycle The sleep control centre is coordinated in the hypothalamus, in a region known as the suprachiasmatic nucleus, which sets and regulates the circadian rhythms of body function around a 24-hour cycle. The hypothalamus receives information from the environment such as the amount of light (via the eyes) or the level of background noise and, together with other sources including alarm clocks and social cues (such as the pattern of sleep following dinner) sets sleep times. In addition, the pineal gland (within the brain) receives light information from the eyes and secretes melatonin, which interacts with the hypothalamus to induce drowsiness, thus marking the onset of sleep. The details of these processes and their interactions are not fully understood and are still under investigation. Arousal from sleep involves increased activity in the reticular activating system. Prior to waking, sensory information that ascends from the body periphery provides the reticular activating system with inputs such as an increasing amount of light or noise in the morning (refer to Fig. 6.14); this system also receives the sudden loud noise of someone calling you or an alarm clock. The reticular activating system then communicates with other brain regions, the most important being the cerebral cortex, to restore consciousness (awakening). During sleep, the flow of communication between the cerebral cortex and the reticular activating system is inhibited. The hypothalamus also has an important role in initiating sleep and coordinates this essential function by receiving information on the amount of light from the eyes, as well as the amount of melatonin secreted from the pineal gland. Awareness or consciousness after sleeping is also supported by the release of hormonal cues coordinated by the hypothalamus.
The cerebellum
The cerebellum (literally meaning ‘little brain’) is located inferior to the occipital lobe of the cerebral hemispheres (see Fig. 6.9) and is composed of grey and white matter; its outside surface is convoluted like the surface of the cerebrum. It is divided into two lobes (left and right) connected by the vermis. The cerebellum is responsible for reflexive, involuntary fine-tuning of motor control for precise activities such as throwing a ball directly to a target, and the delicate precise functions of the fingers of a neurosurgeon or an expert musician. It is also involved in maintaining balance and posture through extensive neural connections with the medulla through the inferior cerebellar peduncle and with the midbrain through the superior cerebellar peduncle. These roles allow precise control of regular activities, such that conscious control is not needed. In this way, you can avoid having to consciously think about not falling over when you walk. Increasingly the role of the cerebellum in some other forms of learning is being recognised, including in abstract thinking and language retention. A major portion of the descending motor pathways (corticospinal tracts) cross to the other side, or decussate, in the medulla. These pathways, together with other areas of decussation in the central nervous system, are the basis for the phenomenon of contralateral control of motor function in the body. FOCU S ON L EA RN IN G
1 Name the 4 major divisions of the brain and their component parts. 2 Describe the functions of the limbic system. 3 Discuss the 2 broad phases of sleep. 4 Explain the importance of sleep. 5 Compare the functions of the precentral gyrus and the postcentral gyrus. Give an example of when these structures operate in coordination. 6 Compare white matter and grey matter.
The spinal cord
The spinal cord is the portion of the central nervous system that lies within the vertebral canal and is surrounded and protected by the vertebral column (spine). The spinal cord is a long nerve ‘cable’ that connects the brain and body, and is responsible for somatic and autonomic reflexes, motor pattern control centres, and sensory and motor modulation. It continues from the medulla oblongata and ends at the level of the first or second lumbar vertebra in adults (see Fig. 6.15). The end of the spinal cord, the cone-shaped conus medullaris, extends through the vertebral canal. Grossly, the spinal cord is divided into vertebral sections (7 cervical, 12 thoracic, 5 lumbar, 5 sacral and 4 coccygeal) that correspond to paired nerves — one on the left and one on the right of the body (see Fig. 6.15). These spinal
CHAPTER 6 The structure and function of the neurological system
A B B
A A A
Thalamus
115
A C C T12
Cervical plexus Brachial plexus
Lumbar plexus Femoral nerve Sacral plexus Sciatic nerve Pudendal nerve
Cerebellum Cervical enlargement
Lumbar enlargement Filum terminale
C1 C2 C3 C4 C5 C6 C7 C8 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3 S4 S5
L1 L2
Conus medullaris
L3 Cauda equina L4 L5 S1 S2 S3 S4 S5
Coccyx Posterior cutaneous nerve of thigh
Coccyx Filum terminale
FIGURE 6.15
Spinal cord within the vertebral canal and exiting spinal nerves. A Posterior view of the brainstem and spinal cord in situ with spinal nerves and plexus. B Lateral view of brainstem and spinal cord. C Enlargement of caudal area showing termination of the spinal cord (conus medullaris) and group of nerve fibres constituting the cauda equina.
nerves emerge at the junction between each vertebrae so that although there are 7 cervical vertebrae, there are actually 8 cervical nerves, with one pair of spinal nerves emerging above C1 as well as one below C1 and so on. A cross-section of the spinal cord (see Fig. 6.16) is characterised by a butterfly-shaped inner core of grey matter (containing nerve cell bodies). At the centre of this grey matter is the central canal which extends through the spinal cord from its origin in the fourth ventricle to the base, and contains cerebrospinal fluid. The grey matter of the spinal cord contains interneurons and axons from sensory neurons (whose cell bodies lie in the dorsal root ganglion) and nerve cell bodies for efferent pathways that leave the spinal cord by way of spinal nerves. The grey matter is surrounded by densely myelinated white matter; nerve fibres carrying sensory (dorsal) and motor (ventral) spinal tracts to and from the brain. It is important to appreciate that the meningeal membranes wrapping the brain extend down the spinal cord in the form of spinal dura to the level of the second sacral vertebrae.
Reflexes
Neural circuits in the spinal cord, when activated, activate specific sets or patterns of motor response. Reflex arcs form
basic units that respond to potentially noxious stimuli and provide protective circuitry for motor output. There are four key aspects of all reflexes: they are involuntary, rapid, require a stimulus to trigger them, and the reflex response is similar every time it is activated. The structures needed for a reflex arc are a receptor, and its associated sensory (afferent) neuron, an integration centre (within the central nervous system), which outputs through a motor (efferent) neuron with its associated effector muscle or gland. The receptor senses the stimulus and the sensory neuron transmits a signal reporting the stimulus, as an action potential, through to the site of integration within the central nervous system. The key here is that the integration typically occurs at the level of the spinal cord using the cell bodies of the neurons in the spinal grey matter. While information about the stimulus is relayed on up the spinal cord to higher brain regions, the initial integration and initiation of the primary response to the stimulus is coordinated at the level of the sensory fibre. This ensures a rapid, if simplistic and highly conserved, response to the stimulus. The motor neuron originating at that spinal level relays a signal to the effector organ, which is often to a muscle, to initiate a rapid response. When the reflex arc occurs through the spinal cord, it is classified as a spinal reflex.
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Central canal
Posterior sulcus
Dorsal root ganglion
Cell body
Sensory neuron
Spinal nerve
White matter
Grey matter (butterfly shape) Anterior fissure
Cell body
Motor neuron
FIGURE 6.16
Cross-section through the spinal cord. Note the outer white matter and inner grey matter. Sensory neurons are located in the dorsal or posterior side, while motor neurons are located in the ventral or anterior side. Arrows indicate the direction of action potentials. The sensory and motor neurons are located together in the spinal nerve.
The two main reflex arcs are the stretch and withdrawal reflexes: • The stretch reflex is the simplest of the spinal reflex arcs and contains only two neurons, meaning that there is only one synapse between the two neurons (monosynaptic reflex). An example of this is the common reflex test performed in clinical practice: the patellar reflex or knee jerk. When the patellar ligament is tapped, the extensor muscle tendon stretches, sending an afferent signal to the spinal cord. This triggers motor neurons that cause the quadriceps to contract and thus kick the foot out, which completes the reflex arc (see Fig. 6.17). • The withdrawal reflex involves multiple synapses (polysynaptic reflex). These reflexes are associated with involuntary removal from a painful or injury-provoking stimulus — for instance, removing your hand when you touch a hot stove or pulling your foot up when you step on a sharp object (see Fig. 6.18). Polysynaptic reflex arcs are usually associated eventually with the sensation of pain, as nociceptive fibres (neurons that carry pain signals; see Chapter 7) transmit the signal to the cerebral cortex, where the individual becomes aware of the pain. It is important to understand that this realisation of tissue damage occurs after the reflex, as the distance to the brain is longer than the path to and from the spinal cord and conscious awareness of the sensation of pain requires interpretation in the cerebral cortex. These processes take time and the withdrawal reflex, working through a spinal reflex arc, means that the body tissue is already removed from the painful stimulus prior to awareness. Thus, reflexes are protective
FIGURE 6.17
The stretch or knee-jerk reflex. A stretch to the muscle stimulates the stretch receptor. 1 The stretch receptor within the quadriceps muscle detects the stretch caused by tapping the patellar tendon. 2 The stretch receptor sends an afferent signal to the spinal cord. 3 In the spinal cord, there is an excitatory synapse with the motor neuron that innervates the quadriceps muscle, as well as an inhibitory synapse with the motor neuron for the hamstrings. 4 As a result, the quadriceps muscle contracts (extensor muscle) 5 Also, the hamstring muscle relaxes, which prevents it from limiting the action of the quadriceps.
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touch information, while the lateral spinothalamic tract is responsible for pain and temperature.
Motor pathways
FIGURE 6.18
The withdrawal reflex. A painful stimulus to the right foot elicits a withdrawal reflex. 1 The cutaneous nociceptor is triggered by the sharp object and sends an afferent signal to the spinal cord. 2 The interneurons in the spinal cord relay motor efferent signals to the flexor muscles and inhibit the extensor muscles in the right leg. 3 Collectively, this causes the right leg to withdraw from the painful source. 4 At the same time, interneuron connections in the spinal cord relay efferent signals to the opposite leg that cause the extensor muscles to contract and flexor muscles to relax. 5 This causes the opposite leg to stabilise your position so that you do not fall over.
and help prevent further injury to the body (see Chapter 7). In addition to the spinal reflexes, which are associated with the somatic nervous system, there are many reflexes associated with the autonomic nervous system. These typically occur without conscious control and involve organ responses, such as increasing the heart rate when a person is frightened. The autonomic reflexes are controlled by the sympathetic and parasympathetic nervous systems and are discussed with individual body systems in later chapters.
Sensory pathways
Afferent pathways transmit information from peripheral receptors, through the spinal cord and eventually terminate in the cerebral cortex or cerebellum, or both. The three clinically important spinal afferent pathways are the posterior (dorsal) column, the anterior spinothalamic tract and the lateral spinothalamic tract (see Fig. 6.19). The posterior part of the spinal cord carries information about where the body is positioned in space, called proprioception. An example of this is that you almost always know where your arms and legs are positioned relative to your body without having to see them. The anterior spinothalamic tract carries
Efferent pathways primarily relay information from the cerebral hemispheres to the brainstem or spinal cord using a series of neuronal pathways. The initiation of movement occurs via neurons within the central nervous system, which synapse with interneurons, which then synapse with motor neurons before projecting into the periphery. It is motor neurons that directly influence muscles. Their cell bodies lie in the grey matter of the brainstem and spinal cord, but their processes extend out of the central nervous system and into the periphery where they synapse in a structure called the neuromuscular junction. Muscle activity (i.e. stimulation and then contraction) is most commonly regulated by the arrival of nerve impulses to the neuromuscular junction (this is discussed in greater detail in Chapter 20). Motor neurons innervate one or more muscle cells. The four most clinically relevant motor pathways are the lateral corticospinal, corticobulbar, reticulospinal and vestibulospinal tracts.9 The corticospinal and corticobulbar pathways are essentially the same tract and their cell bodies originate in and around the precentral gyrus — this is the region where most motor information is initiated. These motor neurons are involved in precise motor movements. The reticulospinal tract (see Fig. 6.19) controls motor movement by inhibiting and exciting spinal activity. The vestibulospinal tract arises from a vestibular nucleus in the pons (responsible for balance) and causes the muscles of the body to rapidly contract to maintain postural support for balance. For example, this becomes activated when an individual starts to fall backwards.
Protective structures of the central nervous system The cranium and vertebral column
The cranium (skull) is composed of eight bones. The cranial vault encloses and protects the brain and its associated structures. The floor of the cranial vault is irregular and contains many foramina (openings) for cranial nerves, blood vessels and the spinal cord to exit. The bony vertebral column (see Fig. 6.15) provides physical protection for the spinal cord.
The meninges
Surrounding the brain and extending down the spinal column beyond the end of the spinal cord are three protective membranes: the dura mater, the arachnoid mater and the pia mater. Collectively they are called the meninges (see Fig. 6.20). THE DURA MATER
The dura mater (meaning literally ‘tough mother’) is the outermost layer, and, around the brain, is composed of two sublayers: the outermost layer, the periosteum (endosteal layer), forms the lining inside the skull; and the inner layer (meningeal layer) forms the outside cover of both the brain
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FIGURE 6.19
Somatic motor and sensory pathways (or tracts). A Lateral corticospinal tract sending signals to skeletal muscles. B Reticulospinal pathway sending signals to muscles involved in posture. C Dorsal column, transmits touch and proprioception. D Lateral spinothalamic tract, transmits pain and temperature signals.
CHAPTER 6 The structure and function of the neurological system
and the spinal cord. Usually, the periosteal and meningeal layers are close together, but in some places there are venous sinuses between them, which are regions that drain venous blood. The meningeal layer is responsible for forming rigid membranes that support and separate various brain structures, as well as helping to limit the movement of the brain inside the hard bony cranium. One of these membranes, the falx cerebri, dips between the two cerebral hemispheres along the longitudinal fissure. The falx cerebri is anchored anteriorly to the base of the brain at the ethmoid bone. The falx cerebelli is a small membrane located between the left and right lobes of the cerebellum. The tentorium cerebelli, a common landmark, is a membrane that separates the cerebellum below from the cerebral structures above. Epidural injections are made into the space just external to the dural covering of the spinal cord. The ligamentum flavum provides an internal lining of the vertebral column, and so the tip of the epidural needle is inserted through the ligamentum flavum to the epidural space, without penetrating the dural layer, and the drug is injected into this space. THE ARACHNOID
Underneath the dura mater is the arachnoid layer, a spongy web-like structure that loosely follows the contours of the Epidural space
A
Subdural space Arachnoid villi Skin Skull
THE PIA MATER
Unlike the dura mater and arachnoid mater, the delicate pia mater adheres to the contours of the brain and spinal cord. It provides support for the rich network of blood vessels serving brain tissue. The choroid plexuses, structures that produce cerebrospinal fluid, arise from the pial membrane. The spinal cord is anchored to the vertebrae by extension of the meninges known as the filum terminale. The meninges continue beyond the end of the spinal cord down into the lower portion of the sacrum. Cerebrospinal fluid contained within the subarachnoid space also circulates down to the second sacral vertebra. This provides a relatively safe place from which to collect a sample of cerebrospinal fluid for assessment, in a procedure known as a lumbar puncture.
Falx cerebri Brainstem
Lateral ventricle
Cerebral hemispheres
Arachnoid
Pia mater
Subarachnoid space
cerebral structures. The subdural space lies between the dura and arachnoid. Many small bridging veins that have little support traverse the subdural space. Their disruption may result in formation of a subdural haematoma (see Chapter 9). The subarachnoid space lies between the arachnoid and the pia mater and contains cerebrospinal fluid. This space is very vascular and if bleeding occurs here it can result in severe damage to the brain (see Chapter 9). In addition, the subarachnoid space is the site for intrathecal injections in the spinal cord.
B
Dura mater (two layers)
Third ventricle
Midbrain Pons Medulla
Thalamus Hypothalamus
Diencephalon
Cerebellum
Cervical enlargement (of spinal cord)
Spinal cord Membranous covering (meninges) Bony covering (vertebral column) Conus medullaris
FIGURE 6.20
Meninges of the brain and spinal cord. Layers of meninges. Note that the meninges seen here are also continuous with the spinal cord.
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Filum terminale
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Cerebrospinal fluid and the ventricular system
Cerebrospinal fluid (CSF) is a clear, colourless fluid similar to blood plasma and interstitial fluid, but it has a different composition to these other fluids. The intracranial and spinal cord structures float in cerebrospinal fluid and are thereby provided some protection from trauma. The buoyant properties of the cerebrospinal fluid also prevent the brain from tugging on meninges, nerve roots and blood vessels, acting as a shock-impact system. The constituents of cerebrospinal fluid are listed in Table 6.6. Between 125 mL and 150 mL of cerebrospinal fluid is circulating within the ventricles (small cavities) of the brain and subarachnoid space at any given time. Four ventricles within the brain are filled with CSF and serve to provide buoyancy and allow circulation of the cerebrospinal fluid: two lateral ventricles (one within each of the right and left cerebral hemispheres); the third ventricle between the left and right sides of the thalamus; and the fourth ventricle between the cerebellum and the brainstem (see Fig. 6.21). A choroid plexus in each ventricle produces the cerebrospinal fluid. These plexuses are characterised by a rich network of blood vessels (supplied by the pia mater) that lie close to the ependymal cells (a type of neuroglial cell) of the ventricles. The cerebrospinal fluid exerts pressure within the brain and spinal cord. When a person is lying down, cerebrospinal fluid pressure is about 5–14 mmHg, but this is the result of a number of factors including the volume of material (brain tissue, blood and CSF) within the cranial vault, venous drainage and compensatory positional arterial constriction and dilation and can double when the person sits up. Beginning in the lateral ventricles, the cerebrospinal fluid flows through the interventricular foramen into the third ventricle and passes through the cerebral aqueduct into the fourth ventricle. From the fourth ventricle the cerebrospinal fluid then continues into the subarachnoid
TABLE 6.6 The composition of cerebrospinal fluid CONSTITUENT
NORMAL VALUE
+
148 mmol/L
Sodium (Na ) +
2.9 mmol/L
Potassium (K ) –
Chloride (Cl )
125 mmol/L –
Bicarbonate (HCO3 )
22.9 mmol/L
Glucose (fasting)
2.8–4.4 mmol/L (60% of plasma glucose)
pH
7.3
Protein
0.15–0.45 g/L
Albumin
80%
Globulin
6–10%
White blood cells
0–6/mm3
Red blood cells
0
spaces of the brain and spinal cord, running through the central canal. The cerebrospinal fluid does not accumulate in the nervous system; instead, it is reabsorbed into the venous circulation through the arachnoid villi. Approximately 600 mL of cerebrospinal fluid is produced and reabsorbed daily. The arachnoid villi protrude from the arachnoid space, through the dura mater, and lie within the blood flow of the venous sinuses. Thus the villi function as one-way valves directing cerebrospinal fluid outflow into the blood but preventing blood flow back into the subarachnoid space. Therefore, cerebrospinal fluid is formed from the blood and, after circulating throughout the central nervous system, it returns to the blood. It should be noted that increases in cerebrospinal fluid pressure can cause severe damage to the brain: this pathophysiological condition, known as hydrocephalus, is examined in Chapter 8.
The blood–brain barrier
The blood–brain barrier describes cellular structures that inhibit some potentially harmful substances in the blood from entering the interstitial spaces of the brain or cerebrospinal fluid. In this way, the neurons that are particularly sensitive to change are protected from the changing environment of the blood, as only some substances from the blood can reach the neurons. The tight junctions between endothelial cells of capillaries in the brain are important in limiting the flow of substances out of the blood and into the cerebrospinal fluid. The astrocytes also assist with the development of this selective barrier (see Fig. 6.22). Metabolites, electrolytes and chemicals can cross into the brain to varying degrees. This has substantial implications for drug therapy because certain types of antibiotics and chemotherapeutic drugs show a greater propensity than others for crossing this barrier — which can limit the choices of drugs that can reach the brain. Importantly, not all potentially harmful substances are blocked by this barrier; for example, lipid-soluble alcohol can easily pass through the blood–brain barrier, where it can affect the brain function.
Blood supply of the central nervous system Blood supply to the brain
The brain receives approximately 15–20% of cardiac output, or 800–1000 mL of blood flow per minute. This constant delivery is vital to brain function — without it, the brain rapidly becomes starved of oxygen and nutrients and the person will be rendered unconscious within a matter of minutes. Carbon dioxide is the primary regulator for blood flow to and within the central nervous system. It is a potent vasodilator and its concentration effects on vasculature help ensure an adequate blood supply. This is most graphically illustrated when an individual hyperventilates (breathes rapidly and deeply). If the individual continues to hyperventilate, the carbon dioxide levels will decrease as it is expelled from the body, cerebral blood flow will decrease and the individual may become light-headed and feel faint.
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Longitudinal fissure A A
Lateral ventricle
A B Interventricular foramen Posterior horn
Anterior horn
Lateral ventricle
Third ventricle
Cerebral aqueduct
Lateral Third ventricle aperture Inferior horn Medial aperture
Fourth ventricle Spinal canal
Cerebral aqueduct Pons
A C
Choroid plexus of lateral ventricle
Superior Subarachnoid sagittal sinus space
Fourth ventricle Medial aperture
Arachnoid granulations
Dura mater (2 layers) Arachnoid
Pia mater Choroid plexus of third ventricle Cerebral aqueduct (of Sylvius) Foramen of Luschka (right lateral aperture) Choroid plexus of fourth ventricle
Roof of fourth ventricle Foramen of Magendie (median aperture)
FIGURE 6.21
The ventricles within the brain and the circulation of cerebrospinal fluid. A Frontal view of the ventricles. B Lateral view of the ventricles. C Each ventricle contains a choroid plexus, which secretes cerebrospinal fluid. The CSF escapes from the fourth ventricle and into the subarachnoid space.
It is clinically important to understand the circulatory supply to the brain. It will assist in an understanding of the brain regions commonly affected by the development of blood clots, causing ischaemic stroke. The brain derives its arterial supply from two systems: the internal carotid
arteries and the vertebral arteries (see Fig. 6.23). The internal carotid arteries supply a proportionately greater amount of blood to the brain. They take their origin from the common carotid arteries, enter the cranium through the base of the skull and pass through the cavernous sinus. After giving
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Astrocyte Tight junctions Foot processes Capillary Endothelial cell
Some substances exit into the brain interstitial fluid FIGURE 6.22
Tight junctions between brain capillary endothelial cells prevent substances from passing between the endothelial cell lining and thereby entering the neural tissue. Astrocytes have foot processes on the capillary that help to maintain the integrity of the blood–brain barrier.
the junction of the pons and medulla to form the basilar artery. The basilar artery divides at the level of the midbrain to form paired posterior cerebral arteries. The circle of Willis, named after the British physician Thomas Willis (see Fig. 6.24), provides an alternative route for blood flow when one of the contributing arteries is obstructed (collateral blood flow). The circle of Willis is formed by the posterior cerebral arteries, posterior communicating arteries, internal carotid arteries, anterior cerebral arteries and anterior communicating artery. The anterior cerebral, middle cerebral and posterior cerebral arteries leave the circle of Willis and extend to various brain structures. Cerebral venous drainage does not parallel its arterial supply, whereas the venous drainage of the brainstem and cerebellum does parallel the arterial supply of these structures. The cerebral veins are classified as superficial and deep veins. The veins drain into venous plexuses and dural sinuses (formed between the dural layers) and eventually join the internal jugular veins at the base of the skull (see Fig. 6.25). Adequacy of venous outflow can significantly affect intracranial pressure. For example, individuals with head injuries who turn or let their heads fall to the side partially occlude venous return, and the intracranial pressure can increase because of decreased flow through the jugular veins.
Blood supply to the spinal cord Posterior auricular artery Occipital artery Maxillary artery Lingual artery Internal carotid artery External carotid artery Vertebral artery Common carotid artery
Superficial temporal artery Ascending pharyngeal artery Facial artery Superior thyroid artery Subclavian artery Brachiocephalic artery
The spinal cord derives its blood supply from vessels that branch off the vertebral arteries and from branches from various regions of the aorta (see Fig. 6.26). The anterior spinal artery and the paired posterior spinal arteries branch off from the vertebral artery at the base of the cranium and descend alongside the spinal cord. Arterial branches from vessels exterior to the spinal cord follow the spinal nerve through the intervertebral foramina, pass through the dura and divide into the anterior and posterior radicular arteries. The radicular arteries eventually connect to the spinal arteries. Branches from the radicular and spinal arteries form plexuses whose branches penetrate the spinal cord, supplying the deeper tissues. Venous drainage parallels the arterial supply closely and drains into venous sinuses located between the dura and periosteum of the vertebrae.
FIGURE 6.23
Major arteries of the head and neck. The main arteries supplying the head and neck stem from branches of the common carotid arteries.
FOCU S ON L EA RN IN G
1 Sketch and label a cross-section through the spinal cord. 2 Briefly describe what information is conveyed in the ascending and descending spinal tracts.
rise to some small branches, these arteries divide into the anterior and middle cerebral arteries. The vertebral arteries originate at the subclavian arteries and pass through the transverse foramina of the cervical vertebrae, entering the cranium through the foramen magnum. They join at
3 Name the protective structures of the central nervous system, and briefly describe each one. 4 Describe the circle of Willis and its role in supplying blood to the brain.
CHAPTER 6 The structure and function of the neurological system
Anterior cerebral artery Posterior communicating artery Posterior cerebral artery Pontine branches Basilar artery Vertebral artery
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Anterior communicating cerebral artery Internal carotid artery Middle cerebral artery
Superior cerebellar artery Anterior inferior cerebellar artery Posterior inferior cerebellar artery
Anterior spinal artery Anterior communicating artery Posterior communicating artery Superior cerebellar artery Anterior inferior cerebellar artery Posterior inferior cerebellar artery
Anterior cerebral artery Middle cerebral artery Internal carotid artery Posterior cerebral artery Pontine branches Basilar artery Vertebral artery Anterior spinal artery
FIGURE 6.24
Arteries at the base of the brain. The arteries that compose the circle of Willis are the two anterior cerebral arteries, joined to each other by the anterior communicating artery and two short segments of the internal carotids, off of which the posterior communicating arteries connect to the posterior cerebral arteries.
Straight sinus Transverse sinus Occipital sinus Sigmoid sinus Superior petrosal sinus
Superior sagittal sinus Inferior sagittal sinus Cavernous sinus Ophthalmic veins Facial vein
Inferior petrosal sinus Internal jugular vein FIGURE 6.25
Large veins of the head. Deep veins and dural sinuses are projected on the skull. Note connections (emissary veins) between the superficial and deep veins.
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Part 2 Alterations to regulation and control
A A
Basilar artery
Vertebral artery Posterior spinal artery Posterior radicular artery
Anterior spinal artery
B
Posterior central artery
Posterior inferior cerebellar artery Anterior radicular artery
Posterior spinal artery Neural branch Posterior radicular artery
Internal spinal arteries
Anterior central artery
Anterior spinal artery
Postcentral branch
FIGURE 6.26
Arteries of the spinal cord. A Arteries of the cervical cord exposed from the rear. B Arteries of the spinal cord diagrammatically shown in horizontal section.
The peripheral nervous system The peripheral nervous system consists of all the neurons outside of the brain and spinal cord. Importantly, the cranial and spinal nerves, including their branches and ganglia (cell bodies located in the peripheral nervous system as opposed to nuclei in the central nervous system), constitute the peripheral nervous system, and these nerves form important connections between the central nervous system and the body extremities. A peripheral nerve (cranial or spinal) is composed of multiple individual axons wrapped in a myelin sheath. There are 12 pairs of cranial nerves (paired = one left, one right; see Fig. 6.27) that connect to nuclei in the brain and brainstem. A description of the function of each is listed in Table 6.7. Most of these cranial nerves are mixed nerves, which means that axons and dendrites of both sensory and motor neurons are located together. Some, however, are primarily sensory or primarily motor. These nerves, while originating from the brain, are considered part of the peripheral nervous system. They are vitally important in clinical practice. Testing each cranial nerve is relatively simple and provides an insight into ongoing brain function. Abnormalities in the responses of the different nerves provide clues to the clinician about the location and extent of nerve damage in the brain. For instance, cranial nerve III is the oculomotor nerve and is responsible for pupillary size and shape. To test the nerve,
the clinician simply shines a light into the individual’s eyes, one at a time: the pupil should constrict due to the increase in light. However, if pupillary constriction occurs in one eye but not the other eye, it may indicate an increase in intracranial pressure in the opposite side of the brain and should be investigated more thoroughly immediately as it could be life threatening. The 31 pairs of spinal nerves derive their names from the vertebral level where they exit. There are eight cervical spinal nerves, but only seven cervical vertebrae. This occurs because spinal nerves emerge above or below the vertebrae — not through the vertebrae, thus the first cervical nerve exits above the first cervical vertebra and the rest of the spinal nerves exit below their corresponding vertebrae. From the thoracic region (and inferiorly), nerves correspond to the vertebral level above their exit (see Fig. 6.28). Spinal nerves contain both sensory and motor neurons and are called mixed nerves. They arise as rootlets lateral to the anterior and posterior horns of the spinal cord. These two spinal nerve roots converge in the region of the intervertebral foramen to form the spinal nerve trunk. Shortly after converging, the spinal nerve divides into anterior and posterior rami (branches). The anterior rami (except the thoracic) initially form plexuses (networks of nerve fibres), which then branch into the peripheral nerves. The thoracic nerves pass through the intercostal spaces and innervate regions of the thorax instead of forming plexuses. The main spinal nerve plexuses innervate the skin and the underlying muscles of the limbs in a specific segmental
CHAPTER 6 The structure and function of the neurological system
125
Trochlear nerve (IV) Olfactory nerve (I)
Optic nerve (II) Oculomotor nerve (III) Abducens nerve (VI)
Trigeminal nerve (V)
Facial nerve (VII) Vestibulocochlear nerve (VIII)
Glossopharyngeal nerve (IX)
Vagus nerve (X)
Accessory nerve (XI) Hypoglossal nerve (XII)
FIGURE 6.27
The 12 cranial nerves. Ventral surface of the brain showing attachment of the cranial nerves.
TABLE 6.7 The functions of the 12 cranial nerves NERVE
TYPE
FUNCTION
I Olfactory
Sensory
Sense of smell
II Optic
Sensory
Sense of sight
III Oculomotor
Mixed (mostly motor)
Movement of eyeball, raising of eyelid, change in pupil size
IV Trochlear
Mixed (mostly motor)
Movement of eyeball
V Trigeminal
Mixed
Chewing of food; sensations in face, scalp, cornea (eye) and teeth
VI Abducens
Mixed (mostly motor)
Movement of eyeball
VII Facial
Mixed
Facial expressions; secretion of saliva and tears; taste; blinking
VIII Vestibulocochlear
Sensory
Sense of hearing and balance
IX Glossopharyngeal
Mixed
Swallowing, secretion of saliva; taste; sensory for the reflex regulation of blood pressure; part of the gag reflex
X Vagus
Mixed
Visceral muscle movement and sensations, especially movement and secretion of the digestive system; sensory for reflex regulation of blood pressure
XI Accessory
Mixed (mostly motor)
Swallowing; head and shoulder movement; speaking
XII Hypoglossal
Mixed (mostly motor)
Speech and swallowing
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Cervical vertebrae
Thoracic vertebrae
Lumbar vertebrae
C1 C2 C3 C4 C5 C6 C7
C1 C2 C3 C4 C5 C6 C7 C8
T1 T2 T3 T4 T5 T6 T7 T8 T9 T10
T1 T2 T3 T4 T5 T6 T7
T11 T12
T11 T12
L1 L2 L3 L4 L5
L1 L2 L3 L4 L5
T8 T9 T10
Dorsal roots of C2, C3 and C4 nerves
Cervical nerves
Transverse processes of vertebrae (cut) Thoracic nerves
Dorsal root ganglion
Dura mater
Lumbar nerves
Sacrum S1 S2 S3 Sacral S4 nerves S5 Coccyx
Coccygeal nerve
FIGURE 6.28
Peripheral nerves. Inset is a dissection of the cervical segment of the spinal cord showing emerging cervical nerves. The spinal cord is viewed from behind (posterior aspect).
organisation. The brachial plexus, for example, is formed by the last four cervical nerves (C5 to C8) and the first thoracic nerve (T1). The brachial plexus innervates the nerves of the arm, wrist and hand. The lumbar plexus (L2 to L4) and sacral plexus (L5 to S5) contain nerves that innervate the anterior and posterior portions of the
lower body, respectively. Some nerves can emerge from their nerve plexus and then innervate organs distant to their origin. For example, the phrenic nerve emerges at the base of the thoracic plexus and then progresses distally to innervate the diaphragmatic muscle to support breathing.
CHAPTER 6 The structure and function of the neurological system
F O CUS O N L E A R N IN G
1 Explain the function of cranial nerves. 2 Describe the anatomy and physiology of the peripheral nervous system. 3 Give two examples of a plexus in the peripheral nervous system.
The autonomic nervous system Although all the components of the nervous system are vital to homeostasis, the autonomic nervous system is probably the most important division to control physiological function throughout the body, ensuring that our body systems remain in homeostatic balance. For this reason, the autonomic nervous system is often the system manipulated pharmacologically in unwell patients. An understanding of the typical actions of this system will enable the clinician to understand a wider range of pharmacological actions as well as the side effects of many drugs. The autonomic nervous system is one of the main efferent systems from the peripheral nervous system to the body cells and organs. The autonomic nervous system consists of two main divisions: • the sympathetic nervous system • the parasympathetic nervous system. A third branch, the enteric nervous system, is specific to the digestive system and is discussed in Chapter 26. Whereas the other main branch of the peripheral nervous system, the somatic nervous system innervates skeletal muscles, the autonomic nervous system innervates the smooth muscle of internal organs, blood vessels and other parts of the body that are not typically controlled by conscious thought, such as the pupils of the eye. The role of the autonomic nervous system is to coordinate and maintain homeostasis using the visceral (internal) organs. It uses innervation of viscera in order to control functions such as regulation of cardiac cycle via control of cardiac muscle, smooth muscle and the glands of the body. This system is considered an involuntary system because we typically cannot will these functions to happen. Interestingly, some afferent information also ascends through this system from the body viscera. However, it is the motor control or efferent function that we will consider in detail. The central nervous system regulates and coordinates the activities of the autonomic nervous system — there are autonomic control areas in the hypothalamus, spinal cord and nuclei of the reticular formation. Central nervous system pathways interconnect all these areas to allow for effective communication and coordination of function. Both divisions of the autonomic nervous system operate using a two-neuron chain system coming from the central nervous
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system to the area of innervation. The ‘chain’ consists of preganglionic neurons (myelinated) and postganglionic neurons (unmyelinated). Recall that a ganglion is a collection of cell bodies in the peripheral nervous system capable of some level of neural integration. However, the location of the ganglia in each division differs; for the sympathetic nervous system, the ganglia are near the spinal cord; and for the parasympathetic nervous system, the ganglia are near the effector organs. This arrangement contrasts with the somatic nervous system, where a single motor neuron travels from the central nervous system to the innervated muscle.
Anatomy of the sympathetic nervous system
The sympathetic nervous system is referred to as the ‘stress’ system, coordinating the physiological ‘fight or flight’ response. This response should be well known to you, as it is activated when the body is placed under some threat — for instance, a dog has barked and chased you, or you have been suddenly frightened and so you have gotten ready to either flee from the situation (flight) or combat the person/ object that has startled you (fight). Like the parasympathetic division, it consists of a two-neuron chain; most of the neurons emerge from the spinal cord between the first thoracic (T1) and the second lumbar (L2) regions of the spinal cord. The preganglionic axons of the sympathetic division form synapses shortly after leaving the cord in the sympathetic ganglia or chain; the sympathetic ganglia run laterally down either side of the cord (see Fig. 6.29). At the sympathetic ganglia, most preganglionic neurons synapse with their respective postganglionic neuron, which extends an axon out of the ganglion to innervate target organs or effectors throughout the body (see Fig. 6.30). This creates a pattern of primarily short preganglionic fibres (from the spine to the adjacent ganglion) and long postganglionic fibres (from the ganglion all the way out to the organ of innovation). Some preganglionic sympathetic neurons innervate the cells of the adrenal medulla, which produces adrenaline and noradrenaline. The myelination of these fibres ensures that the preganglionic action potentials travel quickly to the adrenal medulla and their innervation causes the release of adrenaline and noradrenaline into the bloodstream (see Fig. 6.30). It should be noted that when these substances are released by the adrenal medulla into the bloodstream, they are hormones; however, when they are released by neurons and travel across the synapse, they are neurotransmitters despite being exactly the same substances which activate the same receptors and drive the same effector organ activity. The effect of neurotransmitters is short lasting, whereas release of the same substances as hormones allows for longer-lasting effects at the target organs. This enhancement of the sympathetic nervous system activity by release of hormones is unique: there is no equivalent in the parasympathetic nervous system. It also contributes to the sympathetic nervous system’s role in a body-wide stress
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Preganglionic neuron Postganglionic neuron
Intracranial vessels Eye
C1 C2 C3 C4 C5 C6 C7 C8 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3 S4 S5 Coccyx
Lacrimal gland Parotid gland Sublingual and submaxillary glands Peripheral cranial vessels Larynx Trachea Bronchi and lungs Heart Stomach Liver and gallbladder Adrenal gland Pancreas Kidney Intestines Distal colon Bladder External genitalia
Sympathetic chain FIGURE 6.29
Sympathetic division of the autonomic nervous system. Neurons of the sympathetic nervous system mainly emerge from the thoracic and lumbar regions of the spinal cord, to innervate facial, thoracic and abdominopelvic organs.
response, necessary for the protection of the individual. (The concept of stress and its effects on the body are discussed fully in Chapter 34.) Again, you are probably aware of this effect. While you can quickly become aware of the lack of danger associated with a short rapid frightening stimulus, the physiological effects such as increased heart rate can last for some minutes; indeed the hormonal effects of adrenaline and noradrenaline will remain for as long as these hormones remain in the blood. Again, this is the basis of some therapies, such as the use of EpiPens® (containing epinephrine or adrenaline) in the first line responses to anaphylactic shock.
Anatomy of the parasympathetic nervous system
The parasympathetic nervous system is referred to as ‘peace’ system, coordinating the physiological responses
associated with ‘rest and digest’ systems. The nerve cell bodies of the preganglionic nerves in this division are located in the cranial nerve nuclei and in the sacral region of the spinal cord and therefore constitute the craniosacral division (see Fig. 6.31). Unlike the sympathetic branch, the preganglionic fibres in the parasympathetic division are quite long as they travel close to the organs they innervate before forming synapses with the relatively short postganglionic neurons. Parasympathetic nerves arising from nuclei in the brainstem travel to the viscera of the head, thorax and abdomen within cranial nerves, such as the oculomotor (III), facial (VII), glossopharyngeal (IX) and vagus (X) nerves.
Neurotransmitters and receptors
There are distinct differences in the types and actions of the neurotransmitters of the autonomic nervous system. It
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FIGURE 6.30
Comparison of neurotransmitters and receptors between the sympathetic and parasympathetic nervous systems. Although not part of the autonomic nervous system, the somatic nervous system is included due to its similarity. In each case, the cell body of the first neuron is located in the central nervous system.
is very important that you understand these differences, as a variety of drugs used in clinical practice act on these neurotransmitters and receptors. For instance, individuals with asthma often require a drug called salbutamol, which acts on specific receptors in the lungs that, when stimulated, cause enlargement of the airways (bronchodilation). These receptors are stimulated by the neurotransmitters adrenaline and noradrenaline, and hence salbutamol is called an adrenergic agonist because it mimics the effects of the neurotransmitter adrenaline. However, drugs such as salbutamol are rarely given to people with significant pathophysiological cardiac conditions as the receptors these drugs act on to cause dilation of the airways are also present in myocardial tissue, where they cause increases in heart rate, placing pressure on the coronary circulation and myocardium. Thus, an understanding of the typical physiological response of the body via receptors for these chemicals can help ensure that patients remain safe. It can
also help clinicians understand, predict and manage many of the side effects of these classes of drugs.
Neurotransmitters and receptors of the sympathetic nervous system
The sympathetic nervous system has three main neurotransmitters: acetylcholine, adrenaline and noradrenaline. Acetylcholine is released from the sympathetic preganglionic fibres. In contrast, most postganglionic sympathetic fibres release noradrenaline (with some adrenaline as well) onto their effector organs and thus are described as being adrenergic. The adrenaline (and noradrenaline) can be released as hormones by the adrenal medulla and have the same effects on target cells as the neurotransmitter forms, as they bind to the same receptor types. There is one exception: sweat glands that are innervated by the sympathetic nervous system use postganglionic fibre release of acetylcholine, rather than nor/adrenaline, to
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Thalamus Hypothalamus Lacrimal gland Preganglionic Postganglionic C1 C2 C3 C4 C5 C6 C7 C8 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3 S4 S5 Coccyx
Eye III VII X IX
Nasal mucosa Parotid gland Sublingual and submaxillary glands
Larynx Trachea Bronchi and lungs
Heart Stomach Liver, gallbladder and bile ducts Pancreas Kidney Intestines Distal colon Bladder External genitalia
FIGURE 6.31
Parasympathetic division of the autonomic nervous system. Neurons of the parasympathetic nervous system mainly emerge from the cranial and sacral regions of the spinal cord, to innervate facial, thoracic and abdominopelvic organs.
stimulate the release of sweat. The reason for this remains unknown. Adrenaline and noradrenaline belong to the class of neurotransmitters known as catecholamines. Catecholamines stimulate two major classes of adrenergic receptors: α-(alpha) adrenergic receptors (α1 and α2); and β-(beta)adrenergic receptors (β1, β2 and β3). These adrenergic receptors are structurally similar to each other, with slight differences that still allow the catecholamines to bind differentially and coordinate complex arrays of physiological response (see Fig. 6.32). Cells in the effector organs have particular types of receptors located on their surface; a cell may actually have more than one type of adrenergic receptor (see Table 6.8). α1-adrenergic receptors are found on the smooth muscle of blood vessels, so that when adrenaline or noradrenaline binds to the receptors, it causes contraction of the smooth muscle, resulting in vasoconstriction (a narrowing of
the blood vessels). Most of the α-adrenergic receptors on effector organs belong to the α1 class. α2-adrenergic receptors are located in the pancreas to inhibit secretion of insulin. β1-adrenergic receptors are located mainly on the heart, both in the conduction system and in the muscle of the atria and ventricles. The effects of catecholamines on the heart are increased heart rate and muscle contractility. β1-receptors are also located on the kidney and cause it to release renin (which leads to an increase in blood pressure via activation of the renin-angiotensin-aldosterone (RAAS) system). β2-adrenergic receptors are located in smooth muscle of the respiratory system and cause bronchodilation to help enhance respiratory function; they are also located in other organs, including arterioles and cause vasoconstriction. β3 receptors are located on adipose cells. Some students recall these anatomical differences in receptor distributions by
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thinking about 1 heart (β1) two sets of lungs (β2) many fat cells (β3).
Neurotransmitters and receptors of the parasympathetic nervous system
FIGURE 6.32
Schematic representation of adrenergic neurotransmitters and receptors. Noradrenaline and adrenaline are structurally very similar and both are capable of binding to all adrenergic receptor subtypes (although only some particular receptor types are found on target cells). Pharmacological agents can be targeted to specific receptor subtypes, limiting their interactions and adverse effects at other receptor types on other target cells. (α = alpha; β = beta.)
In the parasympathetic nervous system, both the preganglionic and the postganglionic fibres release acetylcholine. Because the neurotransmitter is acetylcholine, these neurons are known as cholinergic. Acetylcholine works through activation of cholinergic receptors, which are broadly categorised into two groups; nicotinic and muscarinic receptors (see Fig. 6.33). Nicotinic-type acetylcholine receptors are located at the first synapse (in the ganglia) of both the sympathetic and the parasympathetic nervous systems. Although it is not a part of the autonomic nervous system, the synapse between the neuron and voluntary skeletal muscle (of the somatic nervous system) also has nicotinic receptors (see Fig. 6.30). When considering drugs that interact with nicotinic receptors, it is important to remember that these nicotinic receptors are found in both the autonomic and the somatic nervous systems and can affect both systems. Nicotine, one of the many chemicals found in tobacco smoke, activates these receptors. This explains some of the apparently contradictory descriptions of nicotine on the body (stimulant and relaxant). Acetylcholine is also the neurotransmitter released by postganglionic neurons onto the effector organs of the
TABLE 6.8 The effects of the sympathetic and parasympathetic nervous systems on different organs SYMPATHETIC NERVOUS SYSTEM
PARASYMPATHETIC NERVOUS SYSTEM
ADRENERGIC
MUSCARINIC
EFFECTOR ORGAN
RECEPTOR
EFFECT OF STIMULATION
RECEPTOR
EFFECT OF STIMULATION
Blood vessels
α1
Vasoconstriction
–
–
Sinoatrial node
β1
Increased heart rate
M2
Decreased heart rate
Ventricles
β1
Increased force of contraction
–
–
Lung smooth muscle
β2
Bronchodilation
M3
Bronchoconstriction
Smooth muscle
β2
Decreased activity
M3
Increased activity
Sphincters
β2
Constriction (sphincters closed)
M3
Relaxation (sphincters open)
Gastric glands
–
–
M3
Increased secretions
Heart
Digestive system
Eye
α1
Pupil dilation
M3
Pupil constriction
Kidneys
β1
Renin secretion
–
–
Adipose
β3
Breakdown of fat stores
–
–
Pancreas
α2
Inhibits insulin secretion M3
Stimulates insulin secretion
Urinary bladder sphincter
α1
Constriction (sphincter closed)
Relaxation (sphincter open)
α = alpha; β = beta
M3
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FIGURE 6.33
Schematic representation of cholinergic receptors. Acetylcholine interacts with nicotinic and muscarinic receptors.
parasympathetic nervous system, but these effector organs contain muscarinic receptors (see Table 6.8). Muscarinic receptors are located in the heart. The effects of acetylcholine on these receptors include a slowing of the heart rate. Muscarinic receptors are also distributed throughout the body in smooth muscle and glands, and are found within the central nervous system as well as in the parasympathetic nervous system.
Physiology of the autonomic nervous system
Many body organs are innervated by both the sympathetic and the parasympathetic nervous systems. The two divisions usually cause opposing responses; for example, sympathetic stimulation of the heart causes increased heart rate, while parasympathetic stimulation slows the heart rate; and whereas the sympathetic nervous system widens (dilates) airways and increases respiratory rate, the parasympathetic nervous system causes airways to narrow (constrict) and the respiratory rate to slow. The sympathetic nervous system does not always increase organ activity, however, as sympathetic stimulation of the stomach causes decreased digestion, whereas parasympathetic stimulation increases digestive activities.
Sympathetic nervous system: functions
In general, sympathetic stimulation promotes responses for the protection of the individual — hence the ‘fight or flight’ response. For example, sympathetic activity increases blood glucose levels and temperature and raises blood pressure. When considering the functions of the sympathetic system it helps to think ‘E’; where ‘E’ designates control of the body during exercise, excitement, emergency and embarrassment.
In emergency situations, a generalised and widespread discharge of the sympathetic system occurs, known as sympathetic mass discharge. This is accomplished by an increased firing frequency of sympathetic fibres and by activation of sympathetic fibres normally at rest (fibres to the sweat glands, pilomotor muscles and the adrenal medulla, as well as vasodilator fibres to muscle). Regulation of blood vessel tone is considered one of the single most important functions of the sympathetic nervous system, as maintaining adequate blood pressure is essential to ensuring appropriate blood flow to organs. Fig. 6.34 illustrates some of the most important functions of the sympathetic nervous system. The sympathetic nervous system can actually cause both vasodilation (widening of blood vessels) and vasoconstriction (narrowing of blood vessels) at the same time in vessels in different parts of the body. This amazing feat allows blood flow to be directed to tissues that need it most at that point in time — for instance, vasoconstriction limits the amount of blood being supplied to the skin, renal and digestive systems, and simultaneous vasodilation in the heart, skeletal muscles and respiratory system maximises blood flow to those areas, thereby increasing oxygen and nutrient supply and thus, their potential performance. This has the effect of simultaneously causing increased central blood pressure and decreased renal blood flow and thus oliguria (decreased urine production and output, see Chapter 30).
Parasympathetic nervous system: functions
Increased parasympathetic activity promotes rest and restoration of body integrity – hence the term ‘rest and digest’. It is characterised by reduced heart and respiration rates, decreased blood supply to large skeletal muscles, and enhanced digestion. When considering the functions of the parasympathetic system it helps to think ‘D’; where ‘D’ designates control of the body during defecation, digestion and diuresis. Stimulation by the vagus nerve (cranial nerve X) of the gastrointestinal tract increases peristalsis and secretion into the gut lumen, as well as relaxation of the internal sphincters. The vagus nerve has widespread innervation of the organs of the abdomen. Activation of parasympathetic fibres in the head (provided by cranial nerves III, VII and IX) causes constriction of the pupils, tear (lacrimal) and increased salivary secretion. Stimulation of the sacral division of the parasympathetic system contracts the urinary bladder and facilitates relaxation of sphincters associated with digestive excretion. Some physiological functions require a coordinated activation of both divisions; for example, male reproduction requires parasympathetic activation to enable penile erection and then sympathetic activation to coordinate ejaculation. The parasympathetic system lacks the generalised and widespread response of the sympathetic system. In Table 6.8 you will notice that some areas do not have parasympathetic receptors. For instance, most blood vessels involved in the control of blood pressure are innervated
CHAPTER 6 The structure and function of the neurological system
+/– parasympathetic involvement
Adrenal medulla activation
Contraction of arteriolar smooth muscles
Release of adrenaline and noradrenaline
Vasoconstriction
Increased strength of contraction of heart
Increased peripheral resistance Increased blood pressure
Sympathetic activation
Peripheral vasoconstriction
Stimulation of β receptors of muscle vasculature
Stimulation of β receptors of bronchiole vasculature
Metabolic effects
Increased venous return
Vasodilation
Increased bronchodilation
Increased release of adrenaline
CONCEPT MAP
Sympathetic activation
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Increased ventilation Increased cardiac output
Increased blood flow to muscles
Increased oxygenation
Glycogenolysis in the liver Increased blood glucose Used as an energy source
Breakdown of adipose tissue Release of free fatty acids
FIGURE 6.34
Some important functions of the sympathetic nervous system. A Control of cardiac contractility and blood pressure. B Systemic activation during strenuous muscular exercise (‘fight or flight’ response). (β = beta.)
by sympathetic nerves. To decrease blood pressure, therefore, it is more important to block or paralyse the continuous (tonic) discharge of the sympathetic system than to promote parasympathetic activity.
F O CUS O N L E A R N IN G
1 Compare the anatomy of the sympathetic and parasympathetic nervous systems. 2 Define the general function of the autonomic nervous system. 3 Compare how adrenaline and noradrenaline reach their target receptors when they are neurotransmitters and when they are hormones. 4 Compare how the sympathetic and parasympathetic nervous systems affect (a) blood pressure, (b) heart rate and (c) digestion.
Sensory function Although the role of neurons and how they conduct action potentials has been discussed throughout the chapter, in this section we focus on the specialised role of a group of sensory neurons that are involved in our sense organs. Different neurons and their associated receptors sense different stimuli; sensory neurons are particularly abundant in the skin to detect conditions in the external environment. They are also located in deeper body tissues to sense the internal environment. In all cases, the sensory neuron with its associated receptor converts the physical stimulus into action potentials, which must travel from the sensory neuron to the central nervous system. Sensory information is interpreted in the spinal cord and the brain. When sensory messages reach the cerebral cortex area that is specialised for that stimuli, we become consciously aware of the sensation. In this way, the body monitors itself by providing sensory information to the central nervous system. One of the most critical sensations is the ability to detect pain, and
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this is discussed fully in Chapter 7. Finally, you may be wondering where to find a similar focus on motor function of neurons — this is discussed in the musculoskeletal system (Chapter 20).
Somatosensory function Touch
Receptors sensitive to touch are present in the skin and are particularly abundant in the fingers and lips. The sensation of touch involves several neuron types, so that a variety of physical stimuli can be sensed and distinguished. In broad terms, these mechanoreceptors sense mechanical stimuli such as light touch, deep pressure, stretching and vibration. Because a sensitive area of the skin, such as the hands, has a large number of mechanoreceptors, it is easily possible to distinguish between these different types of touch stimulus. In addition, most of these sensations evoke affective or emotional responses that determine whether the sensation is unpleasant, pleasant or neutral.
Temperature
Neurons that sense temperature are known as ther moreceptors, with some being specialised to sense cold and others to sense warm. The more extreme the temperature, the more action potentials the neuron will send. Putting your hand into an esky filled with icy water will cause cold thermoreceptors in your skin to send many action potentials to the central nervous system, giving you thermal awareness of the cold water.
Chemical
The chemoreceptors are a diverse group of neurons that detect the proportion of particular chemicals. Obvious examples of chemoreceptors are the taste buds on the tongue that detect sour, salty, sweet and bitter, and those located within the nasal cavity that allow you to distinguish scents as diverse as peppermint and putrefaction in the air. We also have other chemoreceptors that have a vital role in maintaining normal body function. Chemoreceptors located in blood vessels sense particular substances in the blood such as the proportions of oxygen, carbon dioxide and acid; while chemoreceptors located in the brain detect substances within the cerebrospinal fluid. Detecting these substances is essential, so that any alterations can be corrected to restore homeostasis. We look at the specialised functions of these chemoreceptors in Chapters 22 and 24.
Proprioception
Awareness of the position of the body and its parts depends on impulses from the inner ear and from proprioceptors in joints and ligaments. These stimuli are necessary for the coordination of movements, the grading of muscular contraction and the maintenance of equilibrium.
system for focusing light on the receptors and a system of nerves for conducting impulses from the receptors to the brain. The wall of the eye is formed of the sclera, choroid and retina (see Fig. 6.35). The sclera is the thick, white, outermost layer. It becomes transparent at the cornea in the central anterior region that allows light to enter the eye. The choroid is the deeply pigmented middle layer that prevents light from scattering inside the eye. The iris, part of the choroid, has a round opening, the pupil, through which light passes. Smooth muscle fibres control the size of the pupil so that it adjusts to bright or dim light, and close or distant vision. The innermost layer of the eye, the retina, contains millions of rods and cones — special photoreceptors that sense light. These synapse with neurons that exit the back of the eye at the optic nerve and project to the brain. There are no photoreceptors where the optic nerve leaves the eyeball; this creates the optic disc, or blind spot. Vision is based on light that enters the eye and projects onto photoreceptors. Rods are used for peripheral and dim light vision, and are most abundant at the periphery. Cones, densest in the centre of the retina, detect colour and detail. Lateral to each optic disc is the fovea centralis, which contains only cones — in order for you to see an object in clear focus, that image must project directly onto the fovea centralis (see Fig. 6.35). Nerve impulses pass through the optic nerves to the optic chiasm. As shown in Fig. 6.36, the nerves from the inner (nasal) halves of the retinas cross to the opposite side and join fibres from the outer halves of the retinas to form the optic tracts. The fibres of the optic tracts travel to the primary visual cortex in the occipital lobe of the brain.10 Damage to different areas of the optic nerve cause blindness in different visual fields. Visual axis Pupil
Lens
Cornea
Anterior chamber Iris
Lacrimal duct
Lower lid Lateral canthus Ciliary body
Posterior chamber
Retina Choroid
Optic disc Optic nerve
Sclera Fovea Posterior Central artery cavity and vein
FIGURE 6.35
Vision
The eyes are complex sense organs responsible for vision. Within a protective casing, each eye has receptors, a lens
Internal anatomy of the eye. Main internal structures of the eye include the lens, posterior chamber, retina and the optic nerve.
CHAPTER 6 The structure and function of the neurological system
LEFT
L
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RIGHT
R
1. Lesion of right optic nerve and right eye blindness L R
1
2. Lesion in optic chiasm and bitemporal hemianopia L R
2 3
3. Left optic tract lesion and bilateral right hemianopia
FIGURE 6.36
Visual pathways and defects. This schematic shows the visual image on the left being purple and the right being white; specific defects in pathways (shown as 1, 2 and 3) lead to loss of specific aspects of vision, for example, loss of right eye function.
Light entering the eye is focused on the retina by the lens — a flexible, biconvex, crystal-like structure. The lens divides the anterior chamber into the aqueous and vitreous chambers. Aqueous humour fills the aqueous chamber, helps maintain internal eye pressure and provides nutrients to the lens and cornea. Aqueous humour is secreted by the ciliary processes and reabsorbed into the canal of Schlemm. The vitreous chamber is filled with a gel-like substance called vitreous humour. Vitreous humour helps to prevent the eyeball from collapsing inwards. Six extrinsic eye muscles allow gross eye movements and permit eyes to follow a moving object (see Fig. 6.37). The external structures protecting the eye include the eyelids (palpebrae), conjunctiva and lacrimal apparatus. The eyelids are used to control the amount of light reaching the eyes, and the conjunctiva lines the eyelids. Tears released from the lacrimal apparatus bathe the surface of the eye and prevent friction, maintain hydration and wash out foreign substances.
Hearing
The external auditory canal is surrounded by the bones of the cranium. The opening (meatus) of the canal is just above the mastoid process. The air-filled sinuses (called mastoid air cells) of the mastoid process promote conductivity of sound between the external and middle ear.
Superior oblique Medial rectus Superior rectus
Trochlea
Optic nerve
Levator palpebrae superioris (cut)
Lateral rectus
Inferior oblique
FIGURE 6.37
Extrinsic muscles of the right eye. The extrinsic muscles of the eye connect with the optic nerve posterior to the eye.
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External ear Auricle (pinna)
(Not to scale) Temporal bone
Middle ear
Inner ear
External Tympanic Semicircular auditory membrane canals meatus
Oval window Facial nerve Vestibular nerve Cochlear nerve
Acoustic nerve (VIII)
Cochlea Vestibule Round window Malleus Incus
Stapes
Eustachian tube
Auditory ossicles FIGURE 6.38
The ear. External, middle and inner ears. (Anatomical structures are not drawn to scale.)
The ear is divided into three areas: (1) the external ear, (2) the middle ear and (3) the inner ear. While all three structures are involved with hearing, the inner ear has an additional function in equilibrium. The external ear is composed of the pinna (auricle), which is the visible portion of the ear, and the external auditory canal (meatus), a tube that leads to the middle ear (see Fig. 6.38). Sound waves entering the external auditory canal hit the tympanic membrane (eardrum) and cause it to vibrate. The tympanic membrane separates the external ear from the middle ear. The middle ear is composed of the tympanic cavity, a small chamber in the temporal bone. Three ossicles (small bones known as the malleus, incus and stapes) transmit the vibrations of the tympanic membrane to the inner ear. When the tympanic membrane moves, the malleus moves with it and transfers the vibration to the incus, which passes it on to the stapes. The stapes presses against the oval window, a small membrane of the inner ear. The movement of the oval window sets the fluids of the inner ear in motion (see Fig. 6.39). The eustachian tube connects the middle ear with the throat. Normally flat and closed, the auditory tube opens briefly when a person swallows or yawns, and it equalises the pressure in the middle ear with atmospheric pressure. Equalised pressure permits the tympanic membrane to vibrate freely. The inner ear is a system of osseous labyrinths (bony, maze-like chambers) filled with perilymph. The bony labyrinth is divided into the cochlea, the vestibule and the semicircular canals (see Fig. 6.38). Suspended in the perilymph is the endolymph-filled membranous labyrinth.
Within the cochlea is the organ of Corti, which contains hair cells (hearing receptors). Sound waves that reach the cochlea through vibrations of the tympanic membrane, ossicles and oval window set the cochlear fluids into motion. Receptor cells on the basilar membrane are stimulated when their hairs are bent or pulled by the movement. Once stimulated, hair cells transmit impulses along the cochlear nerve (a division of the vestibulocochlear nerve) to the auditory cortex of the temporal lobe in the brain for interpretation of sound. The semicircular canals and vestibule of the inner ear contain equilibrium receptors. In the semicircular canals the dynamic equilibrium receptors respond to changes in the direction of movement. Within each semicircular canal is the crista ampullaris, a receptor region composed of a tuft of hair cells covered by a gelatinous cupula. When the head is rotated, the endolymph in the canal lags behind and moves in the direction opposite to the head’s movement. The hair cells are stimulated and impulses are transmitted through the vestibular nerve (a division of the vestibulocochlear nerve) to the cerebellum. The vestibule in the inner ear contains maculae — receptors essential to the body’s sense of static equilibrium. As the head moves, otoliths (small pieces of calcium salts) move in a gel-like material in response to changes in the pull of gravity. The otoliths pull on the gel, which in turn pulls on the hair cells in the maculae. Nerve impulses in the hair cells are triggered and transmitted to the brain. Thus, the ear not only permits the hearing of a large range of sounds but also assists with maintaining balance through the sensitive equilibrium receptors.
CHAPTER 6 The structure and function of the neurological system
Semicircular canals
A
B B
Perilymph space Endolymph (within membrane) Ampulla Vestibular nerve
137
Vestibular (Reissner’s) membrane
Scala vestibuli Cochlear duct
Modiolus Cochlear nerve Utricle (in vestibule) Saccule (in vestibule) Scala tympani
Oval window Round window
Cochlea
Hair Tectorial Basilar membrane membrane cells
Cochlear duct
Supporting cells
Organ of Corti
FIGURE 6.39
The inner ear. A The bony labyrinth (orange) is the hard outer wall of the entire inner ear and includes the semicircular canals, vestibule and cochlea. Within the bony labyrinth is the membranous labyrinth (purple), which is surrounded by perilymph and filled with endolymph. Each ampulla in the vestibule contains a crista ampullaris that detects changes in head position and sends sensory impulses through the vestibular nerve to the brain. B The inset shows a section of the membranous cochlea. Hair cells in the organ of Corti detect sound and send the information through the cochlear nerve. The vestibular and cochlear nerves join to form the eighth cranial nerve.
Olfaction and taste
Olfaction (smell) is a function of cranial nerve I. Taste (gustation) is a function of multiple nerves in the tongue, soft palate, uvula, pharynx and upper oesophagus innervated by cranial nerves VII and IX. Dysfunctions of smell and taste may occur separately or jointly. Moreover, impairment of olfactory function is often indicative of other ongoing neurodegeneration.11,12 Unlike other senses, the olfactory system contains neural stem cells which produce new neurons throughout life. Life-long development of olfactory neurons helps ensure retention of olfactory function in otherwise healthy adults well into old age.13 The strong relationship between smell and taste creates the sensation of flavour. If either sensation is impaired, the perception of flavour is altered. Olfactory structures are illustrated in Fig. 6.40. Olfactory cells, located in the olfactory epithelium, are the receptor cells for smell. While seven different primary classes of olfactory stimulants have been listed: (1) camphoraceous (moth balls), (2) musky, (3) floral, (4) peppermint, (5) ethereal (such as essential oils), (6) pungent and (7) putrid, evidence suggests that there are thousands of different classes of olfactory receptors enabling the complex patterns of olfactory stimulation and subsequent perception people receive. The primary sensations of taste are (1) sour, (2) salty, (3) sweet, (4) umami and (5) bitter. Umami receptors are directly stimulated by the neurotransmitter glutamate and
Fibres of olfactory nerve Cribriform plate of ethmoid bone Olfactory tract
Olfactory bulb Frontal bone Nasal cavity
Olfactory recess
Palate Nasopharynx FIGURE 6.40
Olfactory structures. Midsagittal section of the nasal area shows the location of the major olfactory structures.
found in foods containing hydrolysed vegetable proteins or monosodium glutamate (sometimes described as a savoury or meaty taste). Recently a sixth taste receptor responding to carbohydrates (glucose oligomers) has been described.14 Taste buds sensitive to each of the primary sensations are distributed widely across areas of the tongue and buccal cavity.15
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Alterations of sensory function Visual dysfunction
A
ALTERATIONS IN OCULAR MOVEMENTS
Abnormal ocular movements result from dysfunction of cranial nerves III (oculomotor), IV (trochlear) or VI (abducens), and include nystagmus and strabismus: • Nystagmus is an involuntary rhythmic movement of the eyes. It may be caused by an imbalanced reflex activity of the inner ear, vestibular nuclei, cerebellum or nuclei of relevant cranial nerves. Drugs and retinal disease may produce nystagmus. • In strabismus, one eye deviates from the other when the person is looking at an object. This is caused by a hypertonic (weak) muscle in one eye. The primary symptom is diplopia (double vision), often caused by thyroid disease. ALTERATIONS IN VISUAL ACUITY
Visual acuity is the ability to see objects in sharp detail. With advancing age, the lens of the eye becomes less flexible and adjusts slowly, and the sclera changes shape, so that visual acuity declines with age. • Cataracts are caused by a cloudy area within the lens and result from degeneration during ageing. • Retinal detachment occurs as fluid accumulates and separates the retina from underlying tissues, and may result from diabetes. • Glaucoma is characterised by high intraocular pressures (greater than 12–20 mmHg), usually due to excessive fluid within the posterior chamber of the eye. Fluid may be unable to be circulated or drained adequately. This may occur acutely, with a sudden rise in intraocular pressure causing pain and visual disturbances. Increased pressure on the optic nerve blocks its blood supply, leading to nerve destruction. More than 300 000 Australians have glaucoma, and those with diabetes are at increased risk of developing the condition.16 • Age-related macular degeneration (AMD) is a severe and irreversible loss of vision and a major cause of blindness in older individuals. Hypertension, cigarette smoking, diabetes mellitus and age over 60 are risk factors. AMD includes abnormal blood vessel growth, leakage of blood or serum, retinal detachment and loss of photoreceptors, resulting in loss of central vision. This may be treated by laser photocoagulation. ALTERATIONS IN REFRACTION
Alterations in refraction are the most common visual problem, and may be due to the focusing power of the lens or structural abnormalities. The major symptoms are blurred vision and headache. • Myopia, or nearsightedness, occurs when light rays are focused in front of the retina when the person is looking at a distant object (the person can see near objects clearly but distant objects are blurry; see Fig. 6.41).
B
FIGURE 6.41
Alterations in refraction. A Myopic eye. Parallel rays of light are brought to a focus in front of the retina. B Hyperopic eye. Parallel rays of light come to a focus behind the retina in the unaccommodative eye.
• Hyperopia, or farsightedness, occurs when light rays are focused behind the retina when a person is looking at a near object (the person can see distant objects clearly but close objects are blurry; see Fig. 6.41). ALTERATIONS IN COLOUR VISION
Normal sensitivity to colour diminishes with age because of the progressive yellowing of the lens that occurs with ageing. All colours become less intense, although colour discrimination for blue and green is greatly affected. Colour vision deteriorates more rapidly for individuals with diabetes mellitus than for the general population. Abnormal colour vision may also be caused by colour blindness, an inherited trait. Colour blindness affects 8% of the male population and 0.5% of the female population. Although many forms of colour blindness exist, most commonly the affected individual cannot distinguish red from green.17 NEUROLOGICAL DISORDERS CAUSING VISUAL DYSFUNCTION
Vision may be disrupted at many points along the visual pathway, causing various defects in the visual field. Visual changes may cause defects or blindness in the entire visual field or in half of a visual field (hemianopia). Fig. 6.36 illustrates the many areas along the visual pathway that may be damaged and the associated visual changes. Injury to the optic nerve causes same-side blindness. Injury to the optic chiasm (the x-shaped crossing of the optic nerves) can cause various defects, depending on the location of the injury. EXTERNAL EYE STRUCTURE DISORDERS
Infection and inflammatory responses are the most common conditions affecting the supporting structures of the eyes.
CHAPTER 6 The structure and function of the neurological system
Conjunctivitis is an inflammation of the conjunctiva caused by bacteria, viruses, allergies or chemical irritants.18 • Acute bacterial conjunctivitis (pinkeye) is highly contagious and often caused by Staphylococcus, Haemophilus, Streptococcus pneumoniae and Moraxella catarrhalis, although other bacteria may be involved. • Viral conjunctivitis is caused by an adenovirus. Common symptoms are watering, redness and photophobia. • Allergic conjunctivitis is associated with a variety of antigens, including pollens. • Chronic conjunctivitis results from any persistent conjunctivitis. • Preventing spread of the microorganism with hand-washing and use of separate towels is important. Bacterial conjunctivitis is treated with antibiotics.
Auditory dysfunction
Impaired hearing is the most common sensory defect. The major categories of auditory dysfunction are conductive hearing loss, sensorineural hearing loss, mixed hearing loss and functional hearing loss.19 Hearing loss may range from mild to profound. Auditory changes associated with ageing are common and incremental. CONDUCTIVE HEARING LOSS
A conductive hearing loss occurs when a change in the outer or middle ear impairs the conduction of the sound from the outer ear to the inner ear. Conditions that commonly cause a conductive hearing loss include impacted cerumen (wax plugs) or foreign bodies lodged in the ear canal, pharyngotympanic (eustachian) tube blockage or dysfunction, and otitis media. Surgery to remedy otitis media (insertion of grommets) is the most common form of surgery in children. Symptoms of conductive hearing loss include diminished hearing and an altered perception of volume — when the person speaks softly they perceive their voice to be abnormally loud as it is conducted by bone to the inner ear.12 SENSORINEURAL HEARING LOSS
A sensorineural hearing loss is caused by impairment of the spiral organ (organ of Corti) or its central connections. Causes include chronic or extreme noise exposure, age-related degeneration, Ménière’s disease, ototoxicity and diabetes.20 Congenital and neonatal sensorineural hearing loss may be caused by maternal rubella, ototoxic drugs, prematurity, traumatic delivery and congenital hereditary malfunction. Diagnosis is often made when delayed speech development is noted. Presbycusis is the most common form of sensorineural hearing loss and is especially common in elderly people. Its cause may be atrophy of the basal end of the spiral organ, loss of auditory receptors, vascular changes or stiffening of the basilar membranes. Drug ototoxicities (drug side effects that include decreased auditory function) have been observed after exposure to alcohol, the antibiotic gentamycin and other substances. The initial effect is tinnitus
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(ringing in the ear), followed by a progressive high-tone sensorineural hearing loss that is permanent. MÉNIÈRE’S DISEASE
Ménière’s disease is a disorder of the middle ear with an unknown aetiology. There is excessive endolymph and associated pressure that disrupts both vestibular and hearing functions. Recurring symptoms include profound vertigo, nausea and vomiting associated with deafness, and tinnitus (ringing in the ears). Dietary salt (in particular, sodium) has been shown to cause attack of vestibular and hearing alteration, and it appears that stress may also precipitate attacks. Therefore, reduction of dietary salt and diuretics can be used to reduce body salt content. Stress management is also advised. Surgery is used only in severe cases where the symptoms are debilitating. Unfortunately, there is no definitive treatment and the aim of treatment should be to alleviate symptoms, termed symptomatic treatment.21
Ear infections
• Otitis externa is the most common infection of the outer ear and may be acute or chronic.22,23 The most common cause of acute infections are bacterial microorganisms including Pseudomonas, Escherichia coli and Staphylococcus aureus. Infection usually follows prolonged exposure to moisture (swimmer’s ear). The earliest symptoms are inflammation with pruritus, swelling and clear drainage, progressing to purulent drainage with obstruction of the canal. Acidifying solutions and topical antibiotics are used for treatment.24 • Otitis media is the most common infection of infants and children.24 Most children have one episode by 3 years of age. The most common pathogens include Streptococcus pneumoniae and Haemophilus influenzae. Predisposing factors include sinusitis, adenoidal hypertrophy, environmental conditions and immune deficiency. Breastfeeding is a protective factor. Recurrent acute otitis media may be genetically associated.23 Acute otitis media is associated with ear pain, fever, irritability, inflamed tympanic membrane and fluid in the middle ear. The tympanic membrane progresses from erythema to opaqueness with bulging as fluid accumulates. Otitis media with effusion is the presence of fluid in the middle ear, which is also known as glue ear. Treatment includes symptom management, particularly of pain, with watchful waiting, antimicrobial therapy for severe illness and placement of tympanotomy tubes (grommets) when there is persistent bilateral effusion and significant hearing reduction.24 Complications include mastoiditis, brain abscess, meningitis and chronic otitis media with hearing loss. Persistent middle ear effusions may affect speech, language and cognitive abilities. There are some world-class intervention programs currently running in rural Australia, such as the ‘deadly ears’ program, designed to reduce the long-term impacts of otitis media particularly in the Australian Indigenous population.12
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Olfactory and taste dysfunction
Olfactory dysfunctions can be mild or severe. In a person with anosmia — a complete loss of smell — less variety may be incorporated into food choices and there is a greater likelihood of intake of spoiled food, which may impact negatively on nutritional status. Malnutrition is a concern in some groups within our community (refer to Chapter 27), and anosmia may contribute to the condition. Of more immediate concern is the inability to smell harmful substances such as fire, gas, chemicals and spoiled foods, which may have a substantial impact on the individual. A less severe condition is hyposmia, an impaired sense of smell. Olfactory deterioration has been shown to accompany all of the neurodegenerative conditions thus far explored.
These include Parkinson’s disease, Alzheimer’s disease and also those which are less commonly age-related such as posttraumatic stress disorder and schizophrenia. This loss of olfactory sensitivity is more pronounced in women than in men, and precedes other evidence of neurodegeneration. Thus, increasingly, smell tests are being used as screening tests for development of chronic abnormality.11,13 The sense of taste can be impaired by injury. Altered taste may be attributed to injury near the hippocampus. Hypogeusia is a decrease in taste sensation, whereas ageusia is an absence of the sense of taste. These disorders result from cranial nerve injuries and can be specific to the area of the tongue innervated. These conditions can also contribute to the likelihood of developing malnutrition.
FOCUS O N L E ARN IN G
1 Outline which different touch receptors are distributed throughout the body and some sites they are located. 2 List the major structures of the eye, and describe how they contribute to transmission of visual information. 3
Discuss the structure and function of the ear.
FOCU S ON L EA RN IN G
1 Discuss how the nervous system develops in the fetus and infant. 2 List some important structural and functional changes that occur in the nervous system with ageing.
Environmental influences have a significant role in nervous system development. Nutrition, hormones, oxygen levels and external stimulation all affect typical growth patterns. Appropriate proportions of essential nutrients are necessary for proliferation of the nervous system tissue. Maternal lifestyle, nutrition and state of health also have a crucial impact on nervous system development at certain critical periods of maturation. Initial growth of a neural tube that has differentiated secondary brain vesicles is evident by 4 weeks of fetal gestation. The growth and development of the brain occurs rapidly during weeks 15–20 of gestation and again at week 30 through the first year of life, reflecting the development and multiplication of neurons. The head is the fastest growing body part during infancy. One-half of postnatal brain growth is achieved by the first year and is 90% complete by age 6 years. The cortex thickens with maturation and the sulci deepen as cortical functions develop. Cerebral blood flow and oxygen consumption is about twice that of the adult brain during these years. The bones of the infant’s skull are separated at the suture lines forming two fontanels or ‘soft spots’: one diamondshaped anterior fontanel and one triangular-shaped posterior fontanel. The fontanels allow for movement of the plates of the skull during childbirth and then the expansion of the rapidly growing brain. The posterior fontanel may be open until 2–3 months of age; the anterior fontanel normally does not fully close until 18 months of age (see Fig. 6.42). Abnormal intracranial
Frontal suture Frontal bone
Sagittal suture
Anterior fontanel Coronal suture
Parietal bone
Posterior fontanel
Lambdoidal suture Occipital bone
FIGURE 6.42
Cranial sutures and fontanels in infancy. Fibrous union of suture lines and interlocking of serrated edges (occurs by 6 months).
PAEDIATRICS
Paediatrics and the nervous system
CHAPTER 6 The structure and function of the neurological system
conditions, such as those characterised by increased intracranial pressure like hydrocephalus, may also result in distension or bulging of the fontanels and an increased head circumference in excess of that expected with normal growth. Healthcare providers carefully monitor the fontanels for 2 years and head growth during the first 5 years by measuring head circumference and comparing the results with a standardised growth chart. Human neurological functioning is primarily at a subcortical level at birth (impulses are handled by the brainstem and spinal cord). Many reflex patterns mediated by brainstem and spinal cord mechanisms
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are present at birth and then disappear at predictable times during infancy. Absence of expected reflex responses at the appropriate age indicates general depression of central or peripheral motor functions. Asymmetric responses may indicate lesions in the motor cortex or may occur with fractures of bones after traumatic delivery or postnatal injury. As the infant matures, the neonatal reflexes disappear in a predictable order as voluntary motor functions supersede them. Abnormal persistence of these reflexes is seen in infants with developmental delays or with central motor lesions.
Ageing and the nervous system Less myelin is observed, due in part to slowed cell metabolism of the supporting glial cells. Decreased density of dendritic processes and fewer synaptic connections may contribute to gross brain atrophy and also to reduced cognitive function and memory decay. Slowed neural cell metabolism may contribute to reduced neurotransmitter and receptor production and thus less effective neural activation. An imbalance in the amount, distribution and breakdown of neurotransmitters associated with fewer, less functional cells from ageing can lead to functional decrements in the system. In parallel with the structural changes that occur as we age, there are some corresponding changes in neurological function, although these changes vary significantly with individuals. The CNS, like the kidney, has a huge amount of functional reserve. However, with ageing memory impairments typically occur, as do sleep disturbances. There is a decrease in neuromuscular control, with a characteristic change in gait and posture. Cognitive alterations may also be associated with chronic disease. Thus far evidence for maintenance of neural function using ‘brain training’ is limited. However there is good evidence that maintaining cognitive demand, for example participation in language programs, adult learning programs and even the use of diversional therapists in aged care facilities help to maintain cognitive function for longer. Maintaining social connectedness including complex social networks has been shown to slow the development of dementia. Finally, progressive deterioration of sensory function accompanies the ageing process. Hyperopia (longsightedness) is a common age-related change to visual acuity. In the eye, there is a gradual decrease in pupil accommodation (elasticity) and the function of cone-type photopigments and so progressive loss of colour vision. The cornea becomes thicker and less curved, and the lens thickens and becomes more opaque, decreasing visual Continued
AGEING
A number of changes occur in the neurological system with typical ‘healthy’ ageing. These changes include both structural and functional alterations.25–29 The changes are a usual part of ageing and are quite distinct from pathophysiological changes described in later chapters. Several anatomical changes occur progressively with the typical ageing process. The total brain size and weight decreases, particularly in the frontal region, and there is an accompanying narrowing of the gyri and widening of the sulci, and an increase in the size of the ventricles. This apparent atrophy of brain tissue is not necessarily related to cognitive or identifiable neural functions. It arises because of progressive cell loss and the general lack of neural mitosis in the human brain. While neural stem cells in brain regions such as the hippocampus and the olfactory system continue to divide even in late-stage ageing, the overall cell loss is so great as to result in decreased tissue density and volume. Support tissues in the brain also progressively change with ageing. Blood vessels supplying the brain become less elastic and the vessel walls are more vulnerable to plaque formation and damage. The meninges undergo fibrosis and thickening, limiting their supportive protective capacity. This reduces the ‘shock-impact’ effect of the dural layers and increases the risk of blood vessel damage and soft tissue compression with trauma. The permeability of the blood–brain barrier also increases — this may allow the sensitive neurons to be exposed to a greater number of blood-borne substances, which may be detrimental. Expanding ventricular space allows for a greater volume of CSF to form and yet the ependymal cells helping to maintain flow of CSF around the CNS do not increase proportionally so there is less effective circulation of CSF through the CNS. At a cellular level, there is an ongoing decrease in the number of neurons throughout life — interestingly, this is not consistently related to changes in mental function.
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perception. There is also a loss of the number of rods in the retina altering low light or night vision. In the ear, the cochlear hair cells degenerate, fail to regenerate or repair and there is a loss of neurons in the spiral ganglia and organ of Corti. These changes, coupled with a decrease in the sense of vibration result in less hearing ability. Indeed, increasing use of personal sound systems (such as MP3/4 players/smart phones), with loud sounds directed by earplugs directly into the external auditory meatus (ear canal) seems to be enhancing the degeneration of cochlear hair cells and thus increasing auditory dysfunction. A loss of proprioception caused by vestibular dysfunction and neuropathy may increase the risk of falls and injury. After the age of 80, there may be a decrease in sensitivity to odours, which occurs as
a preclinical warning sign of other neurodegeneration and which may be hazardous if toxic substances cannot be detected. The senses of olfaction and smell and the amount of salivation are lessened, which can decrease the enjoyment of eating and contribute to some elderly people preferring simple diets rather than a wide variety of foods. However, loss of smell is not an inevitable consequence of ageing. The olfactory system is one of the highly specialised systems in the central nervous system where neural stem cells (neuron precursors) enable continual production of new neurons throughout life.13 Readily accessible through the nasal nares, these stem cells are providing the basis of a number of clinical trials for interventive nervous system repair and regeneration.30
chapter SUMMARY Organisation of the nervous system • The structural divisions of the nervous system are the central nervous system and peripheral nervous system. The central nervous system is made up of the brain and spinal cord. • The peripheral nervous system is composed of cranial and spinal nerves, which carry impulses towards the central nervous system (afferent or sensory) and away from the central nervous system (efferent or motor) towards target organs or skeletal muscle. • The functional divisions of the peripheral nervous system are the sensory, somatic nervous system and the autonomic nervous system.
Cells of the nervous system • Neurons and neuroglial cells primarily constitute nervous tissue. The neuron is specialised to transmit and receive electrical and chemical impulses, whereas neuroglial cells primarily provide supportive functions. • The neuron is composed of a cell body, dendrites and an axon. A myelin sheath around the axon of neurons forms an insulating sheath that allows quicker nerve impulse conduction. • A number of different neuroglia are found in the central nervous system, including: astrocytes, which provide physical support; ependymal cells, which produce and move cerebrospinal fluid; and microglia, which are phagocytes. Oligodendrocytes form myelin sheaths in
the central nervous system, while Schwann cells perform this function in the peripheral nervous system.
Nerve injury and regeneration • Neurons can repair themselves only if they are in the peripheral nervous system and the injury occurs near the distal end of the axon. With rare exception, neurons do not regenerate in the adult mammalian nervous system.
The nerve impulse • Neurons at rest typically have a stable resting membrane potential. This electrical potential changes during neuronal communication. • The action potential occurs when the neuron is stimulated. It consists of sodium influx (depolarisation), followed by potassium efflux (repolarisation), a brief undershoot of potassium (hyperpolarisation) and finally restoration of the resting membrane potential. • The small gap between neurons is known as the synapse. • Neurotransmitters are responsible for chemical conduction across the synapse. A neurotransmitter is released from the presynaptic neuron, diffuses across the synapse and binds to receptors on the postsynaptic neuron. This results in a change in the resting membrane potential in the postsynaptic neuron. • Myelin around a neuron allows an action potential to travel along the axon much more quickly than in neurons that are not myelinated.
CHAPTER 6 The structure and function of the neurological system
The central nervous system • The brain is contained within the cranial vault and is divided into four gross regions: (1) the cerebral hemispheres, (2) the diencephalon, (3) the brainstem and (4) the cerebellum. • The cerebral hemispheres have an outer cortex, which allows conscious perception and recognition of internal and external stimuli, thought and memory processes, and voluntary control of skeletal muscles. Deep in the cerebral cortex are the cerebral tracts of white matter, which communicate between different regions of the cerebral cortex, and basal nuclei, which function in movement control. • The centre for voluntary control of skeletal muscle movements is located along the precentral gyrus in the frontal lobe, whereas the centre for conscious sensation is along the postcentral gyrus in the parietal lobe. Broca’s area (inferior frontal gyrus) and Wernicke’s area (superior temporal gyrus) are major speech centres. • The limbic system consists of neurons from a variety of brain regions and is the important region for control of mood and emotions. • The diencephalon, including the thalamus and hypothalamus, processes incoming sensory data. It is an important relay area for sending sensory information on to the cerebral hemispheres. It is also fundamental to body homeostasis. • The brainstem is divided into the midbrain, pons and medulla oblongata. The midbrain is primarily a relay centre for motor and sensory tracts, as well as a centre for auditory and visual reflexes. The pons is involved in communicating with the cerebellum. The medulla is an important brain region, in that it contains the primary control centres for heart rate and breathing. Damage to the medulla is likely to be fatal. • Sleep may be divided into REM and non-REM stages, each of which has its own series of stages. While asleep, an individual progresses through REM and non-REM (slow wave) sleep in a predictable cycle. • REM sleep is associated with enhanced parasympathetic activity and fluctuating sympathetic nervous system activity. Non-REM sleep is characterised by increased parasympathetic activity and decreased sympathetic activity. Non-REM sleep accounts for 75% of sleep. • Restorative, reparative and growth processes occur during sleep. Sleep deprivation can cause profound changes in personality and cerebral functioning. • Sleep is coordinated by the pineal gland, melatonin and the hypothalamus. Arousal from sleep occurs due to the actions of the reticular activating system in the brainstem. • The cerebellum is involved in the coordination and refinement of skeletal muscle movement that can be performed without conscious control. • The spinal cord consists of an inner grey matter (in a ‘butterfly shape’) and outer white matter. It contains most of the nerve fibres that connect the brain with the periphery.
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• Sensory pathways ascend through the spinal cord, while motor pathways descend down the spinal cord. Each pathway will decussate (cross to the other side) between the body periphery and the brain. • The central nervous system is protected by the scalp, bony cranium, meninges, vertebral column and cerebrospinal fluid. This fluid is formed from blood components in the choroid plexuses of the ventricles and is reabsorbed in the arachnoid villi (located in the dural venous sinuses) after circulating through the brain and subarachnoid space. It acts as a shock-impact system. • The meninges are thin layers of membrane that cover and provide support. The outermost layer is the dura mater, the middle layer is the arachnoid mater and the pia mater is the layer against the brain tissue. • The blood–brain barrier is provided by tight junctions between the cells of brain capillaries and the astrocytes, which are surrounding supporting cells (neuroglia). • The paired carotid and vertebral arteries supply blood to the brain and connect to form the circle of Willis. The major branches projecting from the circle of Willis are the anterior, middle and posterior cerebral arteries. Drainage of blood from the brain is accomplished through the venous sinuses and jugular veins. • Blood supply to the spinal cord originates from the vertebral arteries and branches arising from the aorta.
The peripheral nervous system • The peripheral nervous system relays information from the central nervous system to muscle and effector organs through cranial and spinal nerve tracts arranged in fascicles (multiple fascicles bound together form the peripheral nerve). It also collects incoming sensory information from internal and external environments and relays them into the central nervous system. • There are 12 pairs of cranial nerves, most of which contain both sensory and motor neurons. The cranial nerves arise from the central nervous system and travel through the peripheral nervous system to widely innervate the cells and organs of the body periphery. • The 31 pairs of spinal nerves exit the central nervous system at the spinal cord. These contain both sensory and motor neurons, and are organised into major nerve plexuses where they move into large regions of the body.
The autonomic nervous system • The autonomic nervous system is responsible for maintaining a steady state in the internal environment. Two opposing divisions make up the autonomic nervous system: (1) the sympathetic nervous system responds to stress by mobilising energy stores and prepares the body to defend itself (fight or flight); and (2) the parasympathetic nervous system conserves energy and the body’s resources (rest and digest). • The sympathetic nervous system uses adrenaline as a neurotransmitter at the effector organs. This system also innervates the adrenal medulla to cause a release of adrenaline and noradrenaline into the blood to travel
Continued
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throughout the body, thereby complementing the effects of direct neural innervation at target tissues. • Adrenergic receptors are found on target cells and organs, and allow adrenaline and noradrenaline to bind. Adrenergic receptors can be divided into the following subtypes, located at different body sites: α1, α2, β1, β2 and β3. • The parasympathetic nervous system uses the neurotransmitter acetylcholine at the effector organs. Cholinergic receptors are muscarinic at target organs, • Both systems use acetylcholine as the neurotransmitter in the ganglion, where it binds to nicotinic receptors, hence the dual effects of nicotine.
•
• •
Sensory function
•
• Mechanoreceptors detect different types of touch including pressure, stretch and vibration, while thermoreceptors detect warm and cold. • Chemoreceptors in the mouth and nose detect chemicals that contribute to the senses of taste and smell. Vital chemoreceptors within the blood and brain are essential for monitoring oxygen, carbon dioxide, electrolytes and pH. • Proprioception describes monitoring of the position and location of the body and its parts. Proprioceptors are located in the inner ear, joints and ligaments. • The wall of the eye has three layers: the sclera, choroid and retina. The retina contains photoreceptors known as rods and cones that receive light through the lens and then convey signals to the optic nerve and subsequently to the visual cortex of the brain. • Structural eye changes caused by ageing often result in decreased visual acuity. • The major alterations in ocular movement include strabismus and nystagmus. • Alterations in visual acuity can be caused by pathophysiological processes such as cataract development, retinal detachment, glaucoma and macular degeneration. • Alterations in refraction by the internal lens, including myopia and hyperopia, are the most common visual disorders. • Conjunctivitis is a common infection of the eye, and can be acute or chronic, bacterial, viral or allergic. Redness, oedema, pain and lacrimation are common symptoms. • The ear is composed of external, middle and inner structures. The external structures are the pinna, auditory canal and tympanic membrane. The tympanic cavity
•
• •
(containing three bones: the malleus, incus and stapes), oval window, pharangotympanic (eustachian) tube and fluid compose the middle ear. They transmit sound vibrations to the inner ear. The inner ear includes the bony and membranous labyrinths that transmit sound waves through the cochlea to the division of cranial nerve VIII. The semicircular canals and vestibule help maintain balance through the equilibrium receptors. Conductive hearing loss occurs when sound waves cannot be conducted through the middle ear. Sensorineural hearing loss develops with impairment of the organ of Corti or its central connections. Ménière’s disease is a disorder of the middle ear that affects hearing and balance. Otitis externa is an infection of the outer ear associated with prolonged exposure to moisture. Otitis media is an infection of the middle ear that is common in children. Accumulation of fluid (effusion) behind the tympanic membrane is a common finding. The perception of flavour is altered if olfaction or taste dysfunctions occur. Sensitivity to odour and taste decreases with ageing. Loss of olfactory function is a common preclinical symptom of other neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease.
Paediatrics and the nervous system • Growth and development of the brain occur most rapidly during fetal development and during the first year of life. • The bones of the skull are joined by sutures; and the wide, membranous junctions of the sutures known as fontanels allow for brain growth. They close by 18 months of age. • At birth, neurological function is primarily at the subcortical level with transition in reflexes as motor development progresses during the first year.
Ageing and the nervous system • Major structural changes that occur with ageing include a decrease in number (and thus density) of neurons and a decrease in brain weight and size. • Decreased myelination and decreased number of synapses are common cellular changes with ageing. • Decreased synaptic plasticity occurs and thus synapse formation. • A progressive slowing of neurological function occurs with advancing age.
CHAPTER 6 The structure and function of the neurological system
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CASE STUDY
ADU LT Matthew and Vanessa are students. Their lecturer has just announced that the exam scheduled for the following week is quite difficult and so they should all ensure that they study well. Matthew and Vanessa decide to study together and discuss what they have already learned about the nervous system to assist each other’s understanding. First, they list some general definitions and descriptions of the main branches of the nervous system. Next, they spend some time chatting about the differences between an action potential, which travels along the axon, and chemical transmission across the synapse. Matthew has a fairly good understanding of some roles of the main divisions of the brain, while Vanessa can explain the structure of the regions of the spinal cord quite well. Complete the following activities as though you were participating in the study session with Matthew and Vanessa.
1
2 3 4 5
Draw a diagram showing the main divisions of the nervous system and give a general definition of the role of each division. (Note: this is not about being a good artist; rather, you need to indicate where the important structures are. You may use your textbook to assist with the drawing if you need to, but you should close the book while you label the important features.) Discuss nerve transmission and draw appropriate diagrams to illustrate the concept. List some important functions of the main regions of the brain. Draw a diagram of the spinal cord and label the important parts. Describe the changes that are coordinated by the autonomic nervous system in response to stressful situations, such as the lecturer’s comment about the exam.
CASE STUDY
AGEING Sandra is a 72-year-old woman living independently in her own cottage. She requires glasses for reading but has no other medical dependencies, exercises daily and has a healthy wellbalanced diet. She still works part-time as an English tutor but is finding it harder and harder to find the ‘mental energy’ to complete class work and marking. She is contemplating starting a diploma in Spanish through a local provider but is concerned that it might be beyond her ability. She sometimes finds concentrating quite difficult and is concerned that she could be developing dementia. She is unable to talk to her family about her concerns as she is worried about
her financial situation and her ability to maintain her independent lifestyle. 1 Outline some of the typical processes of ageing in the human brain. 2 Which neurological (sensory and motor) abilities are most likely to be affected by ageing? 3 Are there specific tests for dementia? 4 Are there some tests you could do to help alleviate Sandra’s concerns about her possible neurodegeneration? 5 Outline some factors Sandra might consider to ensure that her neurological (and cognitive) capacities are maximised during her learning and teaching experiences.
REVIEW QUESTIONS 1 List the main components of the neuron and outline what processes occur at each part. 2 Explain how nerve transmission occurs along the length of the axon, and what happens when it reaches the synapse. 3 Describe the function of the cerebral tracts. 4 List broad functions for each lobe of the cerebral hemispheres. 5 Name the main regions of the brainstem, and explain why the brainstem is such a vital structure.
6 Discuss the sensory and motor functions of the pathways that are found in the spinal cord. 7 Explain why the blood–brain barrier is so important. 8 List some of the main organs and tissues innervated by different types of adrenergic receptors. 9 Outline the most important function of the sympathetic nervous system. 10 Compare the anatomy and physiology of the sympathetic nervous system and parasympathetic nervous system.
Key terms
CHAPTER
7
Pain Judy Craft
Chapter outline Introduction, 147 The definition of pain, 147 Types of pain, 148 Nociceptive pain, 148 Neuropathic pain, 149 Psychogenic pain, 149 Pain terminology, 149 The physiology of pain, 150 Nociceptors, 150 Spinothalamic tract neurons, 153
146
Thalamocortical neurons, 153 Cortical representation of pain, 154 Neuromodulation of pain, 154 Clinical manifestations of pain, 155 Evaluation and treatment, 156 Pathophysiology of pain, 158 Peripheral neuropathic pain, 158 Central pain syndromes, 160 Ageing and pain, 161
acute pain, 149 affective-motivational aspect, 147 allodynia, 150 analgesia, 148 anterior cingulate cortex, 154 beta-endorphin, 155 burning pain, 151 central pain syndromes, 160 central sensitisation, 159 chronic pain, 149 complex regional pain syndromes (CRPSs), 159 encephalin, 155 endorphins, 154 fast-sharp pain, 152 high-threshold mechanoreceptors, 152 hyperalgesia, 150 interoceptive cortex, 154 mononeuropathy, 158 neuromodulators, 154 neuropathic pain, 149 nociceptive pain, 148 nociceptors, 150 opioid receptors, 154 pain threshold, 155 pain tolerance, 155 painful diabetic neuropathy, 159 peripheral neuropathic pain, 158 polymodal nociceptors, 152 polyneuropathy, 158 postherpetic neuralgia, 159 psychogenic pain, 149 referred pain, 150 sensory-discriminative aspect, 147 sharp pain, 151 slow-burning pain, 153 spinothalamic tract, 153 thalamocortical neurons, 153
Introduction Of all the sensations that arise from the human body, pain is one of the most clinically important. It is the sensation of pain that often motivates people to seek medical help as a result of a traumatic injury or a progressive disease,1 and it is usually a consequence of surgical interventions used to treat injuries or disease. Pain is also clinically important as it encourages patients to adopt behaviours that enhance healing (such as limb immobilisation following a fracture). Pain also has a very important physiological role, as it acts as the conditioning stimulus that teaches us to avoid environmental stimuli that cause harm. As children, we learn not to touch sharp objects because it hurts, and even as adults this sensation helps us to adapt to new or unusual environments. In this chapter we consider the physiological basis of pain and then explore some of the clinical consequences of this very important sensation.
The definition of pain Pain is a complex and highly subjective sensation that is affected by a large number of variables and consequently can be difficult to describe. In 1979 the International Association for the Study of Pain (IASP) defined pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage’.2 Although this definition is a little cryptic it does highlight some of the key concepts related to pain. So to help you understand some of the most important elements of this complex sensation, let us have a closer look at this definition. The first thing that the IASP definition reminds us of is that pain is unpleasant. Whether the pain is caused by touching something hot or is the result of a surgical procedure or the growth of a tumour, the experience is likely to be a negative one. Although the intensity of the experience may vary from individual to individual and has been shown to be influenced by sex, race, age, culture, beliefs, previous experience, fear and anxiety,3–5 pain is invariably unpleasant and therefore is something we avoid or try to minimise. The second concept that emerges from the definition is that pain is a sensory experience. In some respects pain is no different from other senses such as hearing, taste or vision. Just as we can look up into the sky at night and define the position of a star, describe how bright it is and even attribute to it a colour, so we can identify the site and intensity of a painful stimulus applied to our bodies. Humans are, in general, very good at identifying the site of an injury that causes pain and can readily distinguish between stimuli of different intensities and indeed modalities. A pin prick applied to the anterior surface of the arm is thus easily distinguishable from a drop of acid applied to the wrist, not just by location but by the sharp quality of the former and the burning sensation produced by the latter. Indeed, experiments using carefully controlled thermal
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stimuli have shown that humans can distinguish between two high-intensity thermal stimuli that differ by as little as 0.1°C.6 This ability to locate a painful stimulus and describe both its intensity and its quality is referred to as the sensory-discriminative aspect of pain. The definition then goes on to point out that pain is much more than a sensation — it is also an emotional experience. Because it is unpleasant (i.e. it is a negative experience) it also elicits an emotional response in that it produces changes in both mental (affective) state and behaviour (motivation). Individuals exposed to a painful stimulus become anxious, tense, distressed or scared and, if the pain is ongoing, they may become depressed, develop a feeling of hopelessness and, in some cases, may even consider suicide. In addition, individuals are motivated to remove themselves from the source of the pain, avoid similar environments in the future, and/or adopt behaviours that enhance healing. The degree to which these responses manifest themselves depends on a number of factors, including the intensity of the pain, its duration, the individual’s past experience and the availability of treatment. However, it is the emotional aspect of pain that predominates in severe or ongoing pain. The changes in mental state and behaviour that are part of the emotional component of pain are collectively referred to as the affective-motivational aspect of pain. The next part of the definition states that pain is caused by ‘actual or potential tissue damage’. This serves to remind us of two very important components about pain. The first is that it is normally produced by stimuli that are sufficiently intense to cause peripheral tissue damage (i.e. damage to peripheral tissues such as skin, muscle or visceral organs). So cutting the skin, impaired blood flow to the heart or damage to the wall of the digestive tract all cause pain because they result in ‘actual’ tissue damage. In other words the stimulus is of sufficiently high intensity for the integrity of the tissue to be compromised and we become aware of this because it results in pain. The second point that is implied by this part of the definition is that pain can also result from stimuli that have the ‘potential’ to cause tissue damage. Therefore, touching something hot or stepping on a sharp object may cause pain, but little or no tissue damage, because the rapid withdrawal reflex removes your limb from the pain source (see Chapter 6). This is possible because the threshold for pain in some tissues is lower than the threshold for tissue damage, so behavioural modifications allow us to remove ourselves from the source of the stimulus or adopt behaviours that minimise tissue damage. Therefore, one important function of pain is to advise us of the presence of stimuli that could cause us harm and thereby provide us with the opportunity to prevent it happening (or reduce its impact). The last part of the definition is probably the most cryptic as it is not immediately obvious what is meant by the phrase ‘or described in terms of such damage’. We know that pain is usually caused by stimuli that cause tissue damage (or have the potential to), but this part of the definition implies that you can experience pain that feels like it is caused by
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A
B
FIGURE 7.1
Congenital insensitivity to pain. Photographs illustrating tissue damage in a 9-month-old boy with congenital insensitivity to pain. A Damage to the left thumb and index finger caused by biting. B Severe mutilation of the tongue.
tissue damage without there being any peripheral tissue damage. Although this sounds counterintuitive, this is exactly the point. People can experience pain in parts of their body that do not exhibit any sign of disease or trauma. For example, a patient may complain of a severe burning pain in their left foot without the limb having been exposed to a heat source or showing any signs of peripheral tissue damage. The pain feels like it was caused by a burn injury, but there is no evidence of any peripheral tissue damage. In the absence of any physical evidence, in the past individuals experiencing this type of pain were sometimes considered hysterical or delusional and the pain was attributed to a psychological disorder. We now know that the majority of such types of pain are the result of damage to the parts of the peripheral and central nervous systems responsible for sensations that arise from the affected tissue. Thus, although there is no peripheral tissue damage, the pain feels like it is caused by such damage. We will later describe this pain as neuropathic pain. One of the factors that can contribute to the variable nature of the pain experienced is that the pain can be modified. In other words, the intensity of the sensation can be affected by behaviour, cognitive factors and clinical intervention. For example, in response to minor burns or cuts many people immediately rub the site of the injury. We do this because we have learned that this reduces the intensity of the pain (i.e. produces analgesia). Furthermore, soldiers in combat situations may suffer quite severe injuries but experience comparatively little pain because of the stress associated with the life-threatening situation. This type of pain modification is not limited to the battlefield, as anyone who has watched any Australian or New Zealand football code can attest. Analgesia can occur in trance-like states associated with certain religious and cultural rituals, and in the clinical environment analgesia can be produced by pharmacological agents, such as opioids, but also through other avenues, such as transcutaneous electrical nerve stimulation, acupuncture and cognitive behaviour modification.
Collectively, pain can be considered a negative multi-dimensional experience that is typically associated with peripheral tissue damage but in some pathological circumstances may exist in the absence of tissue damage. As a subjective experience, pain is highly personalised and may be modified by cultural, situational and psychological as well as clinical interventions. Just how important pain is to the wellbeing of humans is perhaps best illustrated by considering the rather serious consequences of being unable to feel pain. Individuals born with a congenital insensitivity to pain suffer horrendous injuries because they are unaware of the damage they are doing to their bodies when, for example, they sit too close to a fire or bite into their tongue while eating (see Fig. 7.1).7,8 They do not make the regular adjustments to their posture necessary to avoid damaging joints and can be completely oblivious to internal damage caused by disease. Not surprisingly, these types of injuries often become infected, are slow to heal and can be life threatening.
Types of pain Most common types of pain fall into one of three categories that vary in terms of their aetiology (or cause), duration and ease of treatment.
Nociceptive pain
Nociceptive pain is the most common type of pain and its defining characteristic is that it is produced by nociceptive stimuli, which cause or have the potential to cause peripheral tissue damage. Nociceptive pain can be subdivided into two subtypes: • External damage. Pain due to external damage is the most common form of nociceptive pain and you are likely to have experienced it. As the name implies, this type of pain usually involves trauma to the skin but may extend to the underlying tissues. It is relatively mild and has a comparatively short time course, lasting
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a few seconds to a few days. Treatment of this type of pain usually involves simple interventions that assist the healing process of the affected tissues. Moreover, pain relief is relatively easy to achieve through the use of milder forms of analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDs). • Internal damage. Pain due to internal damage is less common and usually more severe than that associated with external damage. It has numerous causes. One of the principal causes is severe trauma, for instance due to bone fractures, surgery or childbirth. This type of pain is also associated with disease. In fact, pain is a symptom of virtually every disease (e.g. cancer, arthritis) at some point during the disease progression. The duration is usually quite a bit longer than that following external injury and typically is in the order of a few days to weeks. Treatment involves removing the cause of the tissue damage, but interim management of pain can be achieved with more powerful opioid analgesics.
RESEARCH IN F CUS Management of acute pain In recent years, there has been a move towards less usage of opioid analgesics, particularly where pain management can be achieved with other medications. In many situations for acute pain, the current trend is to achieve pain management using regular dosing of paracetamol and nonsteroidal anti-inflammatory medications. The combination of these over-the-counter medications is successful in acute pain management for up to 70% of people. These can be effective if used at regular dosing times, and in some cases can avoid the need to progress to the more powerful opioid analgesics.
Neuropathic pain
As the term implies, neuropathic pain is caused by injury or disease of the nervous system rather than a peripheral tissue.9 Fortunately, this type of pain is less common than nociceptive pain. Neuropathic pain is usually more severe and has a time course that can last from a few months to many years — and sometimes the rest of a person’s life. Because of the complex aetiology and the lack of knowledge of the underlying mechanisms, treatment is challenging. In some cases pharmacological interventions, particularly when used in combination, produce positive outcomes for patients. However, for others, pain relief is less satisfactory and specialised ongoing therapies are required in an effort to alleviate the effects of neuropathic pain. Forms of neuropathic pain are dealt with in more detail later in this chapter.
Psychogenic pain
It is well recognised that some people report pain that may be severe and persistent but for which there appears to be
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no underlying pathology. The pain experienced by these patients (typically headaches, abdominal pain, back pain) is indistinguishable from that experienced by people with identifiable injuries or disease. Such pain can be debilitating and consequently interferes with their ability to function normally. In the absence of any physical explanation for the symptoms, despite exhaustive clinical examination and testing, the assumption is made that the pain is the result of a psychological disorder, so it is termed psychogenic pain. It is very likely that some pain of neuropathic origin was at one time incorrectly diagnosed as psychogenic pain due to similarities in symptoms and the absence of any visible cause. However, due to improvements in diagnosis and more sophisticated medical imaging, diagnosis of psychogenic pain is less common.10 FOCU S ON L EA RN IN G
1 Describe what is meant by the sensory-discriminative aspect of pain. 2 Describe what is meant by the affective-motivational aspect of pain. 3 Differentiate between nociceptive, neuropathic and psychogenic pain. 4 Describe some of the ways in which pain can facilitate the healing process.
Pain terminology Whereas some types of pain have a relatively short time course, others last a very long time indeed. In order to discriminate between these types of pain, the terms acute pain and chronic pain are used. Acute pain refers to any pain that lasts less than 3 months. In contrast, chronic pain is any pain that lasts longer than 3 months. The timelines outlined in the previous section suggest that most neuropathic pain is chronic pain, and although this is often the case, the two terms should not be used interchangeably. The terms acute and chronic refer exclusively to the time course of the pain, irrespective of aetiology. For instance, neuropathic pain that resolves within 3 months is considered acute, while cancer-related nociceptive pain that persists for more than 3 months is chronic. Approximately one-fifth of Australians suffer from chronic and recurring pain,11 and you are likely to encounter patients with chronic pain in all areas of the health sector. Another important aspect of pain is the location of the pain. Typically, neuropathic pain feels like it is coming from the part of the body that the affected nerve innervates. For example, a compression injury of branches of the sciatic nerve (shown in Fig. 6.15) caused by damage to a vertebral disc can result in pain in the leg or foot. Interestingly, this disconnection between injury site and pain location is not restricted to neuropathic pain, but also occurs in some forms of nociceptive pain. For example, the first symptom of appendicitis is usually tenderness in the midline
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abdominal region, despite the inflamed appendix being located in the right lower quadrant (see Chapter 27). Similarly, one of the classical signs of myocardial infarction (see Chapter 23) is a shooting pain referred to the left shoulder or arm, when the tissue damage is actually occurring in the heart (see Fig. 7.2). We refer to this type of pain as referred pain. Following injury the affected tissue becomes very sensitive to subsequent stimuli. Thus, we tend to protect a bruised heel or burnt hand because any additional stimulation greatly enhances the pain. The increased sensitivity that follows peripheral tissue damage can be attributed to two factors: there can be an amplified neural response to any subsequent painful stimulus, or a decrease in the threshold such that previously non-painful stimuli now cause pain. To accommodate these two different characteristics we use the term hyperalgesia to describe the situation where the original tissue damage augments the pain produced by subsequent high-intensity (damaging) stimuli. The term allodynia refers to a reduction in the threshold such that pain is now produced by low-intensity
Lung and diaphragm
Liver
Liver
Heart Pancreas Stomach Ovary Kidney
Small intestine
Kidney
Colon Bladder
Appendix
Ureter
A
B B
FIGURE 7.2
Visceral referred pain. Examples of some of the typical sites of referred pain from visceral structures on A the anterior and B the posterior surface of the body. (See also Box 7.2 later in this chapter.)
BOX 7.1
(non-damaging) stimuli. (See Box 7.1 for key pain terminology.) These changes in sensitivity occur in nociceptive pain and many forms of neuropathic pain. For example, individuals with trigeminal neuralgia (an alteration to cranial nerve V causing episodes of excruciating pain to the face) rarely wear high collars or scarves because of mechanical allodynia, where even the gentle touch of such clothing can elicit excruciating pain referred to the face.12
The physiology of pain Since pain is the conscious perception of a stimulus that causes tissue damage, this means that the presence of the stimulus has to be detected in the tissue and then information about the tissue damage relayed to the cerebral cortex, where it is consciously perceived as pain. In order to enable this, small patches of each peripheral tissue (such as skin, muscle and viscera) are connected to regions of the cerebral cortex by a three-neuronal pain pathway (see Fig. 7.3). The first-order neuron in this pathway carries the information from the periphery to the spinal cord, where it synapses with the second-order neuron. This second-order neuron relays the information to a number of sites in the brain, including the thalamus. Some of the brain sites are involved in the autonomic nervous system reflex responses to injury (such as increases in cardiac output or ventilation rate). However, conscious perception of tissue damage is transmitted from the thalamus via the third-order neuron, which relays the information to the cerebral cortex. It is here that the individual becomes aware of the pain. Large numbers of these three-neuronal relays are arranged in parallel to ensure that most tissues in the body are connected to the cerebral cortex. The structure and function of each of these three classes of neuron are considered in more detail in the following section.
Nociceptors
Nociceptors are the first-order neurons in the pain pathway. They are a subpopulation of the primary sensory neurons that collectively are responsible for the detection of all sensations, such as touch, temperature, muscle length and joint position (see Chapter 6). Like other primary sensory neurons, they have a cell body located in the posterior root
Key pain terminology
Acute pain Allodynia Analgesia Chronic pain Hyperalgesia Referred pain
Pain that lasts less than 3 months. Pain due to a stimulus that does not normally provoke pain. Absence of pain in response to a stimulus that would normally be painful. Pain that lasts longer than 3 months. An increased response to a stimulus that is normally painful. Pain perceived as occurring in a region of the body topographically distinct from the region in which the actual source of pain is located.
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Cerebral cortex
Thalamus
Peripheral tissues Spinal cord
Third ventricle
FIGURE 7.3
Basic arrangement of the pain pathway. Schematic diagram showing that the pain pathway consists of three neurons, which connect peripheral tissues (skin, muscle and viscera) with the cerebral cortex. Large numbers of these three neuronal pathways are arranged in parallel to ensure that most tissues in the body are connected to the cortex.
ganglia, just outside the spinal cord, and an axon that runs from the peripheral tissue through a peripheral nerve and terminates within the superficial layers of the posterior horn of the spinal cord (see Fig. 7.4). The important thing about nociceptors is that they are selectively activated by high-intensity stimuli that have the potential to cause tissue damage. Thus, they are not activated by low-intensity (innocuous) stimuli, and only respond when the stimulus is of sufficient intensity to threaten the integrity of the tissue they innervate. In addition, tissue damage leads to the release of substances that produce pain. These substances are intricately involved in the inflammation process (see Chapter 13 for more detail) and often cause a cascade of inflammatory events, such as vasodilation, local swelling and stimulation of nociceptors. The most recognised substances are bradykinin, histamine and prostaglandin. Some substances are released by cells that migrate to the injured site, such as mast cells and white blood cells, while other substances are released by the tissues themselves. These substances flood the injured site during the inflammatory process and have been referred to as an ‘inflammatory soup’ (see Fig. 7.5). Collectively, they stimulate nociceptors, which transmit the pain signals to the brain and then the individual becomes aware of the injured tissue. Not surprisingly, nociceptors have been identified in virtually every peripheral tissue from which we experience pain. However, a lot more is known about the properties of the nociceptors responsible for sensations that arise from the skin than from other structures. Therefore, we begin
FIGURE 7.4
Detailed arrangement of the pain pathway. The relationship between nociceptors (red), spinothalamic tract neurons (blue) and thalamocortical neurons (green) as they course through the peripheral and central nervous systems.
by examining the properties of these cutaneous nociceptors before considering what is known about the neurons responsible for detecting tissue damage in deeper tissues such as muscle and viscera.
Cutaneous nociceptors
Cutaneous pain refers to that associated with the skin. It is well established that there are two distinct pain sensations — sharp pain and burning pain — that differ in their timing and quality. These can be clearly demonstrated by a mechanical injury such as that produced by a paper cut or pin-prick. Very shortly after a mechanical injury we experience a pain that has a ‘sharp’ quality. A few seconds later we experience a second pain sensation that is usually described as ‘burning’. The burning pain can also be elicited by exposure to high temperatures and by the application of pain-producing chemicals such as
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TABLE 7.1 Comparison of the structural and functional properties of cutaneous nociceptors
FIGURE 7.5
Tissue damage leading to inflammation and stimulation of nociceptors. In this example, tissue damage has occurred to the skin causing the release of a ‘soup’ of substances, namely bradykinin, serotonin, potassium and prostaglandin, which stimulate nociceptors. Mast cells degranulate (release the contents of) histamine when triggered by tissue damage, which stimulates the nerve ending but also causes the blood vessels to allow fluid to leak into the extracellular space, causing swelling and more pain stimulation.
acid. Underlying these two sensations are two classes of nociceptor in the skin that are quite distinct in structural and functional properties: high-threshold mechanoreceptors and polymodal nociceptors (see Table 7.1). Cutaneous sensation (all sensation of the skin, including pain) is organised into particular regions known as dermatomes, as the branches from one spinal nerve innervate a defined skin region (see Chapter 18).
High threshold mechanoreceptors
Structurally, high threshold mechanoreceptors have small diameter myelinated axons in which action potentials travel along their length at about 5–15 m/sec (metres per second). The afferent end of this type of neuron is located within the dermis of the skin as simple ‘free nerve endings’ (which function in the same way as dendrites), with none of the specialised structures associated with low threshold mechanoreceptors (such as touch receptors).
FEATURE
HIGH-THRESHOLD MECHANORECEPTORS
POLYMODAL NOCICEPTORS
Axon diameter
Small
Small
Myelin sheath
Yes
No
Conduction velocity
5–15 m/sec
0.5–2.5 m/sec
Activated by lowthreshold stimulus
No
No
Activated by mechanical injury
Yes
Yes
Activated by thermal injury
No
Yes
Activated by damaging chemicals
No
Yes
As the name suggests, high threshold mechanoreceptors are activated by high intensity mechanical stimuli such as a pin-prick, cutting or pinching the skin. They are completely unresponsive to low-threshold stimuli (touch, vibration, warmth) or to painful thermal or chemical stimuli. Clearly this class of cutaneous nociceptor is very well-suited to detecting mechanical injury of the skin as they are activated only by mechanical stimuli at intensities high enough to cause damage. In addition, because these neurons have myelinated axons they are able to relay information about a mechanical injury to the spinal cord rapidly. For these reasons, high threshold mechanoreceptors are responsible for detecting the fast-sharp pain that follows a mechanical injury of the skin.
Polymodal nociceptors
Like high threshold mechanoreceptors, cutaneous polymodal nociceptors have free nerve endings for their afferent end in the dermis, with some projecting into the epidermis. Therefore, they are well positioned to detect stimuli affecting the skin. They have small-diameter axons but no myelin sheath and consequently action potentials travel along these unmyelinated axons relatively slowly (0.5–2.5 m/sec) compared to high-threshold mechanoreceptors. As their name suggests, this class of nociceptors respond to multiple modalities of high intensity stimuli. They respond to the same high intensity mechanical stimuli that activate high-threshold mechanoreceptors but in addition are activated by high temperatures (above 45°C) and a range of chemicals (such as acid). This is important, because these intense thermal and chemical stimuli will cause pain when exposed to the skin. Thus, this class of nociceptor is truly polymodal in that they respond to mechanical, thermal and chemical stimuli of sufficient intensity to cause damage to the skin. As polymodal nociceptors are activated by high intensity mechanical stimuli, but have unmyelinated axons and hence a slow conduction velocity, they are responsible
for the slow-burning pain that follows mechanical injury of the skin. In addition, the burning sensation that is characteristic of heat or chemical injury to the skin is relayed by these receptors. A mechanical injury such as a cut will, of course, activate both high threshold mechanoreceptors and polymodal nociceptors in the skin at exactly the same time. However, because action potentials travel along myelinated axons much more quickly than along unmyelinated axons, the information carried by the high threshold mechanoreceptors reaches the spinal cord before that carried by the polymodal nociceptors. Because this time difference is maintained all the way through to the cerebral cortex the first sensation we perceive is mediated by the high threshold mechanoreceptors and has a sharp quality (fast-sharp pain) and this is followed a couple of seconds later by a burning sensation because of the activity of polymodal nociceptors (slow-burning pain).
Musculoskeletal and visceral nociceptors
Studies of nociceptors in deeper tissues (muscles, joints and visceral organs) suggest that the vast majority have unmyelinated axons and therefore relatively slow conduction velocities.13–15 Some of these are activated by high-intensity mechanical stimuli as well as a variety of pain-producing chemicals. Although the temperature sensitivity of these neurons can be difficult to test, many of them respond to high temperatures, suggesting that they are like polymodal nociceptors. As these neurons are not activated by low-intensity stimuli they are very well-suited at detecting the twisting of joints, the distension of visceral organs, and ischaemia, which often causes pain in deeper tissues. A new class of nociceptor has been identified in joints, muscle and visceral organs that is completely insensitive to stimulation in normal healthy tissue. These nociceptors cannot be activated by either low intensity or high intensity stimulation and are called silent (or ‘sleeping’) nociceptors.15 However, if the peripheral tissue these neurons innervate becomes inflamed, they are activated and may even begin to respond to relatively low-threshold stimuli — that is, stimuli that would not cause pain in healthy tissue. Interestingly, these neurons do not appear to have any physiological role but instead are responsible for the sometimes debilitating pain that is often associated with tissues that become inflamed because of damage or disease.
F O CUS O N L E A R N IN G
1 Discuss why a paper cut causes two sensations that have different qualities and delays. 2 Describe the anatomy of nociceptor cell bodies and axon terminals. 3 Provide an explanation of the type of nociceptor responsible for the pain associated with myocardial infarction (heart attack).
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Spinothalamic tract neurons
The nociceptors that relay action potentials enter the spinal cord (although remember a neuron itself does not travel; rather it is the action potential which moves as it travels along the neuron). The ascending pathway connects the spinal cord with the thalamus and consequently is referred to as the spinothalamic tract (refer to Fig. 6.19). Spinothalamic tract neurons are second-order neurons in the pain pathway and they receive information about peripheral tissue damage from nociceptors and relay it to the thalamus. Spinothalamic tract neurons have their cell bodies located in the grey matter of the posterior horn of the spinal cord (see Fig. 7.4). Therefore, they are well positioned to receive the inputs from the nociceptors that terminate there. The axons of spinothalamic tract neurons cross the midline of the spinal cord anterior to the central canal and then ascend along the length of the spinal cord in the white matter on the opposite side. The axons of spinothalamic tract neurons from different parts of the body appear to run together in a white matter tract (the funiculus, which translates as ‘slender cord’), which is located between the anterior funiculus and lateral funiculus and is known as the anterolateral funiculus (see Fig. 7.4). The axons of spinothalamic tract neurons project out of the spinal cord, through the brainstem and terminate in the thalamus. The thalamus is a large, oval-shaped structure located deep within the forebrain underneath the cerebral hemispheres and lateral to the third ventricle (see Fig. 7.4). It is a major component of the diencephalon, and receives information from all the senses (except smell) and passes this on to the cerebral cortex. The thalamus is made up of a large number of nuclei, named according to their anatomical position. Spinothalamic tract neurons terminate in two structurally distinct regions of the thalamus. Some neurons terminate in a group of nuclei in the posterolateral (back and to the side) part of the thalamus, while another population synapse in the medial (towards the midline) region (see Fig. 7.4). These two different termination sites form the basis for projections from the thalamus to the cerebral cortex. Spinothalamic tract neurons can receive input from nociceptors in various body locations, which may contribute to reasons why referred pain occurs (see Box 7.2 Mechanisms of referred pain).
Thalamocortical neurons
The third-order neurons of the pain pathway collect the information relayed to the thalamus by spinothalamic tract neurons and relay this to the cerebral cortex, and so are referred to as thalamocortical neurons. As there are two thalamic sites that receive information about peripheral tissue damage from the spinothalamic tract, there are two distinct populations of thalamocortical neurons: • Thalamocortical neurons with their cell bodies in the posterolateral parts of the thalamus are activated by
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BOX 7.2
Mechanisms of referred pain
Although the origin of cutaneous and musculoskeletal pain is usually fairly well-defined (that is, we can determine the origin of the pain fairly well), visceral pain can be a little more difficult to localise. For example, pain from the heart is often referred to the left shoulder and arm. It is thought that when many nociceptors from different peripheral tissues merge onto the same spinothalamic tract neurons, the pain will be referred. So, a population of spinothalamic tract neurons may receive input from nociceptors in the left arm as well as the heart. Typically, they are activated by injury of the skin or muscles of the left arm, and the cerebral cortex associates activity in these neurons with arm pain. However, the cerebral cortex cannot distinguish between this and activation of the same neurons by nociceptors in the heart, so the angina pain is referred to the left arm. The exact reason for this is not known.
high-intensity stimulation of small, well-defined regions in the periphery and relay this information in a highly ordered fashion to the somatosensory cortex of the parietal lobe and the adjacent insular cortex. The insula is the lobe of the cerebral cortex hidden behind the parietal and temporal lobes, and the region where these lateral thalamocortical neurons terminate is referred to as the interoceptive cortex (see Fig. 7.4) as it receives sensory information about the physiological condition of the whole body. • Thalamocortical neurons that are located in the medial thalamus tend to be activated by painful stimulation of large areas of the body — for instance, a whole limb — and relay this information to the anterior cingulate cortex of the frontal lobe (see Fig. 7.4).
Cortical representation of pain
There are three known cortical regions that are responsible for the perception of pain: the lateral pain pathway that terminates in the parietal and insular lobes, and a medial pain pathway that terminates in the frontal lobe. Functional brain imaging and analyses of patients with damage to these different cortical areas suggest that they are responsible for different aspects of the pain experience. Brain imaging analyses of both somatosensory and interoreceptive cortices have revealed that they are activated by painful peripheral stimuli.16 In addition, electrical stimulation of the interoreceptive cortex in conscious humans has shown that the pain is located in well-defined peripheral tissues.17 This is supported by the observation that damage to this part of the cortex interferes with pain perception.18 These observations have led to the suggestion that the lateral pain pathway is responsible for the sensory-discriminative aspect of pain (i.e. the position, intensity and modality of the tissue damage).
Analysis of the anterior cingulate cortex with functional imaging has revealed that it is activated by peripheral tissue damage and that these responses can be alleviated by hypnosis.19,20 Furthermore, patients who have damage in this region can still feel pain but are less troubled by it.21 Therefore, it is believed that the medial pain pathway is involved in the affective-motivational aspect of pain.
RESEARCH IN F CUS Medical use of cannabis The use of medical cannabis was approved in 2016 and 2017 in Australia and New Zealand. Marijuana has not been approved as a medicine, and indeed remains an illegal drug; however, it is the chemicals in marijuana known as cannabinoids that have been approved, and it is mainly used in the form of cannabinoid oil or cannabidiol. These cannabinoids, which include tetrahydrocannabinoid (TCH) affect cannabinoid receptors in the nervous system. The main uses for medical cannabis are for chronic pain, neuropathic pain, muscle spasticity particularly associated with multiple sclerosis, nausea and vomiting associated with chemotherapy use for cancer patients, and anorexia (loss of appetite) which leads to severe tissue wasting. Adverse effects of medical cannabis range from dizziness and alterations in memory through to the development of schizophrenia.
Neuromodulation of pain
As well as the neural pathways, several substances are capable of altering the pain pathways. Collectively, these are referred to as neuromodulators. They are found in the pathways that control information about painful stimuli throughout the nervous system. Neuromodulators are substances, other than neurotransmitters, which are released by neurons and transmit signals to other neurons that change the activities of these neurons. It is thought that neuromodulators are released in response to tissue injury (such as prostaglandins, bradykinin) and chronic inflammatory changes (cytokines; see Chapter 12). Excitatory neuromodulators (ones that promote the action potential) include substances such as glutamate, substance P, somatostatin and vasoactive intestinal polypeptide. Inhibitory neuromodulators (ones that delay or stop the action potential) include gamma-aminobutyric acid (GABA), 5-hydroxytryptamine (serotonin), noradrenaline and endorphins. Endorphins (endogenous opioids produced by the body) inhibit transmission of pain impulses in the spinal cord and brain by binding to opioid receptors. These are receptors in the central nervous system that block pain transmission. You may be familiar with the term endorphins as they are released during exercise and produce the ‘runner’s high’ that gives the exercising individual a sense of euphoria, despite being physically drained and experiencing pain. It is thought that endorphins attach to the limbic and prefrontal areas of the brain (involved in emotion), which alters the
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Interneuron Impulse from brain (efferent pathway)
Narcotic
Excitatory impulse (afferent pathway)
Opiate receptor
Pain transmission blocked by release of endorphins
To
s mu a l tha
Interneuron
To thalamus
Dorsal root ganglion
Pain receptors (afferent pathway) FIGURE 7.6
Descending pathway and endorphin release. Endorphin receptors are located close to the known pain receptors in the peripheral tissues and pain pathways in the spinal cord.
individual’s mood. Beta-endorphin is a potent substance, released from the hypothalamus and pituitary gland, which results in analgesic effects. It may also be responsible for general sensations of wellbeing. Encephalin, found in the neurons of the brain and spinal cord, is a weaker analgesic than other endorphins but is more potent and longer lasting than morphine. All endorphins attach to opioid receptors on the cell membrane of the afferent neuron (see Fig. 7.6) and inhibit the release of excitatory neurotransmitters. Opioid analgesics relieve pain by attaching to the opioid receptors and enhancing the natural endorphin response. Stress, excessive physical exertion, acupuncture, sexual intercourse and other factors increase the levels of circulating endorphins, serotonin, noradrenaline and other neurotransmitters, thereby raising the pain threshold. FOCUS O N L E A R N IN G
1 Discuss why a cut in the right thalamus might interfere with the ability to feel pain on the left side of the body. 2 Outline which cortical sites are thought to be involved in the conscious perception of pain. 3 Describe how neuromodulators of pain alter pain signal transmission.
Clinical manifestations of pain Pain is complex and highly subjective, meaning that no two people are likely to experience the same level of pain for a given painful stimulus. Pain tolerance is the amount of time or the intensity of pain that an individual will endure before initiating overt pain responses. Pain tolerance varies greatly among individuals, as well as in the same individual over time, because of the body’s ability to respond differently to noxious stimuli. It is influenced by cultural perceptions, expectations, role behaviours, gender and physical and mental health.22 It generally decreases with repeated exposure to pain, fatigue, anger, boredom, apprehension and sleep deprivation; and may increase with increased alcohol consumption, medication, hypnosis, warmth, distracting activities and strong beliefs or faith. The pain threshold is the lowest intensity at which a stimulus is perceived as pain and may be influenced by genetics.23 Intense pain at one location may increase the threshold in another location. For example, a person with severe pain in one knee is less likely to experience chronic back pain that is less intense. Therefore, an individual with many painful sites may report only the most painful one. Then, when the dominant pain is diminished, the individual identifies other painful areas.
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While pain is a subjective sensation, it may result in changes in the level of autonomic nervous system activation. Patients often experience an increase in heart rate, blood pressure, ventilation, nausea and vomiting, as well as sweating, when experiencing pain, especially acute surgical pain. However, these clinical signs are not universal in all individuals who are experiencing pain. When there is damage to the internal organs, this can also result in activation of the sympathetic nervous system, causing an elevation in cardiovascular and respiratory responses.
Evaluation and treatment The evaluation of pain is often difficult. Nurses are usually the primary clinicians responsible for assessing a patient’s
A
pain. Foremost in the evaluation of pain is to listen to, and believe, what the patient says about their level of pain. There is no single test that assesses an individual’s level of pain and, despite numerous measures to provide an objective measure of pain, the most useful is asking the patient to relate the location, type and duration of the pain, as well as any therapies previously used to effectively alleviate pain. As well as receiving information from the patient about their pain, there are numerous pain measurement tools that the clinician can use to obtain more information about the patient’s pain (see Fig. 7.7). These can be used to assess changes in the patient’s level of pain and response to therapies. In addition, facial pain scales can be used for individuals who may not be able to vocalise their feelings of pain or who cannot speak (see ‘Paediatrics and pain’ below).
Pain intensity scale 0–10 numerical pain intensity scale
0 No pain
B A
3
2
1
4
Mild pain
5 6 Moderate pain
9
7 8 Severe pain
10 Worst possible pain
Pain distress scale Simple descriptive pain distress scale
None
Annoying Uncomfortable
Bad
Dreadful
Agonising, unbearable
C A
0 NO HURT
1 HURTS LITTLE BIT
2 HURTS LITTLE MORE
3 HURTS EVEN MORE
4 HURTS WHOLE LOT
5 HURTS WORST
D A
0
2
4
6
8
10
FIGURE 7.7
Scales for rating the intensity of pain. The numerical and facial scales can be used by patients to self-rate their pain. A Pain intensity scale. B Pain distress scale. C Facial pain scale for children. D Facial pain scale for adults, used in multiple languages.
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The management of pain can be divided into pharmacological and non-pharmacological therapies, or a combination of both. The principal management aim should be to treat the cause of pain, if possible. Second, choose appropriate therapies that target the type of pain. For instance, opioids and NSAIDs target nociceptive pain. If using pharmacological agents, provide doses regularly and prevent pain from arising, such as postsurgical pain. The administration route also becomes important when deciding the severity of the pain. While originally developed for the management of cancer pain, the World Health Organization (WHO) analgesic ladder provides a simple scale for the determination of pharmacological agents in pain management (see Fig. 7.8). The effect of different types of analgesic agents on pain pathways is illustrated in Fig. 7.9. If the pain is severe, chronic and bilateral, then more effective relief can be produced by a midline myelotomy (see Fig. 7.10). The objective of this procedure is to cut the axons of the spinothalamic tract neurons as they cross the midline in front of the central canal. A midline myelotomy is a complicated procedure as it usually requires a laminectomy to access the posterior surface of the spinal cord and special care to ensure that the lesion is made at the correct level in order to target the axons of the appropriate spinothalamic tract neurons. However, the advantage of the procedure is that it cuts the axons of the spinothalamic tract neurons crossing the midline from both sides of the spinal cord and so produces bilateral analgesia, which is
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Perception
Cortex
Thalamocortical projections Systemic opioids
Epidural and local anaesthetics Transmission
Thalamus
Local anaesthetics Transduction
Spinothalamic Primary afferent tract nociceptor
Noxious stimulus
FIGURE 7.9
Schematic diagram outlining the nociceptive pathway for transmission of painful stimuli. Interventions that prevent nociceptive transmission are shown at the points in the pathway that are thought to be their sites of action. Agents that block the transduction of pain actually prevent the generation of pain action potentials. In contrast, agents that block transmission actually stop the relay of action potentials to the cerebral cortex.
Severe pain Opioid + non-opioid ± Adjuvant Moderate pain Opioid + non-opioid ± Adjuvant Mild pain Non-opioid ± Adjuvant Paracetamol NSAID
Codeine Tramadol Oxycodone Step 2
Morphine Oxycodone Hydromorphone Methadone Fentanyl Step 3
Step 1 Advance up the ladder if pain persists FIGURE 7.8
Strategy for pharmacological management of pain using the World Health Organization analgesic ladder. Multiagent therapy is usually required for optimal pain management. Patients with mild pain should be started on a nonopioid analgesic, and those with moderate pain on a step 2 opioid. Many patients can benefit from the addition of a non-opioid to the opioid (e.g. for bone pain) or an adjuvant agent to the opioid (e.g. for neuropathic pain). If this combination does not produce adequate relief or the patient presents with severe pain, step 3 opioids should be begun initially.
FIGURE 7.10
Surgical approaches to pain relief. Two approaches to the surgical alleviation of pain that target the axons of spinothalamic tract neurons as they project through the anterolateral funiculus, A, and cross the midline in front of the central canal, B.
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particularly beneficial when the pain is of visceral origin (see Box 7.3, Surgical treatment of chronic pain.)
Pathophysiology of pain So far we have considered pain from a physiological perspective and have identified it as both having a protective BOX 7.3
Surgical treatment of chronic pain
Due to their well-characterised anatomical location, the axons of spinothalamic tract neurons are sometimes targeted in surgical approaches for the treatment of severe chronic pain in patients whose pain is inadequately controlled by analgesics. Because of the importance of these neurons in the onward transmission of the pain signal, cutting the axons should result in abolition of the pain. In an anterolateral cordotomy (-otomy refers to surgical cutting) the objective is to cut the axons of the spinothala mic tract as they course through the anterolateral funiculus. At one time this involved exposing the lateral surface of the spinal cord with an operation called a laminectomy, so that the cordotomy could be performed under direct visual control. Today, it is performed percutaneously (through the skin) and involves the insertion of an electrode into the anterolateral funiculus of the upper cervical segments of the spinal cord, which is visualised using computed tomography (CT) scanning. The cut is made by heating the tip of the electrode. Anterolateral cordotomy is particularly useful when the pain is unilateral, as the lesion only affects the axons of the spinothalamic tract on one side of the body (see Fig. 7.10A).
function (warning us about environments that can cause us harm) and acting as a stimulus to adopt behaviours that enhance healing. However, when the nervous system components that are responsible for detecting pain are themselves affected by injury or disease, the consequences can be severe and persistent neuropathic pain. It has been estimated that chronic pain affects about 3.2 million Australians and that the total cost of chronic pain on the Australian economy is about $34.3 billion per year — that is, more than $10 000 per person with chronic pain.24 Healthcare costs are estimated to comprise 20% of these costs (about $7 billion per year), mainly due to inpatient, outpatient and out-of-hospital medical costs.24 The different types of peripheral pathophysiological pain are summarised in Table 7.2.
Peripheral neuropathic pain
Peripheral neuropathic pain results from damage to the peripheral nervous system including the cranial nerves, spinal nerves and any of the peripheral nerves that branch from these. Typically the pain feels like it is coming from the parts of the body that the affected nerves innervate — that is, referred pain — and the pain often has a characteristic quality (e.g. burning or shooting). The term mononeuropathy is used where only a single nerve is involved and polyneuropathy is used where multiple nerves are affected. The nerve damage that causes the pain can be the result of a range of factors, including physical injury, disease, infection or poisoning (e.g. chemotherapy). One of the most common causes of painful peripheral neuropathies is where a peripheral nerve is damaged by a traumatic injury. The damage can be caused by a variety of mechanical insults such as nerve compression (following a crush injury) or transection (as the result
TABLE 7.2 Clinical features and likely pathophysiology of peripheral neuropathies PAIN SYNDROME
PATHOPHYSIOLOGY
CLINICAL FEATURES
Complex regional pain syndrome (type II)
Traumatic injury of peripheral nerves causing spontaneous action potentials to be generated in both damaged and intact nociceptors
Ongoing pain, allodynia, hyperalgesia, oedema, cutaneous blood flow and sweating abnormalities
Painful diabetic neuropathy
Hyperglycaemia leading to degeneration of unmyelinated sensory neurons
Loss of sensation and burning pain in feet and hands
Postherpetic neuralgia
Infection of peripheral nerves with varicella zoster virus leading to sensory neuron loss
Loss of sensation, pain and allodynia in dermatome of infected nerve
Lumbosacral radicular pain
Herniated intervertebral disc, resulting in compression injury of spinal nerve causing spontaneous activity in nociceptors
Lancinating (stabbing, piercing sensation) pain in the thigh or lower leg
Phantom limb pain
Spontaneous activation of nociceptors in neuroma and sensitisation of central neurons as a result of nerve transection during amputation
Ongoing cramping or aching pain referred to amputated limb
Trigeminal neuralgia (Tic Compression of the trigeminal nerve (sometimes by an douloureux) atypical blood vessel) as it enters the brain
Episodes of severe, sharp, piercing pain referred to the facial region sometimes triggered by light touch
Chemotherapy-induced peripheral neuropathy
Loss of sensation and spontaneous burning pain
Chemotherapy-induced neurotoxicity of myelinated primary sensory neurons
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of a penetrating injury or surgical procedure). The resultant pain is severe, often has a burning quality and is characterised by both hyperalgesia and allodynia. These types of pain used to be referred to as causalgias but are now known as complex regional pain syndromes (CRPSs).25 Painful diabetic neuropathy is an example of a neuropathic pain caused by either type 1 or type 2 diabetes mellitus. Unfortunately, it occurs in more than 50% of individuals with long-standing diabetes. Painful diabetic neuropathy appears to be due to hyperglycaemia, as the pain can be reduced in severity and delayed in onset by careful control of blood glucose levels.26 The longer the length of the axons, the more susceptible the neurons are to hyperglycaemia, which is why painful diabetic neuropathy is usually characterised by numbness and burning pain in the distal extremities (a ‘stocking and glove’ type distribution) (see Fig. 7.11) that gradually spreads proximally and becomes more severe.27 The lack of sensation in the affected areas may result in the formation of ulcers, which may require limb amputation if they become gangrenous. The major cause of the painful neuropathy appears to be degeneration of unmyelinated axons caused directly by hyperglycaemia, as well as ischaemia caused by hyperglycaemia-induced damage to the blood vessels supplying the peripheral nerves. Further descriptions of diabetes are in Chapter 36. Infections of the peripheral nerves can also result in neuropathic pain. About 20% of Australians will experience shingles (herpes zoster) during their lifetime. In shingles, the virus responsible for chickenpox (varicella) can lie dormant in the sensory nerves for years and then spontaneously erupt to cause a rash and painful blisters in the skin innervated by the infected nerves. Although the rash and blisters usually heal, in some sufferers the pain persists and is referred to as postherpetic neuralgia.
A
B A
C A
FIGURE 7.11
Painful diabetic neuropathy. In poorly controlled diabetes, hyperglycaemia affects the longest sensory neurons first. A Normal intact nervous system. B Diabetes-affected nervous system with degeneration of axons in the distal extremities, resulting in C diabetic neuropathy with the characteristic ‘stocking and glove’ distribution.
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Given the diversity of causes of these peripheral neuropathies, it is perhaps not surprising that the mechanisms that underlie them differ and indeed in many cases remain poorly understood. Probably one of the better understood pathologies is that following a traumatic injury of a peripheral nerve responsible for CRPS. Where the nerve is completely transected (cut) or crushed, the portions of the axons distal to the injury typically degenerate because they are separated from their supporting cell bodies in the posterior root ganglia. This results in sensory loss due to the denervation of the peripheral tissue innervated by the affected nerve, as well as the formation of a neuroma at the site of the nerve damage. A neuroma consists of a disorganised array of scar tissue, neuroglial cells and inflammatory cells, as well as the axons of neurons attempting to regenerate along the damaged nerve and reinnervate the peripheral tissues. The regenerating axons within the neuroma itself appear to be highly sensitive and this is partly responsible for some of the symptoms associated with this type of injury. Action potentials appear to arise spontaneously from the neuroma, which may partly explain the pain in the absence of any peripheral stimuli. The structure itself is also very sensitive to mechanical stimuli, with gentle tapping of the skin overlying the neuroma or movement of the affected limb enough to elicit action potentials and produce pain.28 In some patients, the sympathetic nervous system also appears to play a role in CRPSs, because local anaesthetic blockade of sympathetic ganglia (or pharmacological block of adrenergic receptors) alleviates the pain. This pain appears to be a consequence of intact nociceptors in tissues that have been denervated by the nerve injury, that then become sensitive to noradrenaline released from sympathetic postganglionic neurons nearby.29 These intact nociceptors (which have axons in nerves not affected by the peripheral nerve injury) become sensitised and exhibit spontaneous activity and augmented responses to peripheral stimuli. In addition to these changes in the properties of primary sensory neurons brought about by damage to the nerve, there is evidence to suggest that changes in the properties of neurons within the central nervous system may also contribute to neuropathic pain. Second-order neurons in the parts of the spinal cord receiving input from damaged nerves exhibit higher rates of spontaneous activity, show greatly enhanced responses to nociceptive stimuli applied to the periphery and become sensitive to low-intensity stimuli. The enhanced responsiveness of these neurons in the central nervous system is referred to as central sensitisation and appears to be a consequence of changes in the excitability of the second-order neurons themselves, as well as a reduction in the ongoing inhibitory influence exerted on these neurons by endogenous pain control circuits (disinhibition). Together with the peripheral mechanisms detailed above, these central changes are thought to be responsible for the spontaneous pain, hyperalgesia and allodynia associated with some forms of neuropathic pain.
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There is now compelling evidence to suggest that newborn children have the neural apparatus necessary to perceive pain. Despite this, pain in young children is very poorly managed with analgesics administered infrequently or sometimes not at all. The evaluation of pain in infants and young children represents a significant challenge as they are unable to effectively communicate what they feel and may therefore receive inadequate pain control following traumatic injury or during painful medical procedures (Table 7.3). A number of behavioural assessment tools have been developed to allow carers to
obtain a quantitative estimate of pain in preverbal children. The most popular of these for both procedural and postoperative pain is the Face Legs Activity Cry Consolability (FLACC) scale. The presence of pain-related behaviours associated with each of these five components is scored from 0 to 2 giving an overall rating of 0 (no pain) through to 10 (severe pain). This scale has been used successfully in the assessment of pain in neonates through to teenagers where it is particularly useful in the assessment of individuals with impaired cognitive function.
TABLE 7.3 Pain perception in infants, children and the elderly INFANTS
CHILDREN
Pain threshold
Painful neonatal experiences increase pain sensitivity
Lower or the same as No increase compared adults with middle age
Physiological symptoms
Increased heart rate, blood pressure and ventilatory rate; flushing or pallor, sweating and decreased oxygen saturation
Same as infants; Same as infants and nausea and vomiting children; nausea and vomiting
Behavioural responses
Changes in facial expression, crying and body movements, with lowered brows drawn together; vertical bulge and furrows in the forehead between the brows; broadened nasal root; tightly closed eyes; angular, square-shaped mouth, chin quiver; withdrawal of affected limbs, rigidity, flailing
Individual responses vary
Central pain syndromes
Forms of pain caused by damage to the central nervous system are known as central pain syndromes. Such forms of pain are typically very intense, aching, shooting pains that feel like they are due to damage to peripheral tissues but where clinical examination fails to identify any peripheral tissue damage or peripheral nervous system pathology. The causes of central pain syndromes were first identified by postmortem examination of the brains of individuals with CRPSs, which revealed damage in parts of the brain and/ or spinal cord known to be involved in the processing of pain.30 The damage may be the result of a number of factors, including traumatic injury, tumour, stroke or even the side effects of neurosurgery (see Table 7.4). Because the cause of the pain is not visible, such pain can be particularly frustrating for patients and diagnosis can sometimes be a long and challenging process. The mechanisms responsible for central pain syndromes are not well understood, but it is likely that damage to spinothalamic tract neurons and thalamocortical neurons by the original insult is responsible for triggering ongoing activity in neurons at subsequent levels of the pain pathway. It has been postulated that this activity may be a response to the loss of normal input to these neurons (caused by the damage earlier in the pathway) or the loss of normal inhibitory influences that normally suppress their activity.
THE ELDERLY
Individual responses vary and may be influenced by the presence of painful chronic diseases
TABLE 7.4 Causes of central pain syndromes Vascular lesions (infarction, haemorrhage) Traumatic brain injury Neurosurgery Brain tumours Multiple sclerosis Spinal cord injury Epilepsy
FOCU S ON L EA RN IN G
1 Explain the difference between mononeuropathy and polyneuropathy. 2 List some of the factors that can result in peripheral neuropathic pain. 3 List some of the causes of central pain.
PAEDIATRICS
Paediatrics and pain
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Ageing and pain Given the difficulties associated with assessment of pain in the elderly it is perhaps not surprising that the treatment of pain in older adults is also problematic. Some patients simply don’t believe that their pain can be alleviated, while others are reluctant to take opioid analgesics because of their euphoric side effects or fear of addiction. This is unfortunate as employment of opioid analgesics may be more appropriate given the adverse effects of NSAIDs particularly in individuals with impaired liver or kidney function. Interestingly complementary and alternative medicine approaches seem to be widely accepted by the elderly as alternatives to drugs.
chapter SUMMARY The definition of pain • Pain is clinically important as it encourages patients to seek medical help and adopt behaviours that enhance healing. • Pain has an important physiological role as it teaches us to avoid environmental stimuli that cause harm. • Individuals born with a congenital insensitivity to pain suffer horrendous injuries because they are unaware of the damage they are experiencing. • Pain is a subjective sensation that is affected by a large number of variables and consequently can be difficult to define. • The International Association for the Society of Pain’s definition of pain highlights most of the key elements of pain. • Pain is invariably unpleasant (it is a negative experience) and is therefore something we avoid. • The ability to locate a painful stimulus and determine its intensity and quality is referred to as the sensorydiscriminative aspect of pain. • Pain produces changes in both mental state (affect) and behaviour (motivation), which are referred to as the affective-motivational aspect of pain. • Pain is usually the result of tissue damage but can be caused by stimuli that would cause tissue damage if sustained. • The threshold for pain is lower than the threshold for tissue damage.
• The intensity of the pain experience can be modified by behaviour, cognitive factors and clinical intervention.
Types of pain • Nociceptive pain due to external damage is relatively mild and has a comparatively short time frame. • Nociceptive pain due to internal damage is less common, is usually more severe and has a longer time frame. • Neuropathic pain is caused by injury or disease of the nervous system and can be both severe and persistent. • Psychogenic pain is the result of a psychological disorder, but for the patient it can be just as severe and debilitating as nociceptive pain or neuropathic pain.
Pain terminology • Pain is described as either acute or chronic and these classifications are independent of aetiology. • Chronic pain affects about 20% of Australians. • Referred pain is perceived as originating from a part of the body distinct from the site of tissue damage. • Hyperalgesia is where there is increased pain in response to a stimulus that is normally painful. • Allodynia is where pain results from a stimulus that does not normally produce pain. • The conscious perception of tissue damage occurs in the cerebral cortex.
AGEING
The elderly typically experience a higher incidence of pain compared to other adults and as the population ages it is estimated that chronic pain is likely to affect about 5 million Australians by 2050. The impact of pain in older people can have particularly devastating consequences on their quality of life when it impacts upon their mobility and ability to socialise. The assessment of pain in the elderly can be challenging as some perceive it as an inevitable consequence of ageing or fear the financial burden they perceive may be associated with it. The fact that the pain may also present with comorbidities, including cognitive decline, makes the diagnosis and effective management of pain in older Australians a complex and time-consuming task (Table 7.3).
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The physiology of pain • A three-neuronal pathway relays information about peripheral tissue damage from the periphery to the cerebral cortex. Nociceptors are the first-order neurons in the pain pathway. • There are two classes of cutaneous nociceptor: highthreshold mechanoreceptors and polymodal nociceptors. • Joints, muscle and viscera appear to be innervated by neurons with properties similar to cutaneous polymodal nociceptors. • Joints, muscle and viscera also appear to be innervated by silent (or ‘sleeping’) nociceptors that only become active when these tissues become inflamed as the result of damage or disease. • Although there are a number of neural pathways relaying information about tissue damage between the spinal cord and brain, the most important in terms of the conscious perception of pain is the spinothalamic tract. • Spinothalamic tract neurons are the second-order neurons in the pain pathway and they collect the information delivered to the spinal cord by nociceptors and relay this to the thalamus. • The axons of spinothalamic tract neurons are sometimes targeted in surgical approaches to the treatment of severe chronic pain through a midline myelotomy or anterolateral cordotomy. • Spinothalamic tract neurons terminate in two structurally distinct regions of the thalamus. • Thalamocortical neurons with their cell bodies in the posterolateral parts of the thalamus relay information about tissue damage to the somatosensory cortex and interoreceptive cortex. • Thalamocortical neurons located in the medial thalamus relay information about peripheral tissue damage to the anterior cingulate cortex. • Through the information that they receive from the posterolateral parts of the thalamus, the somatosensory and interoreceptive cortices are thought to be responsible for the sensory-discriminative aspect of pain. • The medial thalamic projection to the anterior cingulate cortex is thought to be responsible for the affectivemotivational aspect of pain. • Neuropathic pain affects up to 7% of the population and contributes significantly to the cost of healthcare in developed countries. • Modulators of pain include substances that stimulate pain receptors (i.e. prostaglandins, bradykinins, substance P, glutamate) and substances that suppress pain (i.e. endorphins, gamma-aminobutyric acid (GABA), serotonin). • Endorphins are endogenous opioids that attach to opioid receptors and inhibit transmission of pain impulses. Encephalins are other opioid peptides.
• Encephalins are present in varying concentrations in the neurons of the brain, spinal cord, and gastrointestinal tract.
Clinical manifestations of pain • Pain tolerance is the duration of time or the intensity of pain that an individual will endure before initiating overt pain response. • Pain threshold is the point at which pain is perceived. • Pain is a subjective symptom but can result in activation of the autonomic nervous system, which causes an increase in heart rate, blood pressure and ventilation, nausea and vomiting as well as sweating.
Evaluation and treatment • Evaluation of pain is often difficult; the patients’ experiences and objective measures guide therapies. • Treating the original cause of pain should be addressed first, followed by pharmacological and nonpharmacological therapies.
Pathophysiology of pain • Peripheral neuropathic pain results from damage to the peripheral nervous system. • Peripheral neuropathic pain can be the result of physical injury, disease, infection or toxicity. • Mononeuropathy is where only a single nerve is involved and polyneuropathy is where multiple nerves are affected. • The neural mechanisms responsible for painful peripheral neuropathies are complex and in many cases remain poorly understood. • Following a traumatic injury of a peripheral nerve the portions of the axons distal to the injury sometimes degenerate and a neuroma may form at the site of the nerve damage. • Action potentials can occur spontaneously in the neuroma and it may be very sensitive to mechanical stimuli, resulting in pain if it is touched or disturbed by movement. • In some cases noradrenaline released from sympathetic postganglionic neurons appears to exacerbate the pain produced by nerve injury. • Central sensitisation of spinothalamic tract neurons is also thought to contribute to peripheral neuropathic pain. • Central pain syndromes are characterised by very severe persistent pain caused by traumatic injury, tumour, cerebrovascular incidents or brain surgery.
Paediatrics and ageing and pain • Newborns and young children have the anatomical and functional ability to perceive pain. Older individuals tend to have a slightly higher pain threshold, probably because of changes in the thickness of the skin and peripheral neuropathies.
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CASE STUDY
ADU LT Peter was a 59-year-old shearer whose best friend was a blue heeler called Red. After noticing blood in his stools Peter visited his local general practitioner and was subsequently diagnosed with carcinoma of the colon. A colon resection was performed and he underwent a complete course of radiotherapy and chemotherapy. Six months later, Peter started to experience abdominal pain. On investigation it was revealed that the malignancy had spread into his urinary bladder and urethra. Peter was readmitted to hospital and in subsequent weeks his pain increased progressively until eventually it could only be controlled with high doses of
intravenous morphine. Twelve months after the onset of the pain, Peter had a midline myelotomy in the mid-thoracic region of the spinal cord. Ten days following this operation, he was able to leave hospital and lived pain-free until his death 5 years later. 1 Explain the physiology of Peter’s abdominal pain. 2 Discuss how morphine controls acute pain. 3 Explain why Peter was likely to experience ongoing pain that was responsive only to high-dose morphine. 4 Outline the aim of a midline myelotomy. 5 Explain why you think a midline myelotomy might provide a better outcome for pain of visceral origin.
CASE STUDY
AGEING Cecil, an 86-year-old man, who worked as a tradesman until his retirement 16 years ago presents to the doctor with lower back pain. He is generally active, playing lawn bowls twice a week, and walking three times per week for 30 minutes each time but his lower back pain is starting to restrict these activities. Upon questioning, Cecil related that the lower pain had affected him for the last 10 years of his working life and had gradually become more severe during retirement. When he was physically examined, there was acute tenderness over L2–L4, but Cecil only rated the pain as 3 out of 10. There were no obvious signs detected. The doctor was unsure of the
origin of the lower back pain and Cecil was instructed to have imaging studies using magnetic resonance imaging (MRI) and prescribed a non-steroidal anti-inflammatory medication to be taken when he experiences pain. 1 Explain the likely physiology of Cecil’s lower back pain. 2 Based on the lack of signs and symptoms experienced by Cecil, is the MRI scan likely to identify an anatomical reason for the lower back pain? 3 What is the significance of acute tenderness over L2–L4? 4 Discuss the effectiveness of NSAIDS for pain management in older people. 5 Provide reasons why Cecil may perceive his pain at a lower level than expected.
REVIEW QUESTIONS 1 Outline the features of the pain experience that are included in the sensory-discriminative aspect of pain. 2 Explain why it is useful for the threshold for pain sensation to be lower than the threshold for tissue damage. 3 Discuss the difference between hyperalgesia and allodynia. 4 Compare and contrast the properties of cutaneous high-threshold mechanoreceptors and polymodal nociceptors. 5 Explain why a skin laceration often causes two pain sensations separated in time. 6 Discuss why a painful stimulus applied to the right side of the body results in activation of the cerebral cortex on the left side of the body.
7 Explain the difference between a midline myelotomy and an anterolateral cordotomy. 8 Which cortical sites are thought to be involved in the conscious perception of pain? In which lobes of the cerebral cortex are they located, and what is their postulated function? 9 Outline some of the pathophysiological mechanisms thought to underlie the neuropathic pain that may arise from a peripheral nerve transection. 10 What is responsible for the nerve damage arising from painful diabetic neuropathy?
Key terms
CHAPTER
8
Concepts of neurological dysfunction Amy Nicole Burne Johnston and Susanne Thompson
Chapter outline Introduction, 165 Alterations in cerebral homeostasis, 165 Cerebral haemodynamics, 165 Intracranial pressure, 166 Cerebral oedema, 170 Hydrocephalus, 172 Alterations in cognitive function, 173
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Alterations in arousal, 173 Cognitive disorders, 185 Alterations in motor function, 190 Alterations in muscle tone, 190 Alterations in movement, 191 Ageing and neurological dysfunction, 191
acute confusional states, 185 arousal, 173 ataxic breathing, 177 autoregulation, 165 brain death, 180 central neurogenic breathing, 177 cerebral blood flow (CBF), 165 cerebral blood volume, 166 cerebral oedema, 170 cerebral perfusion pressure (CPP), 168 Cheyne-Stokes breathing, 177 clonic phase, 182 coma, 174 consciousness, 173 cytotoxic oedema, 171 delirium, 186 dementia, 186 epilepsy, 182 epileptogenic focus, 182 herniation, 168 hydrocephalus, 172 hypercapnia, 168 hypertonia, 190 hypotonia, 190 hypoxia, 168 increased intracranial pressure, 167 interstitial oedema, 171 intracranial pressure (ICP), 167 ischaemic oedema, 171 locked-in syndrome, 180 minimally responsive state, 180 Monro-Kellie hypothesis, 166 paralysis, 191 paresis, 191 post-coma unresponsiveness, 179 rigidity, 191 seizure, 181 spasticity, 190 tonic phase, 182 vasogenic oedema, 170 vomiting, 179
Introduction This chapter is divided into three main sections — each of which covers conditions that can affect either the central or the peripheral nervous system. The first is altered cranial vault homeostasis (maintenance of space inside the skull), which supports the function of the brain when exposed to changes in blood flow, blood volume and intracranial pressure. There are many conditions that can cause such changes, including bleeding into the brain, and often these are life threatening. Volume and pressure changes often result directly from altered cranial homeostasis and so are interrelated. The second class of condition covered in this chapter explores changes to cognition or an individual’s awareness or consciousness level. The third relates to changes in motor function, which can originate from alterations in the central or peripheral nervous systems. It should be noted that changes in cranial homeostasis resulting in altered mentation or motor control can be the result of global (widespread) or focal (small area) processes. For instance, increases in the concentration of neurological irritants, such as urea, can cause global metabolic changes to brain function. In contrast, local damage to the brainstem caused by a tumour or bleeding can also alter consciousness. Therefore, recognising the extent of the cranial disruption is important for determining not only the patient’s prognosis but also the treatment options. There are many networks that provide an individual with the characteristics that define thought, memory, emotion and intellect for that person. These complex pathways are not separate but rather involve the interaction of neuronal connections from different regions of the brain. Furthermore, these pathways interact and usually all are required for effective brain functionality. For instance, the neural networks that are involved in cognitive function include: (1) attentional networks, which provide arousal and maintenance of attention over time; (2) memory and language networks, by which information is assessed, integrated and communicated; and (3) emotional networks, which control feelings and emotions and thus responses. Collectively, these networks are fundamental to the processes of abstract thinking and reasoning. Abstract thinking and reasoning is then organised and made operational through the executive attentional networks — that is, networks that regulate our higher responses, such as in stressful situations (e.g. conflict), where we have the ability to understand and respond in several different ways. The normal functioning of these networks is evident through the motor network, in which the behaviour we exhibit is viewed by others as appropriate. We commence our exploration of these complex processes with changes in cerebral homeostasis. We start with blood flow to the brain, as this is crucial to normal neurological functioning.
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Alterations in cerebral homeostasis Cerebral haemodynamics
There are several aspects of blood flow to the brain (cerebral blood flow, or CBF) that should be examined before exploring the impact that changes to cerebral haemodynamics have on cerebral homeostasis and thus cerebral function. The brain receives a constant supply of blood: this is essential for normal brain function. A continual supply of oxygen and glucose is required because the brain does not store large quantities of ATP and glycogen. It also cannot perform anaerobic metabolism, yet typically has high levels of metabolic activity. If cerebral blood flow ceases for only a few minutes, an individual will become unconscious and remain so without prompt restoration of this flow, with cell ischaemia and death rapidly following. CBF is the total blood flow to the brain. It is approximately 45–55 mL/100 grams of brain tissue/minute, which is about 15–20% of cardiac output, much greater than expected on the basis of simple brain tissue volume. CBF is matched to the local metabolic needs of the brain, thereby maintaining a constant supply of oxygen, glucose and nutrients to meet the requirements of brain activity. This may underlie some variations in CBF including that blood flow is greater to grey matter than to white matter. CBF is regulated, as elsewhere in the body, via the diameter of the cerebral blood vessels — that is, the degree of vasoconstriction and vasodilation. Importantly, changes in blood oxygen and blood carbon dioxide concentrations are the most critical factors in altering cerebral blood vessel diameter. In most cases, carbon dioxide is the most important flow controlling parameter, with increases in arterial carbon dioxide concentration (PaCO2) causing increases in CBF and decreases in PaCO2 resulting in decreases in CBF (see Fig. 8.1). For instance, it has been calculated that an acute decrease in PaCO2 to 25 mmHg can decrease CBF by 30–35% and an increase in PaCO2 to 50 mmHg can cause an increase in CBF of about 75%.1 In cases of profound hypoxaemia, that is when arterial oxygen concentration (PaO2) is below 50 mmHg, CBF increases dramatically to counteract the decline in cerebral oxygenation (see Fig. 8.2). This protective mechanism is crucial to maintaining neuronal functioning and therefore cerebral homeostasis. The other factor controlling cerebral blood flow is cerebral activity; as elsewhere in the body, reduced activity reduces blood flow to that region. This is known as autoregulation. The brain requires a constant blood supply to deliver oxygen, glucose and nutrients and also to remove waste products of metabolism. To achieve this, CBF is kept relatively constant, even when there are changes in peripheral blood pressure. The exact mechanism is not yet fully understood, but it appears that complex physiological mechanisms in the local smooth muscle of the cerebral arteries and metabolic changes (such as arterial carbon
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FIGURE 8.1
The relationship between arterial carbon dioxide concentration and cerebral blood flow. There is an upper and a lower limit of CBF where changes in PaCO2 do not alter CBF. Also, note that small changes in PaCO2 result in larger changes in CBF.
FIGURE 8.3
Cerebral autoregulation. CBF is maintained at near-constant levels over a wide range of blood pressure (50–150 mmHg).
understand, because alterations in neural tissue integrity, such as brain tumours and stroke, can greatly affect the ability of the brain to maintain cerebral autoregulation.1,2 Cerebral blood volume is the amount of blood in the cranial vault (the bony case enclosing the brain) at any given time; it is approximately 10% of total intracranial volume but can alter rapidly and therefore is crucial to intracranial pressure. The remainder of the space is typically filled with brain tissue, protective membranes and cerebrospinal fluid. However, during times of neurological injury, such as haemorrhage in the brain, the blood volume in the ‘brain space’ will increase and exceed 10% of total volume. This can lead to significant problems because the brain is enclosed in a fixed space and therefore another component in the brain will need to decrease in volume by an equivalent amount. We now explore how changes in these volumes can lead to increases in intracranial pressure. FIGURE 8.2
The relationship between arterial oxygen concentration and cerebral blood flow. Note that PaO2 over 50 mmHg causes an increase in CBF to increase the supply of oxygen to brain tissue.
dioxide concentration) are responsible for maintaining a near constant cerebral blood flow. In addition, the vascular wall (the endothelium) may play a role, although this has not been fully elucidated. Nonetheless, the main aspect of cerebral autoregulation is that CBF is near constant across a blood pressure range of 50–150 mmHg (mean arterial pressure; MAP) (see Fig. 8.3). This is very important to
Intracranial pressure
Three main components occupy the cranial vault: blood, cerebrospinal fluid (CSF) and brain tissue. As we have already noted, blood makes up approximately 10% of the cranial volume. The CSF that surrounds the brain and spinal cord typically makes up about 10%; and brain tissue accounts for the other 80%. The skull does not allow for expansion and thus, because these components are in a fixed space, any increase in the volume of one must be compensated by a decrease in the volume of the others. This phenomenon is called the Monro-Kellie hypothesis, and it describes the relationship between the three volumes (see Fig. 8.4). When small increases in one occur, the other two must reduce
CHAPTER 8 Concepts of neurological dysfunction
FIGURE 8.4
Cerebral volumes. A Normal state, approximately 80% is brain tissue, with CSF and blood accounting for 10% each. B An increase in brain tissue with displacement of CSF and blood. This is the most common change. C An increase in CSF causes displacement of brain tissue and blood. D An increase in blood volume causes displacement of brain tissue and CSF. Note the changes are representative only.
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accordingly so as to maintain a stable pressure. However, where larger changes occur in the volume of one component, the other two cannot sufficiently reduce to compensate. More volume squashed into the same confined space leads to increases in intracranial pressure; commonly abbreviated to ICP. ICP is normally about 5–15 mmHg. However, it is actually difficult to quantify because it represents the sum of the pressure exerted by the three components. Therefore, in most cases ICP is approximately equivalent to CSF pressure. In clinical practice, ICP is usually measured either by placing a catheter into the lateral ventricle, thereby measuring CSF pressure, or by placing a catheter directly into brain tissue (Fig. 8.5). Increased intracranial pressure may result from an increase in intracranial content (as occurs with tumour growth), oedema (swelling of the brain) and excessive accumulation of CSF or intracranial haemorrhage. It necessitates an equal reduction in volume of the other cranial content. The most readily displaced content is CSF. This is because, if the brain swells, the volume of CSF can be reduced. However, if ICP remains high after CSF is displaced out of the cranial vault, the cerebral blood volume is then also altered. Venous vessels are relatively easily compressed, reducing blood drainage from the cranial case and forcing an increase in the volume inside the skull and increasing
ICP catheter
Pressure (mmHg)
Transducer
100 90 80 70 60 50 40 30 20 10 0
Patient
Normal 0
Moderate elevation
Significant elevation
10 20 30 40 50 60 70 80 10 20 30 40 50 60 70 80 10 20 30 40 50 60 70 80 Minutes
FIGURE 8.5
Intracranial monitoring. A Coronal section of brain showing potential sites for placement of intracranial pressure monitoring devices. B The intracranial pressure tracing shows normal and elevated intracranial pressure.
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intracranial pressure. If compensation is inadequate, this pathological spiral can continue to progress, ICP will continue to rise and life-threatening conditions precipitate (see explanation of the various stages below). Since the brain is enclosed in a rigid skull, there is relatively little scope for it to move or compress, so when ICP becomes excessive, the brain will be forced through the foramen magnum (the main hole at the base of the skull) or blood flow, both arterial flow into the skull and venous flow out of the skull, will be severely restricted. Both of these scenarios can lead directly to patient death. Fig. 8.6 demonstrates the relationship between intracranial pressure and volume. When the pressure from one compartment — namely CSF, blood or brain tissue — increases, the Monro-Kellie hypothesis states that this must be compensated by a decrease in another compartment (which can be effective, but only to a point). The first stage of compensation usually involves a decrease in the CSF (by CSF resorption). In the case of continuing increases in volume, the second stage involves a decrease in cerebral blood flow — cerebral vasoconstriction occurs in an attempt to decrease the intracranial pressure. Thus, ICP may not initially change because of effective compensatory mechanisms by changes in CSF and blood volume, and hence there may be few symptoms (see Fig. 8.7). However, small increases in volume cause an increase in pressure and the pressure may take longer to return to baseline. This can be detected with ICP monitoring. With continued expansion of the intracranial content, the resulting increase in ICP may exceed the brain’s
FIGURE 8.6
The relationship between intracranial volume and intracranial pressure. The horizontal portion of the curve indicates that if one component is expanding, the other two have the ability to compensate. (Note: this compensation mainly comes about by displacement of CSF and blood.) If the volume expands even more, the compensation of the other components is not enough to maintain intracranial pressure — small volume increments result in large increases in intracranial pressure.
compensatory capacity to adjust by only altering CSF and blood volumes. The pressure begins to compromise neuronal oxygenation, and as a result, systemic arterial vasoconstriction occurs in an attempt to elevate the systemic blood pressure sufficiently to overcome the raised ICP and push oxygenated blood into the compressed cranial space. However, this increased blood volume further increases the intracranial pressure. Clinical manifestations at this stage usually are often subtle and transient, such as episodes of confusion, restlessness, drowsiness and slight pupillary and breathing changes (see Fig. 8.7). As ICP begins to approach cranial arterial pressure, arterial flow into the brain tissue reduces and the brain tissues begin to experience hypoxia (low oxygen levels) and hypercapnia (high carbon dioxide levels; also often referred to as hypercarbia) and the individual’s condition deteriorates rapidly. Clinical manifestations include decreasing levels of consciousness (assessed via Glasgow Coma Score) or central neurogenic hyperventilation (abnormal deep and rapid breathing), widened pulse pressure (the difference between systolic and diastolic blood pressure), bradycardia and pupils that become constricted and sluggish (see Fig. 8.7). Dramatic sustained rises in ICP are not seen until all compensatory mechanisms have been exhausted. Then dramatic rises in ICP occur over a very short period. Autoregulation fails to maintain a constant blood flow and is lost. Accumulating carbon dioxide may still cause vasodilation locally, but without autoregulation, this vasodilation causes the blood pressure in the vessels to drop and blood volume to increase. The brain volume is thus further enhanced and ICP continues to rise. Small increases in volume can therefore cause dramatic increases in ICP (see Fig. 8.6) and the ICP takes much longer to return to baseline. As ICP begins to approach systemic blood pressure, the blood pressure in the brain (the cerebral perfusion pressure, or CPP) falls (the blood just cannot force its way into this confined space) and cerebral perfusion slows dramatically. The brain tissues experience severe hypoxia and acidosis (an increase in hydrogen ion concentration; see Chapter 29) and become progressively less functional. ICP is not evenly and uniformly distributed throughout the compartments inside the cranial vault. As a result, the brain tissue can shift from the compartment of greater pressure to a compartment of lesser pressure. This tissue shift is termed herniation (see Figs 8.7 and 8.8). As tissue moves, associated vessels can become compressed and the herniating brain tissue’s blood supply then becomes compromised, causing further ischaemia and hypoxia in the herniating tissues. The volume of content within the lower pressure compartment increases, exerting pressure on the brain tissue that normally occupies that compartment and further impairing its blood supply. Small haemorrhages often develop in the compromised brain tissue. Thus the herniation process markedly and rapidly increases ICP. Mean arterial pressure soon equals ICP and so cerebral blood flow ceases. The various types of herniation syndromes are outlined in Box 8.1.
CHAPTER 8 Concepts of neurological dysfunction
STAGES OF COMPENSATION Mental status
Awake and alert
Episodes of confusion Restlessness Lethargy
Pupils
Equal and reactive
Equal and reactive
Breathing
Normal (eupnoea)
Normal (eupnoea)
Blood pressure
160 Systolic 120 80 Diastolic
Pulse
160 120 80
BEGINNING DECOMPENSATION
DECOMPENSATION (HERNIATION)
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DEATH
Beginning inability to stay awake continuing on to progressively deeper coma Small, reactive pupils Bilateral progressing to slowing of response to light dilation and Ipsilateral dilation fixation and fixation Normal, may slow some then progressing to Cheyne-Stokes breathing Central neurogenic hyperventilation apneustic or ataxic breathing Pulse pressure
Slight irregularity
Full and bounding
Therapy Surgical or medical intervention best here
Surgical or medical intervention needed here
Surgical or medical intervention usually futile here
FIGURE 8.7
Clinical manifestations of compensated and uncompensated raised intracranial pressure.
Tumour
Midline 1
Tentorium 2 3
Haematoma (blood clot)
5
Cerebellum
4
Foramen
FIGURE 8.8
Herniation of the brain. Schematic diagram showing the various types of brain herniation. 1 Cingulate herniation, in this case caused by an adjacent tumour. Note that the brain moves sideways, which is termed midline shift. 2 Transtentorial uncal herniation with midbrain compression, in this case caused by an acute haematoma. 3 Central herniation with vertical descent of the brainstem. 4 Cerebellar tonsillar herniation through the foramen magnum with compression of the medulla. 5 Upward cerebellar herniation with upper brainstem compression.
One aspect of raised ICP needs a special mention. The blood pressure that supplies the neurons of the brain is termed the cerebral perfusion pressure (CPP). This pressure determines whether neurons receive blood or not and is often altered during raised ICP. In clinical practice CPP is determined from the blood pressure and ICP using the following equation: CPP = MAP − ICP = 90 mmHg − 5 mmHg = 85 mmHg
The normal range of CPP is approximately 70 to 100 mmHg.3 Three injury states are possibly related to cerebral blood flow: too little cerebral perfusion; normal cerebral perfusion but an elevated intracranial pressure exists; and too much cerebral blood volume. Treatments for these injury states are directed at improving or maintaining CPP, as well as controlling intracranial pressure. A brain, particularly an injured brain, requires a CPP of greater than 70 mmHg. If ICP is sufficiently elevated, CPP will decrease. In fact, a vicious cycle can occur, with increasing ICP leading to a decrease in CPP. This decreases blood flow to the neurons and, if this is sustained, hypoxic tissue will eventually die (infarction). The dead tissue causes swelling (oedema), which further increases ICP. This is summarised diagrammatically in Fig. 8.9.2
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BOX 8.1
Herniation syndromes
Supratentorial herniation Uncal herniation. Occurs when the uncus shifts from the middle fossa through the tentorial notch into the posterior fossa, compressing the third cranial nerve and the mesencephalon. Uncal herniation is generally caused by an expanding mass in the lateral region of the middle fossa. The classical manifestations of uncal herniation are a decreasing level of consciousness, pupils that become sluggish before fixing and dilating, Cheyne-Stokes breathing, and the appearance of decorticate and then decerebrate posturing. Central herniation. Involves the straight downward shift of the diencephalon through the tentorial notch. It may be caused by injuries or masses located around the outer perimeter of the frontal, parietal or occipital lobes, extracerebral injuries around the central apex (top) of the cranium, and bilaterally positioned injuries or masses. The individual rapidly becomes unconscious; moves from Cheyne-Stokes breathing to apnoea (no breathing); develops small, reactive pupils and then dilated, fixed pupils; and passes from decortication to decerebration. Infratentorial herniation
CONCEPT MAP
In the most common syndrome, also known as tonsillar herniation, the cerebellar tonsil shifts through the foramen magnum because of increased pressure within the posterior fossa. The clinical manifestations are an arched stiff neck, paraesthesias in the shoulder area, decreased consciousness, respiratory abnormalities and pulse rate variations. Occasionally the force produces an upward transtentorial herniation of a cerebellar tonsil or the lower brainstem. No specific set of clinical manifestations is associated with infratentorial herniation.
exacerbates
manifests as
Cerebral oedema
– space occupying lesions e.g. neoplasm – cerbral haemorrhage – closed head injury – hydrocephalus
contributes to Increase ICP decreases
Swelling
Cerebral blood flow
results in decreases Infarction of brain tissue eventually leads to
Perfusion pressure CPP = MAP – ICP
Ischaemia causes
Blood flow to affected area of brain
decreases
FIGURE 8.9
Cycle of increased intracranial pressure leading to reductions in cerebral perfusion pressure. This cycle is continued as the tissue dies and swells, leading to further increases in intracranial pressure. CPP = cerebral perfusion pressure; ICP = intracranial pressure; MAP = mean arterial pressure.
Cerebral oedema
Cerebral oedema is an increase in the fluid content of brain tissue (see Fig. 8.10). The result is increased extracellular or intracellular tissue volume. It occurs after brain insult from trauma, infection, haemorrhage, tumour, ischaemia, infarct, metabolic derangement or hypoxia. The harmful effects of cerebral oedema are caused by distortion of the blood vessels, displacement of brain tissues and eventual herniation of brain tissue from one brain compartment to another (see Fig. 8.8).
PATHOPHYSIOLOGY
There are four different types of cerebral oedema — left untreated, all can be devastating. • Vasogenic oedema is clinically the most important type and is caused by the increased permeability of the capillary endothelium (the lining cells of the blood vessels) of the brain after injury to the vascular structure. The blood–brain barrier is disrupted and plasma proteins leak into the extracellular spaces, drawing water with them and increasing the fluid content of
CHAPTER 8 Concepts of neurological dysfunction
A
B
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oedema are hypoxic or ischaemic injury, typically secondary to traumatic brain injury (TBI) or stroke.3 • Ischaemic oedema follows cerebral infarction (death of neurons, often following a stroke). The ischaemia has components of both vasogenic and cytotoxic oedema. The initial oedema is confined to the intracellular compartment, but over several days, brain cells begin to undergo necrosis and die, releasing lysosomes (see Chapter 3). In this autodigestive process, the blood– brain barrier’s permeability increases, contributing to the oedema. Significant oedema slowly develops after a large hemispheric stroke and is often fatal.4 • Interstitial oedema is seen most often with noncommunicating hydrocephalus (see next section). The oedema is caused by movement of CSF from the ventricles into the extracellular spaces of the brain tissues. The brain fluid volume increases predominantly around the ventricles, with increased hydrostatic pressure within the white matter. The size of the white matter reduces because of the compression and rapid disappearance of myelin lipids. CLINICAL MANIFESTATIONS
FIGURE 8.10
Cerebral oedema. A Normal brain. Note the pattern of gyri and sulci. B Gross cerebral oedema. Note the widened, flattened gyri and narrowed sulci from the swelling of the brain tissue.
the brain parenchyma (neuronal, glial and endothelial cells). Vasogenic oedema starts in the area of injury and spreads, with fluid accumulating in the white matter of the ipsilateral side (on the same side) because the parallel myelinated fibres separate more easily. Oedema promotes more oedema because of ischaemia from the increasing local pressure. Vasogenic oedema can arise due to tumours, haemorrhage, infections, haemorrhagic and ischaemic strokes, as well as brain trauma. Clinical manifestations of vasogenic oedema include focal neurological deficits such as cranial nerve disturbances or hemiparesis (one-sided weakness), which provide clues as to the location of damage in the brain, disturbances of consciousness and severe increases in ICP. Vasogenic oedema resolves by diffusion of fluid out of brain tissues. This process can be enhanced pharmacologically. • In cytotoxic oedema, toxic factors directly affect the cellular elements of the brain parenchyma, causing failure of the active ions transport systems, such as the Na+/ K+ ATPase pump. The cells lose their potassium and gain larger amounts of sodium. Water follows sodium, moving by osmosis into the cells, so that the cells swell. Cytotoxic oedema occurs principally in the grey matter and may increase vasogenic oedema. Cytotoxic oedema can significantly alter global neurological function and result in coma, with cells in both the grey and white matter being affected. Common causes of cytotoxic
The signs and symptoms of cerebral oedema can vary. If cerebral oedema is compensated by a decrease in CSF and blood flow, then neurological function may not be significantly impaired. However, when cerebral oedema is significant or ongoing, clinically evident increases in ICP may occur. The clinical manifestations of raised ICP include — but are not limited to — headache, nausea and vomiting, altered cranial nerve responsiveness and a decrease in consciousness. If left untreated, these clinical manifestations will progress and a decrease in global cerebral function will result. Patients with severe cerebral oedema may present with coma and changes in pupillary light reactions. EVALUATION AND TREATMENT
The treatment of cerebral oedema is dependent on the type of oedema and the extent of the increased ICP. For instance, if a brain tumour is causing localised oedema, patients will often be treated with corticosteroids, such as dexamethasone. Moreover, the tumour can be surgically debulked or removed. In the acute phase of cerebral oedema, osmotic diuretics (mannitol) can reduce the water volume and lower the effects of oedema. The use of mannitol helps to reduce ICP by altering osmosis, as it increases plasma osmolarity and therefore decreases water in the tissues. Caution needs to be demonstrated when using mannitol to reduce ICP as effects of the drug are non-selective and complications such as fluid overload, hypovolaemia and rebound cerebral oedema can occur.5 Cerebral and systemic cooling are also increasingly common interventions used to reduce ICP and also brain tissue metabolic requirements. Elevating the head of the bed to 30 degrees is also beneficial in reducing ICP, although caution is required if there are any concerns of cervical injury (neck). Raising the head of the bed decreases ICP without compromising cerebral perfusion pressure.5
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TABLE 8.1 Types of hydrocephalus TYPE
MECHANISM
CAUSE
Noncommunicating
Obstruction of CSF flow between ventricles
• Congenital abnormality • Aqueduct stenosis (narrowing) • Arnold-Chiari malformation (brain extension through foramen magnum) • Compression by tumour
FIGURE 8.11
Ventricular drain. The catheter is inserted into the lateral ventricles and excess CSF is drained when the ICP increases. This temporarily lowers the ICP, but ultimately does not treat the primary cause.
There are other options for clinicians to manage cerebral oedema if there is an accompanying raised ICP. These include hyperventilation to lower (‘blow off ’) carbon dioxide, which will cause cerebral vasoconstriction; or alternatively, a catheter can be inserted into the lateral ventricles and excess CSF can be drained to lower the ICP (see Fig. 8.11). These two methods employ other mechanisms to reduce the pressure and do not actively treat the cause of the cerebral oedema. It should be noted that changing the CSF or blood flow involves using the principles of the Monro-Kellie hypothesis — that is, when one volume increases, the other volumes must decrease by a similar amount to maintain homeostasis between the brain tissue, blood and CSF. Hyperventilation produces a short-term reduction in ICP due to the vasoconstriction that it causes. Maintaining PCO2 between 30 mmHg and 35 mmHg is ideal. Routine hyperventilation should be used with caution, as it can cause secondary brain injury if vasoconstriction is extreme and cerebral blood flow is compromised, and for these reasons is currently contraindicated in the setting of acute traumatic head injury.5
Hydrocephalus
The term hydrocephalus refers to various conditions characterised by excess fluid in the cranial vault or
Communicating Impaired • Infection with absorption inflammatory adhesions of CSF within • Compression of subarachnoid subarachnoid space by a space tumour • High venous pressure in sagittal sinus • Head injury • Congenital malformation
subarachnoid space, or both. Hydrocephalus occurs because of interference with CSF flow caused by increased fluid production, obstruction within the ventricular system or defective reabsorption of the fluid. The types of hydrocephalus are reviewed in Table 8.1. Hydrocephalus may develop from infancy through to adulthood. Congenital hydrocephalus (i.e. ventricular enlargement before birth) results in an increased volume of CSF (see below).6 Non-communicating hydrocephalus — obstruction within the ventricular system — is seen more often in children; and communicating hydrocephalus — defective reabsorption of CSF from the cerebral subarachnoid space — is found more often in adults. Most cases of hydrocephalus develop gradually and insidiously over time. Acute hydrocephalus, however, may develop in a couple of hours in people who have sustained head injuries. Acute hydrocephalus contributes significantly to raised ICP.
Congenital hydrocephalus is characterised by an increased volume of CSF. It may be caused by blockage within the ventricular system where the CSF flows, an imbalance in the production of CSF or a reduced reabsorption of CSF. The pressure within the ventricular system pushes and compresses the brain tissue against the skull cavity. When hydrocephalus develops before fusion of the cranial
sutures, the skull can accommodate this additional spaceoccupying volume and preserve neuronal function. The overall incidence of hydrocephalus in developed countries is approximately 1 per 1000 live births with higher rates amongst developing countries due to prevalence of neonatal infection.
PAEDIATRICS
Paediatrics and congenital hydrocephalus
CHAPTER 8 Concepts of neurological dysfunction
PATHOPHYSIOLOGY
The obstruction of CSF flow associated with hydrocephalus produces dilation of the ventricles proximal to the obstruction. This is evident on computed tomography (CT) and magnetic resonance imaging (MRI) scans (see Fig. 8.12). Obstructed CSF is under pressure, causing atrophy of the cerebral cortex and degeneration of the white matter tracts. There is selective preservation of grey matter. When excess CSF fills a defect caused by atrophy, a degenerative disorder or a surgical excision, this fluid is not under pressure; therefore, atrophy and degenerative changes are not induced.
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FOCU S ON L EA RN IN G
1 Explain how cerebral blood flow is regulated. 2 Discuss the importance of cerebral autoregulation to normal neuronal functioning. 3 Describe how increased intracranial pressure can result in brain herniation. 4 Describe the 4 different types of cerebral oedema. 5 Describe how communicating hydrocephalus differs from non-communicating hydrocephalus.
CLINICAL MANIFESTATIONS
Acute hydrocephalus presents with signs of rapidly developing increased ICP. The person quickly deteriorates into a deep coma if not treated promptly. Normal-pressure hydrocephalus (dilation of the ventricles without the increased pressure) develops slowly, with the individual or family having a decline in memory and cognitive function. An unsteady, broad-based gait (walking style) with a history of falling is common. Additional clinical manifestations are apathy, inattentiveness and indifference to self, family and the environment. Urinary incontinence is often present. EVALUATION AND TREATMENT
The diagnosis is based on physical examination and CT and MRI scans. Hydrocephalus can be treated by surgery to resect cysts, neoplasms or haematomas. A ventricular bypass into the normal intracranial channel or into an extracranial compartment using a shunting procedure is one of the most common neurosurgical procedures for the treatment of hydrocephalus. In normal-pressure hydrocephalus, reduction in CSF through a diuresis regimen is often used.
A
B
FIGURE 8.12
Hydrocephalus. MRI scans of patients with hydrocephalus. A Lateral view showing dilated ventricles (*). B Coronal view also indicating increase in CSF in ventricles (*), which is indicative of hydrocephalus.
Alterations in cognitive function We have looked at the changes in brain function that arise from blood supply alterations or from lesions that increase ICP. Now we turn to explore the changes to cognitive function in the brain and how these changes may manifest in patients.
Alterations in arousal
The underpinning concepts of ‘consciousness’ are still not fully understood. Clinically, full consciousness is considered to be a state of being conscious, being aware of oneself and the environment and with the ability to enact a set of typical and characteristic responses to that environment. The fully conscious individual responds to external stimuli, such as noise, light, pain and temperature changes, with a wide array of responses. Any decrease in this state of awareness and responsiveness is considered a decrease in consciousness. Consciousness involves arousal and coherent content of thought. Arousal is an individual’s state of awareness — that is, is the person aware of their surroundings? This complex state is mediated by the reticular activating system, which includes the brainstem and fibres that project to and from the cerebral cortex (see Chapter 6). When a person temporarily loses cerebral function, such as following a blow to the head, the brainstem and diencephalic brain regions can maintain the vital functions of the body, with arousal usually returning in a short period of time. However, if there are widespread permanent alterations in cerebral function, then vital autonomic functions (such as sustained independent breathing) are maintained, but the reticular activating system does not resume typical activity patterns and the individual has no awareness of their environment. It should be noted that cognitive cerebral functions cannot occur without a functioning reticular activating system. Therefore, if an individual sustains permanent damage to their reticular activating system, arousal is not possible and hence the individual remains unconscious. An altered level of consciousness with acute onset may be caused by various factors including alteration to brain
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or of the entire brainstem either by direct invasion or by indirect impairment of its blood supply. In addition, decreased awareness may result from compression of the reticular activating system by a disease process. This compression may result from direct pressure or compression as structures either expand or herniate. Causes include accumulations of blood or pus, neoplasms and demyelinating disorders. CLINICAL MANIFESTATIONS AND EVALUATION
FIGURE 8.13
Tentorial plate. Note that the tentorial plate is a fold of dura that separates the cerebral hemispheres from the cerebellum, but is used to differentiate between neurological insults.
structure, metabolic disturbances or psychogenic alteration with a psychological origin. Structural causes are divided according to whether the original location of the pathological condition is above or below the tentorial plate (a dural fold that separates the cerebrum from the cerebellum; see Fig. 8.13). Pathological processes include infectious, vascular, neoplastic, traumatic, congenital (developmental), degenerative and metabolic causes. Metabolic causes are further divided into hypoxia, electrolyte disturbances, hypoglycaemia, drugs and toxins (both endogenous and exogenous). Alterations in consciousness range from slight drowsiness to coma. PATHOPHYSIOLOGY
Processes above the tentorial plate (supratentorial) produce changes in arousal by either diffuse or localised dysfunction. Disease processes may produce diffuse dysfunction (e.g. encephalitis — inflammation of the brain) and may affect the cerebral cortex or the underlying subcortical white matter. Localised dysfunction is generally caused by masses that directly impinge on deep structures of the diencephalon or that secondarily compress these structures in the process of herniation. Such localised destructive processes directly impair function of the thalamus or hypothalamus. Disorders outside the brain but within the cranial vault can produce diffuse dysfunction. Examples include neoplasms, closed-head trauma with subsequent subdural bleeding and accumulation of inflammatory material including pus in the subdural space. Disorders within the brain tissue proper — bleeding, infarcts and emboli, and tumours — function primarily as ‘masses’. With processes below the tentorial plate (infratentorial), arousal declines by direct disruption of the lower sections of the reticular activating system and its afferent pathways
The cause of an altered level of arousal may be functional or organic. Functional conditions arise when no discrete anatomical location can be found for the alteration — for instance, headaches and insomnia. In contrast, organic conditions come about when there are structural alterations that can be specifically isolated — for instance, brain tumours, bleeding or contusions. Both conditions may contribute to an altered level of arousal or consciousness. Further distinctions can be made between metabolic factors and structural factors (see Table 8.2). Metabolic factors include changes in biochemistry that affect brain function. For example, when acute liver failure occurs affected patients are unable to metabolise ammonia, which in elevated concentrations is neurotoxic and can lead to coma. Structural factors are similar to organic factors — they are areas where cellular damage has occurred and this alters central nervous system (CNS) homeostasis. Patterns of clinical manifestations help in determining the extent of brain dysfunction and serve as indices for identifying increasing or decreasing CNS function. The types of manifestations suggest the cause of the altered arousal state (see Table 8.3). Five categories of neurological function are critical to the evaluation process: 1 level of consciousness 2 pattern of breathing 3 size and reactivity of pupils and other cranial nerve reflexes 4 eye position, tracking and reflexive responses 5 skeletal muscle motor responses.
Level of consciousness
The level of consciousness is the most critical clinical index of nervous system function, with alterations indicating either improvement or deterioration of the individual’s condition. The most common way of assessing an individual’s level of consciousness is to use an objective assessment tool such as the Glasgow Coma Scale (GCS; see Table 8.4). The scale assesses an individual’s ability to open their eyes and manage their verbal and motor responses. Collectively, these provide information about the individual’s gross level of consciousness. A person who is alert and oriented to self, others, place and time is considered to be functioning at the highest level of consciousness, which implies full use of all the person’s cognitive capacities. From this normal alert state, levels of consciousness diminish in stages, each of which is clinically defined (see Table 8.5). Decreases in the level of consciousness can alter many physiological processes. Some of the major processes are
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TABLE 8.2 Clinical manifestations of metabolic and structural causes of coma MANIFESTATIONS
METABOLICALLY INDUCED COMA
STRUCTURALLY INDUCED COMA
Blink to threat (cranial nerves II, VII)
Equal
Asymmetric
Optic discs (cranial nerve II)
Flat, good pulsation
Papilloedema (optical disc swelling)
Extraocular movement (cranial nerves III, IV, VI)
Roving eye movements; normal doll’s eyes
Nerve palsy (paralysis of body part)
Pupils (cranial nerves II, III)
Equal and reactive, may be dilated (e.g. atropine), pinpoint (e.g. opiates) or midposition and fixed
Asymmetric or nonreactive; may be midposition (midbrain injury), pinpoint (pons injury), large (tectal injury)
Corneal reflex (cranial nerves V, VII) Symmetric response
Asymmetric response
Grimace to pain (cranial nerve VII)
Symmetric response
Asymmetric response
Motor function movement
Symmetric
Asymmetric
Tone
Symmetric
Spastic, flaccid, especially if asymmetric
Posture
Symmetric
Decorticate, especially if symmetric; decerebrate, especially if asymmetric
Deep tendon reflexes
Symmetric
Asymmetric
Babinski’s sign
Absent or symmetric response
Present
Sensation
Symmetric
Asymmetric
TABLE 8.3 Differential characteristics of states causing coma MECHANISM
MANIFESTATIONS
Supratentorial mass lesions • Initiating signs usually of focal cerebral dysfunction compressing or displacing the • Signs of dysfunction progress anterior to posterior diencephalon or brainstem • Neurological signs at any given time point to one anatomical area • Motor signs often asymmetric Infratentorial mass of destruction causing coma
• History of preceding brainstem dysfunction or sudden onset of coma • Localising brainstem signs precede or accompany onset of coma and always include oculovestibular abnormality • Cranial nerve palsies usually manifest ‘bizarre’ respiratory patterns that appear at onset
Metabolic coma
• Confusion and stupor commonly precede motor signs • Motor signs are usually symmetric • Pupillary reactions are usually preserved • Asterixis (tremor of the wrist), myoclonus (brief, involuntary twitching in a muscle), tremor and seizures are common • Acid–base imbalance with hyperventilation or hypoventilation is common
discussed below. Each area of the GCS assesses function of different areas of the brain. Spontaneous opening of the eyes indicates the arousal mechanisms of the brain are active; monitoring the reticular activating system (in the brainstem and hypothalamus). The best verbal response indicates that the patient is aware of themself and their surroundings. It also demonstrates a high degree of interaction between the patient and the environment. The best motor response suggests the patient is able to follow instruction to move their limbs in a purposeful manner.7
When assessing the patient’s level of consciousness using the GCS it is important to document the best response achieved by the patient within a given clinical context. For example, if the right side of the body displays decorticate movement and the left side displays decerebrate movement, the decorticate movement is noted on the GCS chart. This is because the highest level of function achieved by the brain is decorticate posturing. Similarly, if a patient is sleeping and needs to be roused to be assessed but maintains a wakeful state throughout the assessment and is not drowsy then the patient is able to score a ‘4’ for ‘Eyes opens spontaneously’
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TABLE 8.4 Glasgow coma scale CATEGORY OF RESPONSE
APPROPRIATE STIMULUS
RESPONSE
Eyes open
• Approach to bedside
• Spontaneous response
4
• Verbal command
• Opening eyes to name or command
3
• Pain
• Lack of opening of eyes to previous stimuli but opening to pain
2
• Lack of opening of eyes to any stimulus
1
• Appropriate orientation, conversant, correct identification of self, place, year and month
5
• Confusion, conversant but disorientation in one or more spheres
4
• Inappropriate or disorganised use of words (e.g. swearing), lack of sustained conversation
3
• Incomprehensible words, sounds (e.g. moaning)
2
• Lack of sound, even with painful stimuli
1
• Obedience to command
6
• Localisation of pain, lack of obedience but presence of attempts to remove offending stimulus
5
• Flexion withdrawal — flexion of arm in response to pain without abnormal flexion posture
4
• Abnormal flexion, flexing of arm at elbow and pronation, making a fist
3
• Abnormal extension, extension of arm at elbow, usually with adduction and internal rotation of arm at shoulder
2
• Lack of response
1
Best verbal response
Best motor response
• Verbal questioning with maximum arousal
• Verbal command (e.g. ‘raise your arm, hold up two fingers’) • Pain (pressure on proximal nail bed)
SCORE
TABLE 8.5 Levels of altered consciousness STATE
DEFINITION
Confusion
Loss of ability to think rapidly and clearly; impaired judgement and decision making
Disorientation
Beginning loss of consciousness; disorientation to time followed by disorientation to place and impaired memory; lost last is recognition of self
Lethargy
Limited spontaneous movement or speech; easy arousal with normal speech or touch; may or may not be oriented to time, place or person
Obtundation
Mild to moderate reduction in arousal (awakeness) with limited response to the environment; falls asleep unless stimulated verbally or tactilely; answers questions with minimum response
Stupor
A condition of deep sleep or unresponsiveness from which the person may be aroused or caused to open eyes only by vigorous and repeated stimulation; response is often withdrawal or grabbing at stimulus
Coma
No verbal response to the external environment or to any stimuli; noxious stimuli such as deep pain or suctioning do not yield motor movement
Light coma
Associated with purposeful movement on stimulation
Coma
Associated with non-purposeful movement only on stimulation
Deep coma
Associated with unresponsiveness or no response to any stimulus
and not a ‘3’ for ‘Eyes open to speech’. In children it is also important to consider normal sleep patterns for the child and incorporate that information into your findings.
Breathing pattern
Characteristic breathing patterns help evaluate the neuroanatomical level of brain dysfunction and coma (see
Fig. 8.14). Rate, rhythm and pattern should be evaluated. Breathing patterns can be categorised as hemispheric or brainstem breathing patterns (see Table 8.6). With normal breathing, a neural centre in the medulla produces a rhythmic breathing pattern. When consciousness decreases, lower brainstem centres regulate the breathing pattern, responding primarily to changes in PaCO2 levels
CHAPTER 8 Concepts of neurological dysfunction
Cheyne-Stokes breathing Central neurogenic hyperventilation Apneustic breathing Cluster breathing
One minute
Ataxic breathing
FIGURE 8.14
Abnormal breathing patterns with the corresponding level of anatomical insult.
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(measures of carbon dioxide in arterial blood). The result can be the irregular breathing associated with posthyperventilation apnoea. Cheyne-Stokes breathing results from an increased ventilatory response to carbon dioxide stimulation, causing hypercapnia and diminished ventilatory stimulus. Changes in PaCO2 produce irregular breathing, contributing to ‘overbreathing’ with carbon dioxide stimulation (‘blowing off ’ CO2). The PaCO2 level then decreases to below normal and breathing stops until carbon dioxide reaccumulates bringing the PaCO2 level back to normal. With opiate or sedative drug overdose, the respiratory centre in the brainstem is depressed so the rate of breathing gradually decreases until respiratory failure occurs. Central neurogenic breathing is also a ventilatory response to carbon dioxide and is characterised by deep and rapid breathing. It is an abnormal breathing pattern and often an indicator of poor prognosis. Ataxic breathing occurs when the injury has extended to or is associated with the medulla. It is
TABLE 8.6 Abnormal breathing patterns BREATHING PATTERN
DESCRIPTION
LOCATION OF INJURY
Hemispheric breathing patterns Normal
After a period of hyperventilation that lowers the arterial carbon dioxide pressure (PaCO2), the individual continues to breathe regularly but with a reduced depth
Response of the nervous system to an external stressor — not associated with injury to the CNS
Posthyperventilation apnoea
Respiration stops after hyperventilation has lowered the Associated with diffuse bilateral metabolic PaCO2 (arterial oxygen pressure) level below normal. Rhythmic or structural disease of the cerebrum breathing returns when the PaCO2 level returns to normal
Cheyne-Stokes breathing
The breathing pattern has a smooth increase (crescendo) in the rate and depth of breathing (hyperpnoea), which peaks and is followed by a gradual smooth decrease (decrescendo) in the rate and depth of breathing to the point of apnoea, when the cycle repeats itself. The hyperpnoeic phase lasts longer than the apnoeic phase
Bilateral dysfunction of the deep cerebral or diencephalic structures, seen with supratentorial injury and metabolically induced coma states
Brainstem breathing patterns Central neurogenic A sustained, deep, rapid but regular pattern (hyperpnoea) hyperventilation occurs, with a decreased PaCO2 and a corresponding increase in pH and PaO2
May result from CNS damage or disease that involves the midbrain and upper pons; seen after increased intracranial pressure and blunt head trauma
Apneustic breathing
A prolonged inspiratory cramp (a pause at full inspiration) occurs; a common variant of this is a brief end-inspiratory pause of 2 or 3 seconds, often alternating with an endexpiratory pause
Indicates damage to the respiratory control mechanism located at the pontine level; most commonly associated with pontine infarction but documented with hypoglycaemia, anoxia and meningitis
Cluster breathing
A cluster of breaths has a disordered sequence with irregular pauses between breaths
Dysfunction in the lower pontine and high medullary areas
Ataxic breathing
Completely irregular breathing occurs, with random shallow and deep breaths and irregular pauses. Often the rate is slow
Originates from a primary dysfunction of the medullary neurons controlling breathing
Gasping breathing pattern (agonal gasps)
A pattern of deep ‘all-or-none’ breaths is accompanied by a slow respiratory rate
Indicative of a failing medullary respiratory centre
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characterised by a lack of breathing coordination and breathing appears to be irregular, hence the name. It is associated with an increase in mortality. In summary, the more inferior the level of insult in the brainstem, the poorer the prognosis.
Pupillary changes
Anatomically, brainstem areas that control arousal are adjacent to areas that control the pupils. In this way, clinicians examine pupillary changes to determine the extent of injury because the pupillary changes indicate the presence and level of brainstem dysfunction (see Fig. 8.15). For example, severe ischaemia and hypoxia usually produce dilated, fixed pupils. The third cranial nerve (oculomotor) controls pupillary constriction, and compression of the nerve causes contralateral dilation of the pupil. This occurs because the oculomotor nerve is compressed when there is an increase in intracranial pressure, which may be a precursor to uncal herniation, or movement of the uncus (medial part of the temporal lobe) downwards increasing pressure on the midbrain of the brainstem. Therefore, pupillary
changes are crucial for effective neurological assessment of a patient who is experiencing a decreased level of consciousness. Some drugs affect pupils and must be considered in evaluating individuals in comatose states. For instance, large concentrations of atropine (used as an anticholinergic agent) cause full dilation and fixing of the pupils. Opiates, such as morphine, cause pinpoint pupils. Severe barbiturate intoxication may produce fixed pupils. It is important to note that some people have normally unequal pupils. Conducting a thorough health history is important to ascertain if this is the case. Size, shape and response to light are all important findings to document.
Oculomotor responses
Resting, spontaneous and reflexive eye movements change at various levels of brain dysfunction. For instance, individuals with metabolically induced coma generally retain ocular reflexes even when other signs of brainstem damage are present. Therefore, evaluation of the movement of the eyes is also essential for thorough assessment of the level of consciousness.
Metabolic imbalance
Small, reactive and regular
Diencephalic dysfunction Small and reactive
Dysfunction of tectum (roof) of the midbrain Large ‘fixed’ hippus
Dysfunction of third cranial nerve Sluggish, dilated and fixed
Pontine dysfunction Pinpoint
Midbrain dysfunction Midposition and fixed FIGURE 8.15
Pupillary changes due to injury at different levels of the brain. The pupillary changes correspond to the level of consciousness.
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TABLE 8.7 Abnormal motor responses with decreased responsiveness MOTOR RESPONSE
DESCRIPTION
LOCATION OF INJURY
Abnormal motor responses, upper extremity flexion with or without extensor responses in the leg (decorticate rigidity)
Slowly developing flexion of the arm, wrist and fingers with adduction in the upper extremity, and extension, internal rotation and plantar flexion of the lower extremity
Suggest hemispheric damage above midbrain
Extensor responses in the upper and lower extremities (decerebrate posturing, decerebrate rigidity)
Opisthotonos (hyperextension of the vertebral column) with clenching of the teeth; extension, abduction and hyperpronation of the arms; and extension of the lower extremities
Associated with severe damage involving the caudal diencephalon or midbrain
In acute brain injury, shivering and hyperpnoea may accompany unelicited recurrent decerebrate spasms
Acute injury often causes limb extension regardless of location
Extensor responses in the upper extremities accompanied by flexion in the lower extremities
Indicates pontine level dysfunction
Flaccid state with little or no motor response to stimuli
Damage to lower pons
Motor responses
Motor responses help evaluate the level of brain dysfunction and determine the most severely damaged side (hemisphere) of the brain. The pattern of response noted may be: (1) purposeful; (2) inappropriate, generalised motor movement; or (3) not present at all. Motor signs indicating loss of cortical inhibition that are commonly associated with decreased consciousness include reflex grasping, reflex sucking and rigidity. Abnormal flexor (decorticate) and extensor (decerebrate) responses in the upper and lower extremities are defined in Table 8.7 and illustrated in Fig. 8.16.
A
B
Vomiting
Yawning, vomiting and hiccups are complex reflex-like motor responses that are integrated by neural mechanisms in the lower brainstem. These responses may be stimulated by physical compression or by diseases involving tissues of the medulla oblongata (e.g. infection, neoplasm, infarct). They also occur relative to other, more benign, stimulation of the vagal nerve. Most CNS disorders produce nausea and vomiting. Vomiting without nausea indicates direct involvement of the central neural mechanism. Vomiting often accompanies CNS injuries that: (1) involve the vestibular nuclei (involved in balance and spatial orientation) or its immediate projections, particularly when double vision (diplopia) is also present; (2) impinge directly on the floor of the fourth ventricle; or (3) produce brainstem compression secondary to increased intracranial pressure.
Post-coma unresponsiveness
Essentially, when brain damage is severe, individuals will experience a decreasing level of consciousness often leading to coma and death (see Table 8.5). However, individuals who survive and remain in a prolonged deep coma are in
C
FIGURE 8.16
Decorticate and decerebrate responses to painful stimuli. A Decorticate response. Flexion of arms, wrists and fingers with adduction in upper extremities; extension, internal rotation and plantar flexion in lower extremities. B Decerebrate response. All four extremities in rigid extension, with hyperpronation of forearms and plantar extension of feet. C Decorticate response on right side of body and decerebrate response on left side of body.
a post-coma unresponsiveness state.7 Previously, this was termed persistent vegetative state, but this description has been changed in Australia because it implies that the state is permanent and the word ‘vegetative’ was considered too negative.8 In contrast, post-coma unresponsiveness better
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describes the level of consciousness of the individual following coma. It has been defined as: • complete lack of responses that suggest a cognitive component • preservation of sleep–wake cycles and cardiorespiratory function • partial or complete preservation of hypothalamic and brainstem autonomic functions.9 The post-coma unresponsive individuals sometimes do emerge from their comatose state — that is, sleep–wake cycles are observable over time — but only brainstem reflexes are present. Imaging studies indicate low levels of brainstem activity, but there is a complete lack of awareness of self or of the surrounding environment and cerebral function is lost. The individual’s vital autonomic functions, such as blood pressure and breathing, are maintained without support. There is bowel and bladder incontinence. The individual does not speak any comprehensible words or follow commands. Recovery grows increasingly unlikely as the state persists. In some individuals, a gradual return to some level of responsiveness occurs. These individuals are considered to be in a minimally responsive state. In this state, individuals may have cognitively mediated behaviour that initiates a minimal level of purposeful response. For instance, these individuals may be able to respond to simple commands with, say, finger movement, as opposed to reflex responses.9 It should be noted that the chances of these individuals returning to full neurological function are remote. Finally, some individuals exhibit a coma-like appearance but do not have any abnormality in their level of arousal or cognition. These individuals have locked-in syndrome. This is quite distinct from post-coma unresponsiveness and the minimally responsive state, because there is only specific damage to the motor tracts in the ventral brainstem without damage to the cerebrum.10 Therefore, the efferent pathways are disrupted and the individual has a limited capacity to communicate but not lack of awareness. These individuals cannot communicate through speech or body movement but are fully conscious, with intact cognitive function. They retain eye movement and can use blinking as a means of communication.9
Brain death
Brain death occurs when the brain is damaged so completely that it can never recover and cannot maintain the body’s internal homeostasis. On postmortem examination, the brain is autolysing (self-digesting) or already autolysed, because the brain tissue has died. Brain death has occurred when there is no evidence of function above the foramen magnum11 — that is, in the cerebral hemispheres or brainstem — for an extended period. The abnormality of brain function must result from structural or known metabolic disease and must not be caused by a depressant drug, alcohol poisoning or hypothermia. For brain death to occur there must be severe brain injury with sustained increased ICP above systemic blood pressure, such that intracranial blood flow ceases.12
In Australia and New Zealand brain death guidelines have been determined. They state that: Determination of brain death requires that there is unresponsive coma, the absence of brainstem reflexes and the absence of respiratory centre function, in the clinical setting in which these findings are irreversible. In particular, there must be definite clinical or neuro-imaging evidence of acute brain pathology (e.g. traumatic brain injury, intracranial haemorrhage, hypoxic encephalopathy) consistent with the irreversible loss of neurological function.12 The following preconditions must be present before clinical determination of brain death: • normothermia (core temperature >35°C) • normal blood pressure (systolic blood pressure >90 mmHg and mean arterial pressure >60 mmHg) • the individual must not be affected by sedative drugs • there must be no severe electrolyte, metabolic or endocrine disturbance • neuromuscular function must be intact (that is, the individual must not be paralysed) • brainstem reflexes must be able to be examined • apnoea testing must be able to be performed (apnoea refers to the state of not breathing).12 The clinical testing of brain death requires two medical practitioners with specific experience and qualifications to perform two separate clinical examinations of the brain death test. The clinical test examines three main categories: coma, absence of brainstem reflexes and absence of breathing. The test and responses for brain death determination are included in Table 8.8. It should be noted that if any test results are not conclusive, the patient cannot be confirmed as brain dead. Furthermore, if brain death cannot be determined conclusively from clinical testing, demonstration of an absence of intracranial blood flow can be used via imaging techniques (see Fig. 8.17).12 The Australian and New Zealand Intensive Care Society (ANZICS) recommends that in children brain death studies have the same criteria as for adults.12 FOCU S ON L EA RN IN G
1 Differentiate between supratentorial and infratentorial herniation. 2 Discuss how structural as well as metabolic factors can produce coma. 3 Discuss why the level of consciousness is the most critical index of central nervous system function. 4 Describe how Cheyne-Stokes breathing pattern appears in coma. 5 Explain the relationship between oculomotor changes and the level of coma. 6 Differentiate between post-coma unresponsiveness, locked-in syndrome and brain death.
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TABLE 8.8 Brain death clinical tests RESPONSES THAT INDICATE BRAIN DEATH
TYPE OF CLINICAL TEST
CLINICAL TEST
Coma
Apply noxious stimuli to elicit motor response (e.g. periorbital rub, sternal rub)
Absence of movement
Pupillary light reflex (cranial nerves II & III)
Shine a bright light into the eye and observe pupillary constrictor response
No pupillary constriction response
Corneal reflex (cranial nerves V & VII)
Touch the corneas with soft cotton wool or gauze and examine the eye response
No blinking or withdrawal response
Reflex response in trigeminal distribution (cranial nerves V & VII)
Apply pain over the trigeminal distribution, e.g. pressure over the supraorbital nerve
No facial or limb movement
Vestibulo-ocular reflex (cranial nerves III, IV, VI & VIII)
The external auditory canal must be cleared before testing can occur. Elevate the head to 30°. Instil 50 mL of ice-cold water into the ear canal using a syringe. Hold the eyelids open and observe for eye movement for a minimum of 60 seconds
No eye movement in response to the cold water; the eyes remain in the midline within the socket
Gag reflex (cranial nerves IX & X)
Stimulate the posterior pharyngeal wall
No gag response
Brainstem reflexes
Cough/tracheal reflex (cranial nerve X) Stimulate the tracheobronchial wall
No cough response observed
Apnoea testing
No breathing effort is seen during testing
Pre-oxygenate patient with 100% oxygen for at least 5 minutes. Disconnect patient from ventilator and observe continuously for any spontaneous breathing. Take arterial blood gas to document increase in PaCO2
FIGURE 8.17
Brain death study. A CT scan of a 73-year-old man showing compression of the brainstem (arrow). Note the lack of gyri and sulci as the brain has swollen following global neuronal death.
Seizures
A seizure results from a sudden, explosive, disorderly discharge of cerebral neurons and is characterised by a rapid, transient alteration in brain function, usually involving motor, sensory, autonomic or psychic clinical manifestations and altered level of arousal. Neurons both produce and
transmit electrical impulses and the rate of neuronal electrical signalling is different according to the activity of the individual. For instance, during sleep, electrical activity is reduced compared to when performing complex tasks such as talking to a passenger while driving a motor vehicle. Nonetheless, the neuronal electrical discharges are ordered and coordinated. During a seizure, the electrical impulses are uncoordinated and many neurons fire simultaneously at a faster rate than normal, which produces a brief disruption in the brain’s coordinated electrical functions. Seizure disorders represent a syndrome, however, and not a specific disease entity. The alteration in level of arousal is temporary. It should be noted that the term convulsion is sometimes applied to seizures, but it should be applied to the jerky, contract-relax (more correctly termed, tonic-clonic) movement associated with some seizures. Seizures are common — approximately 10% of people worldwide have one seizure during their lifetime.13 In addition, it is estimated that 50% of those who have one seizure will have more seizures. If seizures are recurrent, without any underlying correctable cause, the individual will be diagnosed with epilepsy. The World Health Organization estimates that 50 million people worldwide have epilepsy. The vast majority (up to 90%) are found in developing countries.13 In Australia, there are a reported 400 000 people with epilepsy.14 For approximately half of all people with epilepsy the onset occurs before 20 years of age, and there is another peak around 60 years of age.14 Approximately 3% of people will be diagnosed with epilepsy in their lifetime.15 The prevalence of epilepsy is 5–7 persons per 1000.16
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PATHOPHYSIOLOGY
Any disorder that alters the neuronal environment may cause seizure activity, so, theoretically, anyone may experience a seizure. The seizure threshold of some persons, however, apparently is genetically lower. Diseases or other processes that involve the nervous system can produce a seizure disorder. The onset may indicate the presence of an ongoing primary neurological disease. Aetiological factors in seizures generally include (1) cerebral lesions, (2) biochemical disorders, (3) cerebral trauma and (4) epilepsy, which can result from the following conditions: • metabolic defects • congenital malformation • genetic predisposition • perinatal injury • postnatal trauma • myoclonic syndromes • infection • brain tumour • vascular disease • fever • drug or alcohol abuse. Causes of recurrent seizures are age related (see Table 8.9). Seizures may be precipitated by a range of events. All of the following can result in seizure activity: hypoglycaemia; fatigue or lack of sleep; emotional or physical stress; febrile illness; large amounts of water ingestion; constipation; use of stimulant drugs; withdrawal from depressant drugs (including alcohol); hyperventilation; and some environmental stimuli, such as blinking lights, a poorly adjusted television screen, loud noises, certain music, certain odours or merely being startled. Epilepsy is now thought to be the result of complex genetic mutations17 with environmental effects that cause abnormalities in brain synapses or connections, or an imbalance in chemicals that the brain uses to send signals or abnormal nerve connections made while attempting to repair itself after injury.16 A group of neurons may exhibit a paroxysmal (short, frequent attacks) depolarisation shift and function as an epileptogenic focus. These neurons are hypersensitive and are more easily activated by conditions that change their depolarisation threshold. Examples include hyperthermia, hypoxia, hypoglycaemia, hyponatraemia, repeated sensory stimulation and certain sleep phases. Epileptogenic neurons fire more and more frequently. When the intensity reaches a threshold point, cortical excitation spreads. Excitation of the subcortical, thalamic and brainstem areas corresponds to the tonic phase (muscle contraction with increased muscle tone) and is associated with loss of consciousness. The clonic phase (alternating contraction and relaxation of muscles) begins when inhibitory neurons in the cortex, anterior thalamus and basal nuclei react to the cortical excitation. The seizure discharge is interrupted, producing intermittent muscle
TABLE 8.9 Causes of seizures in different age groups AGE AT ONSET
PROBABLE CAUSE
Neonates ( 1 month and < 12 • Genetic disorders (metabolic, years) degenerative, primary epilepsy syndromes) • Developmental disorders • Trauma • Idiopathic Adolescents (12–18 years)
• Trauma • Genetic disorders • Infection • Brain tumour • Illicit drug use • Idiopathic
Young adults (18–35 • Trauma years) • Alcohol withdrawal • Illicit drug use • Brain tumour • Idiopathic Older adults (>35 years)
• Cerebrovascular disease • Brain tumour • Alcohol withdrawal • Metabolic disorders (uraemia, hepatic failure, electrolyte abnormalities, hypoglycaemia) • Alzheimer’s disease and other degenerative CNS diseases • Idiopathic
Note: febrile refers to fever; idiopathic means the cause is unknown.
contractions that gradually decrease and finally cease. The epileptogenic neurons are exhausted.15 During seizure activity, the demand for oxygen is approximately 60% greater than usual. Although cerebral blood flow also increases, oxygen is rapidly depleted, along with glucose, and lactate accumulates in brain tissue.
CHAPTER 8 Concepts of neurological dysfunction
Continued, severe seizure activity holds the potential for progressive brain injury and irreversible damage.
Types of seizure disorders
The International League Against Epilepsy (www.ilae -epilepsy.org) has attempted to modify the International Classification of Epileptic Seizures without consensus. Seizures are classified in different ways: by clinical manifestations, site of origin, electroencephalogram (EEG) findings or response to therapy. In addition, a number of terms are used to describe seizure activity and these are defined in Table 8.10. There are more than 40 different types of seizures; however, the most common classification is to divide them into generalised and partial seizures, which are then further subdivided. A simplified version of the International Classification of Epileptic Seizures is presented in Fig. 8.18 and discussed below.
TABLE 8.10 Terminology applied to seizures TERM
DEFINITION
Aura
A partial seizure experienced as a peculiar sensation preceding the onset of generalised seizure that may take the form of gustatory, visual or auditory experience or a feeling of dizziness, numbness or just ‘a funny feeling’
Prodrome
Early clinical manifestations, such as malaise, headache or a sense of depression, which may occur hours to a few days before the onset of a seizure
Tonic phase
A state of muscle contraction in which there is excessive muscle tone
Clonic phase
A state of alternating contraction and relaxation of muscles
Postictal phase
The time period immediately following the cessation of seizure activity Seizures
Partial
Generalised Absence (petit mal)
Simple
Unclassified Atonic (drop attacks) Tonic
Complex Myoclonic
Tonicclonic
FIGURE 8.18
Classification of epileptic seizures. See the text for an explanation of the different types of seizures.
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The primary difference between generalised and partial seizures is where the epileptic activity occurs: • Partial, or focal, seizures usually involve only a portion of the brain. These are the most common type of seizure; approximately 60% of people who have seizures have partial seizures — mostly teenagers and the older population. The seizures are often subtle and the person may seem not to be aware of their environment, without any other clinical manifestation. • In contrast, generalised seizures, as the name implies, involve widespread epileptic activity in both hemispheres of the brain. They usually result in unconsciousness for a period. It should be noted that partial seizures can progress to generalised seizures in some cases. Partial seizures can be subdivided as follows: • Simple partial seizures. Simple partial seizures involve a short-lived seizure with no loss of consciousness or awareness. They usually involve only one area of the brain; the area of neuronal epileptic activity will dictate the type of symptoms the person will experience. For instance, if the seizure focus is in the sensory area of the brain, the person may experience numbness or pins and needles in a body area. In addition, some people may have an aura immediately before the seizure. This is a distinct warning sign that a seizure is imminent and it can be visual, motor or sensory — for instance, the person may have a strange taste in their mouth. Auras have not been fully explained, but it is likely that the anatomical location of seizure origin in the brain is related to the type of seizure. • Complex partial seizures. In contrast to simple partial seizures, in complex partial seizures consciousness and arousal are lowered, which can make the person appear confused. The most common location of the epileptic focus is either the temporal or the frontal lobe of the brain. The other defining characteristic feature is that the person experiencing the seizure may respond to vocalisations but demonstrate repetitive, odd actions, such as fidgeting, saying unusual sounds or walking around. The time frame for the seizure is 3 minutes or less. Generalised seizures can be subdivided as follows: • Absence seizures. Absence seizures, previously referred to as petit mal seizures, are brief episodes (less than 10 seconds) where the person may stare without facial expression and be unresponsive. These seizures commence in childhood and it may appear that the child is daydreaming. • Myoclonic seizures. Myoclonic refers to the muscle jerks that are brief and usually involve one or a group of muscles. In this case the person does not lose consciousness but may fall or drop an item if they were holding it in their hands. • Tonic-clonic seizures. Tonic-clonic seizures, previously referred to as grand mal seizures, are the type of seizure that the general population associates with epilepsy. The
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person experiencing the seizure loses consciousness, then their body stiffens from a generalised muscle contraction (tonic phase), which is rapidly followed by a strong rhythmical movement of the limbs that appears jerking-like (clonic phase). One distinguishing characteristic is the often loud, sudden cry that people vocalise before commencement of the tonic phase. This occurs when a volume of air is forced past the vocal cords immediately before the tonic contraction. The seizure lasts for about 2–3 minutes and is accompanied by a confused, tired phase after the convulsions have ceased. This is referred to as the postictal phase. • Tonic seizures. As the name implies, the person experiences an increase in muscle tone and the body will stiffen. These seizures can cause considerable injury if the person falls after the onset of the seizure. • Atonic seizures. The ‘a’ before tonic means without. Therefore, during these seizures the person loses muscle tone, often causing them to fall to the ground if they were standing. There is usually no loss of consciousness and recovery is rapid. Any seizure that does not follow the pattern of either a partial or a generalised seizure type is referred to as an unclassified seizure, also known as an atypical seizure. Any seizure activity can result in a postical phase. The duration and severity of the postictal phase varies from patient to patient and may be different from other episodes of seizure activity. Patients generally present with varying degrees of
confusion and lethargy while postictal. Most unclassified seizures occur in early childhood and are not associated with a loss of consciousness.18 EVALUATION AND TREATMENT
The health history, physical examination and laboratory tests of blood and urine can identify systemic diseases known to promote seizures. Radiographic studies (CT and MRI scans) and cerebrospinal fluid examination (lumbar puncture to sample the CSF) help identify neurological diseases associated with seizures. Therefore, most tests are to exclude cranial pathology that may explain the seizure activity. When these tests have ruled out any extraneous cause of the epilepsy, an EEG is used to assess the type of seizure and determine its focus. EEGs measure the electrical activity in the cerebral cortex. EEGs are not a definitive test for seizure activity as some of the population have abnormal EEG readings despite the absence of seizure activity. Furthermore, in some instances abnormal electrical activity is not detectable despite the presence of seizure activity. EEGs are most useful when used in association with patient history to diagnose seizure disorders. Treatment involves correcting or controlling the cause and, if none is identified, administering anti-seizure medications to suppress seizure activity. Surgery may be useful (see Research in Focus). Counselling may also be of value. Prevention of epilepsy is the direction that some research has taken.17
Seizures in childhood may occur because of many reasons. Certain types of seizures may have a genetic component or familial predisposition, or they can result from maternal diseases or congenital structural anomalies of the CNS. From the newborn period through to childhood, asphyxia (choking — difficulty breathing), intracranial haemorrhage, CNS infections, injury, electrolyte imbalances and inborn errors of metabolism may cause seizures. Often the cause of seizures is unknown. The incidence of epilepsy varies greatly with age and is estimated to be 0.5–1% of children, with onset occurring during infancy or childhood. It is estimated that 30% of epilepsy diagnoses occur within the first 4 years of life. One of the most common types of seizures in childhood is that of febrile seizures, with an estimated cumulative incidence rate of 2–14%. Approximately 5% of children under the age of five will experience a febrile convulsion at some point. They are classified as seizure accompanied by fever (> 38°C) in the absence of CNS infection or other conditions that may induce convulsions, such as electrolyte disturbances or head trauma. As a result, febrile convulsions are considered the
most common neurological disorder in children. Febrile convulsions are generally short lived, generally lasting only up to a few minutes and the child apparently recovers fully. Despite the occurrence and prevalence of febrile-induced seizure activity in children, the cause of febrile convulsions remains unclear. It was often thought that the rate of core temperature increase was the reason for the seizure, but this has been shown to be erroneous. It is more likely that febrile seizures arise from a combination of genetic and environmental factors. The seizures are often generalised tonic-clonic seizures lasting for approximately 2 minutes. They usually only occur once during the febrile state, but children with abnormal radiological or EEG findings may have an increased risk of epilepsy. Partial seizures are seen in about 10–15% of febrile seizures. In the majority of cases, no specific treatment is required. The core temperature should be reduced and the child should be observed for a period of time until normothermia returns. A rapid reduction in body temperature using paracetamol or ibuprofen does not reduce the incidence or recurrence of febrile seizures. There is some discussion
PAEDIATRICS
Paediatrics and seizures
CHAPTER 8 Concepts of neurological dysfunction
that prolonged febrile convulsions may increase the risk of developing subsequent seizure activity, however this link has yet to be definitively established. Approximately 1% of children who experience febrile seizures will be diagnosed with epilepsy.
Causes of seizures in children Re-occurring seizures Idiopathic Haemorrhage/trauma
Non re-occurring seizures Febrile illness Intracranial infection
F O CUS O N L E A R N IN G
1 Provide a definition of seizure. 2 Describe how seizures are different from epilepsy. 3 Explain why many conditions can precipitate seizures. 4 Describe the different types of seizures and provide a short description of each. 5 Explain the major clinical considerations for assessing and managing a patient in seizure.
RESEARCH IN F
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Epilepsy surgery stands the test of time Theodore and Kelley, researchers at the National Institute of Neurological Disorders and Stroke (NINDS), obtained information from 48 people and families about individuals who had right or left temporal lobe surgery for seizures between 1965 and 1974. Twenty-one were free of seizures that caused loss of consciousness, and three had been free of these types of seizures for 19 years. The others died or were never completely free of seizures causing loss of consciousness. Theodore and Kelley believe this type of surgery is underutilised because individuals shy away from brain surgery as a treatment option. The decision to pursue surgical treatment must balance the potential benefit of seizure control and the effect on cognitive function.
Cognitive disorders
In healthcare settings, many patients experience changes in their cognitive function and it is often difficult to understand the pathophysiological alterations that have brought on these conditions. For instance, following surgery with a general anaesthetic (substances that induce unconsciousness), many patients, especially the elderly, may experience behavioural changes that are not usually associated with that particular individual. In fact,
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Re-occurring seizures Non re-occurring seizures Toxins Drugs Infections Toxins Hypoglycaemia Space-occupying lesions Congenital defects Metabolic disorders Uraemia Acute cerebral oedema Allergy Haemorrhage Migraine Cardiovascular dysfunction
some patients may have psychotic episodes that appear to have a psychiatric origin. However, in the vast majority of cases, the problem is an alteration to the neurological system, precipitated by environmental factors such as pain or sleep deprivation leading to a confused state. It is important to consider these conditions and to differentiate between delirium, dementia and depression, as these may overlap. In addition, there is an increasing incidence of autism in children (see later in the chapter), which is a developmental disorder that affects executive function. This means that higher-level control of actions, especially new and novel actions, may be impaired.
Acute confusional states
The term confusion is used by health professionals to describe a patient’s mental status. It means that the person does not have the ability to be clear in their thoughts; this state is related to cognitive dysfunction. Therefore, it can be applied to many clinical situations. Acute confusional states result from cerebral dysfunction secondary to a range of different states (see Table 8.11) — for instance, drug intoxication, metabolic disorder, anaesthetics or nervous system disease. Withdrawal from alcohol, barbiturate or other sedative drug ingestion is a common cause. Acute confusional states may begin either suddenly or gradually, depending on the amount of exposure to the toxin. These states often occur with febrile illnesses, systemic diseases (e.g. heart failure), head injury, anaesthesia or certain focal cerebral lesions. These states may also be generated by conditions such as unrecognised and untreated urinary tract infections. Delirium is one of the most common acute confusional states and is often under-diagnosed. PATHOPHYSIOLOGY
Acute confusional states arise from disruption of a widely distributed neural network involving the reticular activating system of the upper brainstem and its projections into the thalamus, basal nuclei and specific association areas of the cortex and limbic areas. In most cases, both cerebral hemispheres are affected.
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TABLE 8.11 Common causes of the acute confusional state Intoxications
Alcohol; prescription, over-thecounter and illegal drugs
Withdrawal states
Alcohol, sedative-hypnotic drugs
Nutritional deficiencies
Thiamine, vitamin B12, folate, niacin
Metabolic disorders
Electrolyte and acid–base disturbances; hepatic, renal, pancreatic disease
Infections
Pneumonia, urinary tract infection, sepsis, AIDS
Endocrine disorders
Hypo- and hyperthyroidism, hypoand hyperglycaemia, hypo- and hyperadrenocorticism
Structural brain disease
Traumatic brain injury, seizure disorders, stroke, subarachnoid or intracerebral haemorrhage, epidural or subdural haematoma, encephalitis, brain abscess
Postoperative states
Anaesthesia, electrolyte disturbances, fever, hypoxia, analgesics
Trauma to the brain or conditions that increase ICP can lower consciousness and cause deficits in cognition. Most metabolic disturbances that produce an acute confusional state interfere with neuronal metabolism or synaptic transmission. This may be due to a lowering of oxygen and glucose delivery, thereby suppressing global neuronal function. Many drugs and toxins also interfere with neurotransmission function at the synapse. CLINICAL MANIFESTATIONS
The predominant feature of an acute confusional state is impaired or lost concentration. The person is highly distractible and unable to concentrate on incoming sensory information or on any one particular mental or motor task. The onset of an acute confusion state is usually abrupt. Initial clinical manifestations are often difficulty with concentration, restlessness, irritability, insomnia and poor appetite. Later there are misperceptions, illusions and hallucinations. Obsessions, compulsive behaviour and rituals may also be evident. In other acute confusional states, the individual exhibits decreases in mental function, specifically alertness, attention span, accurate perception, interpretation of the environment and reaction to the environment. Forgetfulness is prominent and the individual is frequently sleepy. Delirium, a major type of acute confusion state, typically develops over 2–3 days and is seen initially with altered level of consciousness, hallucinations and restlessness. Some people experience seizures. Unpleasant, even terrifying, dreams may occur. Diagnosis of delirium is not always
immediate or even rapid. The sudden onset of an acute confusional state requires that other psychiatric and organic causes are initially identified and/or eliminated to provide an accurate diagnosis. Delirium has been estimated to affect up to 42% of the hospitalised elderly population.19 In a fully developed delirium state, the individual is completely inattentive and perceptions are grossly altered, with extensive misperception and misinterpretation. Hallucinations may be present. The person appears distressed and often perplexed; conversation is incoherent. Tremor and high levels of restless movement are common. Violent behaviour may be present, but not always. The individual usually cannot sleep, is flushed and has dilated pupils, has a rapid pulse (tachycardia), core body temperature is elevated and profuse sweating (diaphoresis) can also be present. Delirium typically abates suddenly but in some instances it can resolve gradually in 2–3 days; occasionally delirium states in some individuals can persist for weeks. EVALUATION AND TREATMENT
The initial goals in evaluating an acute confusional state are to: 1 establish that the individual is confused, by performing a neurological examination that is appropriate for the individual — for example, confusional assessment method or Mini-Mental State Examination 2 determine the cause of the confused state — that is, whether it has an organic origin (infection, drug withdrawal) or a psychiatric origin. A complete history and physical examination, as well as laboratory tests (electrocardiogram and blood, urine, CSF and radiological studies) are needed. These are performed to exclude causes, such as those listed in Table 8.11. Once the cause is established, treatment is directed at controlling the primary disorder, with supportive measures used as appropriate (see Fig. 8.19). The cause of delirium can remain undetected in some individuals and not all cases of delirium recover full neurological function. In some instances the use of antipsychotic medication may be required to prevent permanent cognitive dysfunction. The determination between delirium and dementia needs to be addressed. The primary differences are that delirium is a reversible condition, associated with acute confusion that normally has an underlying cause — when this is rectified, the delirium abates. In contrast, dementia is a progressive and irreversible condition that is associated with pathological changes in the CNS.
Dementia
Dementia is an umbrella term that refers to a progressive failure of many cerebral functions not caused by an impaired level of consciousness.20 The result may be a decrease in orientation, memory, language and executive attentional networks. Because of declining intellectual ability, the individual exhibits alterations in behaviour. Dementia is a major neurodegenerative condition that slowly affects
CHAPTER 8 Concepts of neurological dysfunction
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Safety of patient, family and staff (e.g. bedside companion, immediate pharmacological intervention)
Psychoeducational support for patient, family and staff
Antipsychotic prescription if it is not contraindicated Regular + PRN (when necessary)
Search for underlying aetiological factors and provide correction if possible
Re-evaluate antipsychotic efficacy and tolerance
Psychoeducational support for patient, family and staff
FIGURE 8.20
Metabolic deficits in Alzheimer’s disease. The positron emission tomography (PET) scan shows parietotemporal hypoperfusion or hypoactivity indicated by the arrows. The darker regions are areas of low metabolic activity.
FIGURE 8.19
Delirium management flowchart. The management of delirium is aimed at reducing the symptoms and treating the underlying causes.
the ability of the person to function normally and is one of the most prevalent disabling conditions in older Australians. Currently, almost 30 million people worldwide live with dementia — more than the combined populations of Australia and New Zealand. In 2011, it was estimated that approximately 298 000 people in Australia had dementia.21 The reason for the gender imbalance remains unclear, however 62% of those affected by dementia in Australia are women. According to the Australian Institute of Health and Welfare (AIHW) in 2010 dementia was the third leading cause of death in Australia with approximately 25 people per day dying from the condition. Research indicates that Indigenous Australians are more likely to develop dementia earlier, as Indigenous Australians were found to have a three-fold increase in dementia prevalence compared to the overall Australian population.22 As this condition is associated with ageing, it is predicted that by 2050 almost 1 million Australians will have dementia23 and as a result, in August 2012, dementia was recognised as a national health priority area. The most prevalent dementia is Alzheimer’s disease, which is discussed in detail in Chapter 9. PATHOPHYSIOLOGY
There are more than 100 different conditions that can cause dementia.24 There are numerous causes of dementia, stemming from a variety of underlying pathophysiological processes.24,25 Mechanisms leading to dementia include degeneration, compression, atherosclerosis and trauma. Genetic predisposition is associated with the degenerative diseases, including Alzheimer’s disease and Huntington’s disease. Central nervous system infections, including the
human immunodeficiency virus (HIV) and slow-growing viruses associated with Creutzfeldt-Jakob disease are associated with dementia, in addition to changes in motor function. Excessive alcohol use in some individuals has also been linked to the development of dementia. Dementia results from progressive nerve cell degeneration, brain atrophy and hypoperfusion of particular areas of the brain, such as the parietal and temporal lobes (see Fig. 8.20). CLINICAL MANIFESTATIONS
There are many clinical manifestations of dementia, but the onset is always gradual. One of the first signs is short-term memory loss, with mood swings and a decline in the individual’s ability to perform all their activities of daily living. As the condition progresses, the individual may experience the following three conditions: • Agnosia: a defect of pattern recognition — a failure to recognise the form and nature of objects. Agnosia can be tactile, visual or auditory, but generally only one sense is affected. • Apraxia: an impaired capacity to perform motor activities that were previously achievable. • Dysphasia: an impairment of comprehension or production of language. Comprehension or use of symbols, in either written or verbal language, is disturbed or lost. The condition in dementia patients leads to aphasia, which is total loss of the comprehension or production of language. Expressive dysphasia involves primarily expression deficits — that is, the individual may be able to speak, yet the sentences are not clear and may not make sense. Receptive dysphasia occurs when the individual can speak, yet does not understand what is being spoken to them. As the dementia worsens, the individual’s personality may change and mood swings become common. The
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person with dementia does not recognise their family members and their manner may be flat or aggressive. Towards the late stage of dementia, the individual loses memory capacity, cannot perform activities of daily living like feeding and requires full care. The condition progresses to coma and ultimately death, most commonly due to chest infections. EVALUATION AND TREATMENT
Establishing the cause for dementia may be complicated, but individuals with clinical manifestations of dementia should be evaluated with laboratory and neuropsychological testing to identify underlying conditions that may be treatable. Unfortunately, no specific cure exists for most progressive dementias. Therapy is directed at maintaining and maximising the use of the remaining capacities, restoring functions if possible and accommodating for lost abilities. Helping the family to understand the process and to learn ways to assist the individual is essential.
Depression
Depression is a mood disorder that can involve affective, cognitive and physiological manifestations. In older individuals, depression is often under-diagnosed and can be misinterpreted as dementia, due to the lack of initiative, insomnia, increased confusion and general apathy. Furthermore, it has been estimated that depression or depressive symptoms are present in approximately 40% of patients with dementia. Depression is discussed in more detail in Chapter 39.
RESEARCH IN F
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Exercising the body can benefit the mind There is good evidence from rodent models that exercise prompts nerve cells to multiply and to increase and strengthen their connections, and even protects them from harm. It also appears to increase cognitive functioning in these animals and enable better and more complete recovery from brain injury such as stroke. The benefits of exercise may extend to the brain and nerves that are diseased or damaged in persons with Alzheimer’s disease, Parkinson’s disease and spinal cord injury. Release of serotonin and neurotrophic factors (nerve growth factors) appears to account for the exercise effect, but further research including in humans is needed to fully understand the effects of exercise on the brain.
FOCU S ON L EA RN IN G
1 Explain why individuals may experience confusion. 2 Discuss how delirium arises and list some of the clinical manifestations. 3 Describe dementia and differentiate between dementia and delirium. 4 Explain why differentiation between depression, dementia and delirium is critical for patients. 5 Describe how depression can be mistaken for dementia.
The autism spectrum disorders are a group of conditions that include the common neurological deficits of communication, social interaction and stereotyped behaviour. The disorder of ‘classic’ autism is the most common; however, the disorder is described as a spectrum to focus attention on the reality that no two children display an entirely classic presentation. For instance, the spectrum includes children with Asperger’s syndrome, Rett syndrome and pervasive developmental disorder. There is an increasing incidence of children with autism spectrum disorders in countries such as Australia and New Zealand. In Australia, the diagnosis rates for autism spectrum disorders have risen significantly, reflecting the changes in the rest of the world over the last 10–15 years. There has been a 79% increase in the number of children diagnosed with this condition in Australia since 2009. This has been attributed to a combination of changing diagnostic criteria and an increased awareness among health professionals, therefore causing some conjecture as to the actual increase in prevalence. In Australia, it is estimated that some 11 700 children under the age of
16 years are on the autism spectrum, with up to 125 000 people having some form of autism spectrum disorder. Further to this, it is now estimated that approximately 1 in 88 children has an autism spectrum disorder. More male children are diagnosed with autism than females, with an average male/female ratio of 3.8 : 1. PATHOPHYSIOLOGY
The exact cause of autism spectrum disorders is unknown. These complex neurodevelopmental disorders have a biological basis. There is a likely familial component, although this has not been fully identified. The predominance in males compared to females is highly suggestive of a genetic link. The two main theories regarding autism spectrum disorder genes are those genes (1) involved in brain development and (2) responsible for neurotransmitter function. Increasingly, there is evidence that abnormalities in particular regions of the brain are the cause of autism spectrum disorders, so much so that imaging systems have been proposed as an alternative form of diagnosis with
PAEDIATRICS
Paediatrics and autism spectrum disorders
CHAPTER 8 Concepts of neurological dysfunction
reliability of 85–90% in some studies. Neuroanatomical imaging suggest often lateralised abnormalities in several areas of the brain, including the amygdala, hippocampus, septum, mammillary bodies and cerebellum. The brains of people with an autism spectrum disorder have been shown to be slightly larger and heavier than people without the disorder. In addition, some of the brain regions have neurons that seem to be developmentally immature. There appears to be widespread brain dysfunction at both the cortical and the subcortical levels. It has been suggested that environmental factors play a role in the development of autism spectrum disorders. Problems during the perinatal period, such as maternal illness, are likely to be involved. Low birth weight, prematurity and events during delivery have not consistently been shown to lead to an increased incidence of autism spectrum disorders. It was suggested in the 1990s that childhood immunisations might affect the rates of autism spectrum disorders, but this has conclusively been shown to be false, despite parental concerns. Recent evidence suggests that there is a neuroinflammatory role in the development of autism, possibly associated with altered gut microflora. Children with autism commonly experience digestive and bowel abnormalities and there are some hypotheses linking these as manifestations of a single underlying physiological abnormality. A proportion of children with autism appear to have dysfunction in the production of cell energy (by the mitochondria) that may arise from environmental triggers in genetically predisposed people. This may arise from abnormal food digestion associated with altered gut flora and thus subsequent accumulation of toxic byproducts altering typical cell metabolism. Thus, the neurological symptoms associated with autism spectrum disorder may be secondary to other physiological abnormalities. This would fit with other symptomatology associated with autism spectrum disorder including common abnormalities in trace elements and reduction of symptomatology during antibiotic therapy. CLINICAL MANIFESTATIONS
Children with an autistic spectrum disorder have a triad of impairments (see Fig. 8.21). This includes, but is not limited to: 1 impairment in social interactions or relationships, such as lack of facial expression, eye contact or spontaneous actions in behaviour 2 communication problems, either as delayed or lack of spoken language, inability to sustain conversations or stereotyped and repetitive language 3 restricted, repetitive and stereotypic behaviour, such as specific routines, repetitive movements (rocking) or persistent preoccupation with inanimate objects and general lack of imagination or interest in varied stimuli.
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Impaired social interaction skills
AUTISM Communication problems
Stereotypic behaviour
FIGURE 8.21
Autism spectrum disorders, or triad of cognitive impairments.
The social, behavioural and cognitive deficits are often present in early childhood (under the age of 3 years); however, they may be subtle and parents may not recognise these manifestations. The first contact with health professionals is often due to speech delays, which are more noticeable. The main deficits that are noticeable over time include: • lack of eye contact • flat facial expressions • no vocalisations in response to parents • lack of recognition of parents’ voices • delayed speech, including babbling • lack of nonverbal communication, such as finger pointing • no interaction with others, instead living in their own world • repetitive behaviours, such as lining up objects, rather than constructive play. EVALUATION AND TREATMENT
Evaluation is difficult because of the need for a comprehensive, multidisciplinary assessment, which is often not available to parents. There is no single definitive biological or medical marker for autism spectrum disorder. In many cases, the child may be demonstrating signs of autism, yet parents do not perceive differences, often meaning that diagnosis is delayed. There are standardised identification tools, including the modified Checklist for Autism in Toddlers (M-CHAT). Treatment and other intervention in autism is typically dependent on the severity of autism. Much of the focus is placed on behavioural and adaptive therapies with the strongest evidence of efficacy found using applied behaviour analysis, identifying positive behaviours for support and problem behaviours for reduction. Other therapies commonly used with autism spectrum disorder and showing some level of success for children with this Continued
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condition and their families include application of the Early Start Denver Model and speech-language therapies. Psychological interventions maybe coupled with pharmaceutical therapy to treat aggression, irritability and repetitive behaviours. However, several atypical antipsychotic medications such as risperidone and aripiprazole have been shown to be of benefit when
F OCU S O N L E ARN IN G
1 Outline some of the clinical manifestations of autism. 2 Explain why early identification of autism spectrum disorder is problematic and important. 3 Identify some of the behavioural and pharmacological therapies that can support people with autism spectrum disorder.
Alterations in motor function Movements are complex patterns of activity controlled by the central nervous system. General motor dysfunctions may produce changes in muscle tone, movement and complex motor performance.
Alterations in muscle tone
Normal muscle tone involves a slight resistance to passive movement. Throughout the range of motion, the resistance is smooth, constant and even. The abnormalities of muscle tone can be divided into either decreased tone (hypotonia) or increased tone (hypertonia) (see Table 8.12).
treating such behavioural symptoms in children. Weight gain was the most commonly cited side effect of the administration of risperidone. As speech is often delayed in persons with autism, intensive speech therapy is often required early in life. Occupational therapy to assist with the development of motor skills is also often a focus of adaptive therapies.
Hypotonia
In hypotonia (decreased muscle tone), passive movement of a muscle occurs with little or no resistance. Hypotonia or flaccidity (a state in which the muscle may be moved rapidly without resistance) occurs when the nerve impulses needed for muscle tone are lost, such as in spinal cord injury or stroke. Individuals with hypotonia tire easily or are weak. They may have difficulty rising from a sitting position, sitting down without using arm support, and walking up and down stairs, as well as an inability to stand on their toes. Because of their weakness, accidents during walking and self-care activities are common. The joints become hyperflexible, so persons with hypotonia may be able to assume positions that require extreme joint mobility. The muscle mass atrophies because of decreased neural input entering the motor unit and muscles appear flabby and flat. Muscle cells are gradually replaced by connective tissue and fat.
Hypertonia
In hypertonia (increased muscle tone), passive movement of a muscle occurs with resistance. Spasticity results from hyperexcitability of the stretch reflexes and is associated with damage to the motor, premotor and supplementary motor areas, as well as lateral
TABLE 8.12 Alterations in muscle tone ALTERATIONS
CHARACTERISTICS
CAUSE
Hypotonia
• Passive movement of a muscle mass with little or no resistance
Thought to be caused by decreased muscle spindle activity as a result of decreased excitability of neurons
• Muscles may be moved rapidly without resistance Flaccidity
• Associated with limp, atrophied muscles and paralysis
Occurs typically when nerve impulses necessary for muscle tone are lost
Hypertonia
• Increased muscle resistance to passive movement
Results when the lower motor unit reflex arc continues to function but is not mediated or regulated by higher centres
• May be associated with paralysis • May be accompanied by muscle hypertrophy Spasticity
• A gradual increase in tone causing increased resistance until tone suddenly reduces, which results in clasp-knife phenomenon
Exact mechanism unclear; appears to arise from an increased excitability of the alpha motor neurons
Rigidity
• Muscle resistance to passive movement of a rigid limb that is uniform in both flexion and extension throughout the motion
Occurs as a result of constant, involuntary contraction of muscle
CHAPTER 8 Concepts of neurological dysfunction
corticospinal tract damage (review using Fig. 6.19). Increased deep tendon reflexes (hyperreflexia) and the spread of reflexes accompany it. Rigidity produced by tonic reflex activity mediated by motor neurons may be continuous or intermittent. The involved muscles are firm and tense; the increase in muscle movement is even and uniform throughout the range of passive movement. The muscles may atrophy because of decreased use. However, hypertrophy occasionally occurs as a result of the overstimulation of muscle fibres. Overstimulation occurs when the motor unit reflex arc remains intact and functioning but is not inhibited by higher centres. This causes continual muscle contraction, resulting in enlargement of the muscle mass and firm muscles.
Alterations in movement
Movement requires a change in the contractile state of muscles. Abnormal movements occur when central nervous system dysfunctions alter muscle innervation. Researchers have found that dopamine, a neurotransmitter in the brain, apparently functions in several movement disorders. Some
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result from too little dopamine activity, whereas others result from too much. Still others are not primarily related to dopamine function. Paresis (weakness) is partial paralysis with incomplete loss of muscle power. Paralysis is loss of motor function so that a muscle group is unable to overcome gravity. The way to describe paresis and paralysis is by using a prefix that describes the limbs involved. Therefore, hemiparesis and hemiplegia refer to paresis and paralysis of the upper and lower extremities on one side. Paraplegia is paralysis of the lower extremities — individuals with spinal cord injuries in the lower spinal cord have paraplegia; and quadriplegia refers to paralysis of all four limbs — it occurs in individuals who have spinal cord injuries at the cervical level. Quadriplegia (or tetraplegia) can often also extend to limited or lack of control of the neck and head. FOCU S ON L EA RN IN G
1 Differentiate between hypotonia and hypertonia. 2 Describe the difference between paresis and paralysis.
Ageing and neurological dysfunction of brain function for the ‘inevitable wear and tear’ model is reasonable. While many of the benefits of ‘brain training’ systems proposed to maintain cognitive function are not generalisable across the wide cognitive spectrum, it is clear that healthy older adults can adapt neurological function, perhaps by decreases in cerebral lateralisation or shifts in cognitive processing regions, to maintain complex neurological function in later life.
chapter SUMMARY Alterations in cerebral homeostasis • Cerebral blood flow is the total blood flow to the brain and is approximately 15–20% of total cardiac output. • Changes in oxygen and carbon dioxide blood concentrations are the most critical factors in altering blood vessel diameter. • Autoregulation and cerebral blood volume are important determinants of cerebral blood flow. • There are three main volumes that occupy the cranial vault: blood, cerebrospinal fluid and brain tissue.
• The Monro-Kellie hypothesis refers to the relationship between the blood, cerebrospinal fluid and brain tissue. Changes in one volume need to be offset by changes in the other two volumes to maintain a stable pressure. • Intracranial pressure is normally about 5–15 mmHg. • Increased intracranial pressure may result from oedema, excess cerebrospinal fluid, haemorrhage or tumour growth. When intracranial pressure approaches arterial pressure, hypoxia and hypercapnia produce brain damage. Continued
AGEING
One of the apparently inevitable consequences of ageing is a gradual atrophy of central nervous tissue, resulting in a decrease of brain mass. Decreased brain volume and declining levels in neuropeptides such as brainderived neurotrophic factor, have previously been linked to declining neural function, particularly cognitive function in older people. However experimental evidence suggests that substitution of the ‘use it or lose it’ model
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• Cerebral oedema is an increase in the fluid content of the brain resulting from infection, haemorrhage, tumour, ischaemia, infarct or hypoxia. • The shifting or herniation of brain tissue from one compartment to another disrupts the blood flow of both compartments and damages brain tissue. • There are four types of cerebral oedema: vasogenic oedema, cytotoxic oedema, ischaemic oedema and interstitial oedema. • Hydrocephalus comprises a variety of disorders characterised by an excess of fluid within the cranial vault or subarachnoid space, or both. • Hydrocephalus occurs because of interference with cerebrospinal fluid flow, caused by increased fluid production or obstruction within the ventricular system or by defective reabsorption of the fluid.
Alterations in cognitive function • Full consciousness is an awareness of oneself and the environment, with an ability to respond to external stimuli with a wide variety of responses. • Consciousness has two components: arousal and content of thought. • A decreased level of arousal occurs by diffuse bilateral cortical dysfunction, bilateral subcortical reticular formation, brainstem dysfunction and localised hemispheric dysfunction. • Supratentorial alterations produce changes in arousal by diffuse or localised dysfunction. • Infratentorial alterations produce changes in arousal by direct destruction of the reticular activating system and its pathways. • An alteration in breathing pattern and level of coma reflects the level of brain dysfunction. • Pupillary changes reflect changes in the level of brainstem function, drug action and response to hypoxia and ischaemia. • Level of brain function manifests by changes in generalised motor responses or no responses. • Loss of cortical inhibition associated with decreased consciousness produces abnormal flexor and extensor movements. • Post-coma unresponsiveness refers to an altered level of consciousness with a complete lack of responses that suggest a cognitive component, preservation of the sleep–wake cycles and cardiorespiratory function and partial or complete preservation of hypothalamic and brainstem autonomic functions. • Brain death occurs when the brain is damaged so completely that it can never recover and cannot maintain the body’s internal homeostasis. • Brain death can be diagnosed from clinical examination only. • Seizures represent a sudden, chaotic discharge of cerebral neurons, with transient alterations in brain function. Seizures may be generalised or focal and can result from cerebral lesions, biochemical disorders, trauma or epilepsy. • Epilepsy is now thought to be the result of complex genetic mutations with environmental effects that cause
• •
• •
•
• •
• • •
•
•
abnormalities in brain wiring or an imbalance in chemicals that the brain uses to send signals or abnormal nerve connections made while attempting to repair itself after injury. There are more than 40 different types of seizures, with the most common classification split into partial and generalised seizures. Febrile seizures are the commonest childhood seizure, can occur between 6 months and 6 years and are thought to be a combination of genetic and environmental factors. Genetic mutations in sodium channel receptor genes have been demonstrated in children who experience febrile seizures. Acute confusional states are characterised chiefly by a loss of detection and, in the case of delirium, an intense autonomic nervous system hyperactivity. Acute confusional states result from cerebral dysfunction secondary to a range of different states — for example, drug intoxication, metabolic disorder, anaesthetics or nervous system disease. Acute confusional states arise from disruption of a widely distributed neural network involving the reticular activating system of the upper brainstem and its projections into the thalamus, basal nuclei and specific association areas of the cortex and limbic areas. In most cases, both cerebral hemispheres are affected. Delirium is a major type of acute confusion state. Dementia is a progressive failure of many cerebral functions not caused by impaired level of consciousness. It is a major neurodegenerative condition that slowly affects the ability of the person to function normally. Dementia may result in a decrease in orienting, memory, language and executive attentional networks. Dysphasia is an impairment of the comprehension or production of language. Expressive dysphasia involves primarily expression deficits — that is, the individual may be able to speak, yet the sentences are not clear and may not make sense. Receptive dysphasia occurs when the individual can speak, yet does not understand what is being spoken to them. Autism spectrum disorders are a group of conditions that have the common neurological deficits of communication, social interaction and stereotyped behaviour. Autism is a complex neurodevelopmental disorder that is likely to have a genetic component, with environmental changes contributing to the disorder.
Alterations in motor function • Motor dysfunction may be characterised as alterations of motor tone, movement and complex motor performance. • Hypotonia and hypertonia are the main categories of altered tone. • Paresis refers to a partial paralysis with incomplete loss of muscle power. • Paraplegia refers to loss of motor function so that a muscle group cannot overcome gravity.
CHAPTER 8 Concepts of neurological dysfunction
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CASE STUDY
ADU LT Rade was a 25-year-old male involved in a serious motor vehicle accident. He was the driver and sole occupant of the car and was speeding when he crashed into a roadside pole. He was not wearing a seatbelt. At the scene, the ambulance crew found that he had an 8 cm laceration of the forehead and was unconscious, with a Glasgow Coma Score of 3 (no eye movement, no vocalisation and motor movement). His pupils were non-reactive to light but were fixed and dilated at 6 mm. The crew inserted an artificial airway, which enabled mechanical ventilation. Then they urgently transported Rade to the nearest acute care hospital, where, after a thorough
clinical investigation, it was determined that he was brain dead. 1 Describe the pathophysiological events that have to occur for a patient to be considered brain dead. 2 Differentiate between coma and brain death. 3 Describe how the clinical examination for brain death determines that there is no brain function. 4 Describe why an artificial airway may be required for oxygenation. 5 Ascertain how organs for transplant remain viable in brain-dead patients.
CASE STUDY
AGEING An 87-year-old patient, Elizabeth, has recently been admitted to hospital. Although she had been otherwise well, she experienced a sudden inability to open her left eye. Upon admission, it was found that she had a large brain tumour within the frontal lobe of the cerebrum. 1 Give a general description of the cerebral blood flow, including how changes in oxygen and carbon dioxide can alter cerebral blood flow. 2 Describe changes to Elizabeth’s cerebral blood flow in the early stages prior to admission, when the tumour remained relatively small.
3
Explain how the brain tumour may tend towards an alteration in intracranial pressure. 4 Describe the Monro-Kellie hypothesis, in relation to Elizabeth’s condition. 5 In the event that Elizabeth’s condition were not adequately diagnosed and treated, describe the serious consequences that might lead to Elizabeth’s death.
REVIEW QUESTIONS 1 Describe how cerebral blood flow is regulated. 2 Discuss the Monro-Kellie hypothesis and how it relates to increased intracranial pressure. 3 Describe the pattern of events during increasing intracranial pressure, eventually leading to brain herniation. 4 Provide a rationale for the difference between post-coma unresponsiveness and brain death. 5 Discuss the differences between the 4 types of cerebral oedema.
6 Describe what a seizure is and explain why people have seizures. 7 Discuss why older people have acute confusional episodes. 8 Differentiate between confusion, delirium and dementia. 9 Describe the autism spectrum disorders and possible causes. 10 Differentiate between hypotonia and hypertonia, and paresis and paralysis.
Key terms
CHAPTER
9
Alterations of neurological function across the life span Matthew Barton and Amy Nicole Burne Johnston
Chapter outline Introduction, 195 Cerebrovascular disorders, 195 Stroke, 195 Cerebral aneurysm, 202 Vascular malformation, 203 Headache and migraine, 204 Trauma to the central nervous system, 205 Brain trauma, 205 Spinal cord trauma, 209 Degenerative disorders of the central nervous system, 212 Alzheimer’s disease, 212 Parkinson’s disease, 214 Huntington’s disease, 216
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Multiple sclerosis, 217 Motor neuron disease, 218 Peripheral nervous system and neuromuscular junction disorders, 219 Guillain-Barré syndrome, 219 Myasthenia gravis, 219 Infection and inflammation of the central nervous system, 220 Meningitis, 220 Encephalitis, 222 Abscesses, 222 Tumours of the nervous system, 223 Cranial tumours, 223
abscess, 222 Alzheimer’s disease, 212 arteriovenous malformation (AVM), 203 autonomic hyperreflexia, 210 blunt trauma, 205 cerebral aneurysm, 202 cerebral palsy, 228 cholinergic crisis, 220 contusions, 206 diffuse axonal injury (DAI), 207 embolic stroke, 197 encephalitis, 222 ependymomas, 225 gliomas, 224 Guillain-Barré syndrome, 219 haemorrhagic stroke, 197 headache, 204 Huntington’s disease, 216 intracerebral haemorrhage, 197 ischaemic stroke, 196 lacunar infarcts, 197 meningiomas, 226 meningitis, 220 migraine, 204 motor neuron disease, 218 multiple sclerosis (MS), 217 myasthenia gravis, 219 myasthenic crisis, 220 nerve sheath tumours, 226 neuroblastoma, 228 oligodendrogliomas, 225 Parkinson’s disease, 214 penetrating trauma, 205 saccular aneurysms (berry aneurysms), 202 spina bifida, 227 spina bifida occulta, 227 spinal shock, 210 stroke (cerebrovascular accident), 195 subarachnoid haemorrhage, 197 thrombotic stroke, 197 transient ischaemic attacks (TIAs), 197
CHAPTER 9 Alterations of neurological function across the life span
Introduction Alterations in central and peripheral nervous system function can be caused by traumatic injury, vascular disorders, tumour growth, infectious and inflammatory processes, metabolic derangements (including those arising from nutritional deficiencies and drugs or chemicals) and degenerative processes. The disruptions to homeostasis of the nervous system described in this chapter are relatively common and often disabling and debilitating, which reflects the importance of understanding this system for provision of quality healthcare. In this chapter, we begin by considering the most significant alteration of the neurological system in our community — cerebrovascular disorders, with the main one being stroke (cerebrovascular accident, also known as ‘brain attack’ to reflect the same urgency of medical care associated with a heart attack). Stroke is among the leading causes of death and disability in our society and therefore its impact is substantial. For those who survive stroke, the disability is often severe and they may require substantial support. Throughout the remainder of the chapter, we discuss a range of other conditions that affect the brain and spinal cord and can cause symptoms such as forgetfulness, abnormal motor function and sensory deficits. We have included some diseases that are relatively rare, in terms of incidence and prevalence. However, these conditions are included because they are actually quite significant in the healthcare setting. The chronic nature of these diseases is such that they will progressively worsen and require more clinical attention.
Cerebrovascular disorders Cerebrovascular disease is the most frequently occurring neurological disorder and is responsible for more than 7.8% of all Australian deaths.1 Cerebrovascular disease includes all abnormalities of the brain that are caused by pathological processes within cranial blood vessels. The brain abnormalities induced by cerebrovascular disease are either (1) ischaemic, with or without infarction (necrosis or death, of brain tissue) or (2) haemorrhagic, including vessel wall abnormalities or rupture of preexisting vascular malformations. The most common clinical manifestation of cerebrovascular disease is stroke (cerebrovascular accident).
Stroke
Stroke (or cerebrovascular accident, CVA) is a leading cause of disability in Australia and New Zealand and is the second-highest cause of death for Australians (see Table 9.1).2 Stroke occurs mainly among those older than 60 years of age, but can affect younger people as well, with 20–25% of strokes occurring in individuals younger than 60 in Australia and New Zealand.2,3 The average age of people suffering from their first stroke in Australia is 72 years for males and 77 years for females.2 Stroke is more common
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TABLE 9.1 Leading causes of death in Australia CAUSE OF DEATH
2011
Number Rank Coronary heart disease
21 513
1
Stroke
11 251
2
Dementia and Alzheimer’s disease
9864
3
Trachea and lung cancer
8114
4
Chronic lower respiratory diseases
6570
5
Diabetes
4209
6
Colon and rectal cancer
4087
7
Blood and lymph cancer (including leukaemia)
3978
8
Heart failure
3488
9
Diseases of the kidney and urinary system
3386
10
Prostate cancer
3294
11
Breast cancer
2937
12
Influenza and pneumonia
2492
13
Pancreatic cancer
2416
14
Suicide
2272
15
Skin cancer
2087
16
Accidental falls
1845
17
Hypertensive diseases
1802
18
Cardiac arrhythmias
1612
19
Cirrhosis and other diseases of the liver
1589
20
in females, perhaps due to the fact that it occurs mainly in old age and females tend to live approximately 5 years longer than males in Australia and New Zealand (see Chapter 33 for more on life expectancy). In addition, people with both hypertension and type 2 diabetes mellitus are four times more likely to have a stroke and eight times more likely to die from stroke.2,4 In its mildest form, a cerebrovascular accident is so minimal as to be almost unnoticed; but in its most severe state, paralysis, coma and death result. Each year, approximately 45 000 Australians and 9000 New Zealanders are affected by stroke, with more than 8000 (in Australia) of these cases being fatal.2,4–6 Overall, the rates of stroke have declined in recent years (see Fig. 9.1), which may be due to factors such as increased public awareness of the symptoms of stroke and improvements in the early diagnosis of stroke. The percentage of people who require hospitalisation for stroke is much higher for Indigenous than for non-Indigenous Australians.6 A stroke occurs when a blood vessel (artery) supplying the brain with oxygen and nutrients is altered, usually by either a lack of flow or rupture. Neurons can only survive without oxygen for a very limited amount of time, so if the blood flow is insufficient for more than approximately 5 minutes, death of the neurons occurs. Neurons within
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Deaths per 100 000 population
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80 70 Males Females 60 50 40 30 20 10 0 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007
Year FIGURE 9.1
Death rates from stroke, Australia, 1987–2007 (per 100 000 population). The death rates from stroke have been declining over recent decades.
FIGURE 9.2
Types of stroke. The main types of stroke are ischaemic and haemorrhagic. See the text for details of the different types of stroke.
the brain do not regenerate (refer to Chapter 6) so the damage is permanent if blood flow is not restored. Death of neurons is called a cerebral infarct; hence a cerebral infarction is another name for a stroke. The type and severity of the symptoms of stroke depend on which blood vessel/s is affected; however, impairment of blood supply to the vital brain structures, such as the brainstem, is often fatal. Strokes are classified according to their pathophysiology (see Fig. 9.2): • ischaemic — blockage of cerebral vessels supplying brain tissue • haemorrhagic — bleeding from the cerebral vessels into brain tissue.
Ischaemic strokes
The vast majority of strokes are ischaemic (75–85%).5 The high frequency of ischaemic strokes is because more people experience inappropriate blockages than cranial vessel damage. Ischaemic strokes occur due to a blockage in the blood vessels supplying the brain. The two subtypes of ischaemic strokes are thrombotic and embolic. In addition, a transient ischaemic attack (TIA) is a short-term (less than 24 hours) partial or full obstruction of blood supply; if this lasts for longer than 24 hours, then it is classified as a thrombotic stroke. An ischaemic stroke results from alterations to neuronal function that persists for more than 24 hours. Neurons cannot survive without a constant supply of oxygen; a
CHAPTER 9 Alterations of neurological function across the life span
disrupted blood supply will result in neuronal death within a few minutes. These are usually the neurons that rely directly and exclusively on oxygen and nutrient supply via the occluded vessel. Further, there is a larger surrounding region of neural tissue which is supplied only in part by the affected (occluded) vessel and in part by alternative vessels, and thus vessel occlusion only partially removes nutrient supply. This region, the penumbral region, is the primary target of latter therapeutic intervention. Without timely and effective clinical intervention, larger areas of tissue disintegration will appear 48 to 72 hours after infarction. Permanent disruptions to brain function will eventuate, which is why strokes are often fatal. THROMBOTIC STROKE
A thrombotic stroke (cerebral thrombosis) occurs when there is a blockage inside a blood vessel that supplies brain tissue with oxygen- and nutrient-rich blood (see Fig. 9.2). The blockage may occur in arteries entering the brain, commonly in the internal carotid artery (carotid stenosis),7,8 or in the smaller vessels within the brain (the intracranial vessels). Blockages often arise around deposits in vessel walls that are usually formed by fatty plaques through the process of atherosclerosis (details in Chapter 23). The plaques contain substances that are lipid based, thus people with high blood cholesterol have a much higher risk of ischaemic stroke.2 The atherosclerotic plaque creates an inviting location for blood cells to accumulate and form into a clot or thrombus, particularly if the atherosclerosis has ruptured. This thrombus builds and can occupy so much of the vessel lumen that it forms a blockage so that blood flow cannot proceed past it; hence neurons that are downstream of the thrombus are deprived of oxygen. Transient ischaemic attacks (TIAs) are temporary decreases in brain blood flow and ischaemia, resulting in brief changes in brain function, such as changes in vision, speech, motor function or levels of consciousness. TIAs may be due to partially occluding or mobile blood clots or to vessels undergoing spasm and narrowing, causing a transient (temporary) reduction or blockage of circulation. Identifiable neurological deficits are typically completely clear within 24 hours, leaving no evidence of dysfunction or permanent brain injury. In most cases, the TIA is actually resolved within the first hour.9 TIAs are a warning sign of cerebrovascular disease and that another TIA or stroke is likely. The recurrence of another TIA is high, and it may occur as soon as 24–72 hours after the first TIA.10 After a TIA, the patient must be supported to modify the risks associated with stroke. Indeed, the TIA on its own can actually be a significant neurological event; in one study, more than 10% of patients suffered disability or death 2 weeks after the initial TIA, despite receiving the recommended treatment.7 Lacunar infarcts are particularly small ischaemic strokes (usually caused by a thrombus less than 15 mm in diameter) and involve the small cerebral arteries, for example those supplying deep brain regions such as the basal nuclei and pons. Lacunar infarcts are strongly associated with hypertension, smoking and diabetes mellitus.11 Because of
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their location and small area of infarction, these strokes may result in limited motor and sensory deficits only, rather than the wide range of symptoms seen with larger areas of infarction. Furthermore, evidence demonstrates that mortality and morbidity is reduced in patients following lacunar infarcts compared with other types of strokes.12 EMBOLIC STROKE
An embolic stroke involves fragments that break from a thrombus formed outside the brain. The most common example is when an embolic fragment, formed in the heart during abnormal heart function, known as atrial fibrillation (see Chapter 23), breaks away and travels to the brain. If an embolic stroke is suspected, investigations of the heart are necessary to establish the cause. The embolus can become wedged in small brain vessels causing obstruction and ischaemia to the brain tissue distal to the occlusion. In people who experience an embolic stroke, a second stroke typically follows because the source of emboli continues to exist, which produces more emboli. The characteristic feature distinguishing between a thrombotic stroke and an embolic stroke is the origin of the clot; the clot originates in the brain vessels in thrombotic strokes and in a vessel outside of the brain in embolic strokes. Fat emboli are less common and sometimes develop following fractures of long bones, as the fatty material from within the yellow bone marrow can enter the bloodstream as an occluding bolus.13
Haemorrhagic stroke
In contrast to ischaemic stroke where the neuronal damage is due to inadequate blood flow, haemorrhagic stroke occurs in response to bleeding in the brain. As a result of the haemorrhage, a haematoma is then formed by this localised collection of blood outside of a blood vessel; the haematoma remains as the blood cannot escape. There are two main types of haemorrhagic stroke: • Intracerebral haemorrhage accounts for about 10–15% of all strokes and is typically related to hypertension (high blood pressure) and ruptured aneurysms (see the next section). Other causes include bleeding into a tumour, haemorrhage associated with bleeding disorders, anticoagulation medications (substances that limit blood clotting), head trauma and illicit drug use (particularly sniffing cocaine).14 • Subarachnoid haemorrhage accounts for about 5% of all strokes and results in bleeding into the subarachnoid space that contains cerebrospinal fluid (CSF). This type of haemorrhage can cause a significant haematoma which causes an increase in intracranial pressure. In a subarachnoid haemorrhage, blood escapes from a defective or injured vessel into the subarachnoid space (see Fig. 9.3). In haemorrohagic stroke, the bleed increases intracranial volume and impairs the circulation of the CSF; together, these lead to an immediate increase in intracranial pressure,15 which returns to near baseline in about 10 minutes. Cerebral blood flow also decreases, which reduces blood supply to the brain. The expanding mass of clotted blood, now known
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• cigarette smoking, which increases the risk of stroke by 50% • obesity or being overweight • poor diet • lack of exercise • drinking too much alcohol, 6 or more standard drinks/ day. Because these risk factors are highly preventable, with adequate patient education and support stroke has been described as highly preventable.16 While most of the lifestyle risk factors are particularly relevant to ischaemic stroke, importantly hypertension is the main risk factor for both ischaemic and haemorrhagic stroke. CLINICAL MANIFESTATIONS
FIGURE 9.3
Subarachnoid haemorrhage. The growing blood volume in the area underneath the arachnoid mater — the subarachnoid space — compresses the nearby brain tissue.
as a haematoma, compresses and displaces brain tissue (see Chapter 8). The blood is also extremely irritating to the neural tissues and stimulates an inflammatory reaction. Macrophages and microglia appear to clear away the blood. The cerebral haemorrhage resolves through reabsorption and a cavity forms, surrounded by a dense gliosis, after removal of the blood. Mortality in subarachnoid haemorrhage is 50% at 1 month post-haemorrhage.15 Haemorrhages are typically described as either massive, small, slit or petechial. Massive haemorrhages are several centimetres in diameter; small haemorrhages are 1–2 cm in diameter; slit haemorrhages lie in the subcortical area; and petechial haemorrhages are the size of a pinhead. The most common sites for hypertensive haemorrhages are in the basal nuclei (55%), the thalamus (10%), the cortex and subcortex (15%), the pons (10%) and the cerebellar hemispheres (10%). Stroke risk factors that you cannot control: • age — as you get older, your risk of stroke increases • gender — stroke is more common in women • a family history of stroke. Medical stroke risk factors: • transient ischaemic attack (TIA) • ischaemic heart disease • atrial fibrillation (irregular pulse) • diabetes, which increases the risk of ischaemic stroke three-fold • rheumatic or valvular heart disease Lifestyle stroke risk factors that you can control: • hypertension (high blood pressure) — most important • hyperlipidaemia/dyslipidaemia (high cholesterol)
The noticeable signs and symptoms of stroke are shown in Box 9.1 and these are used to educate the public and those at risk about stroke. (See also Research in Focus: Two new warning signs found for impending stroke.) BOX 9.1
Signs of stroke (FAST)
The FAST test involves asking these three simple questions: 1 Face — Check their face. Has their mouth drooped? 2 Arms — Can they lift both arms? 3 Speech — Is their speech slurred? Do they understand you? Time is critical. If you see any of these signs call 000 straight away. Other signs and symptoms may include one, or a combination of: • Weakness, numbness or paralysis of face, arm or leg • Difficulty speaking or understanding • Dizziness, loss of balance or an unexplained fall • Loss of vision, sudden blurring or decreased vision in one or both eyes • Headache, usually severe and abrupt onset or unexplained change in the pattern of headaches • Difficulty swallowing
ISCHAEMIC STROKE
Following ischaemic stroke, fluid accumulates between neurons, which results in cerebral oedema. Cerebral oedema reaches its maximum in about 72 hours and takes approximately 2 weeks to subside. Most people survive an initial hemispheric ischaemic stroke unless there is massive cerebral oedema, which is nearly always fatal. Clinical manifestations of ischaemic stroke vary, depending on the artery obstructed. Different sites of obstruction create different occlusion syndromes, and if the area of damage is unilateral (restricted to one side of the brain), then symptoms will typically only be seen on the contralateral (opposite side of the body; see Fig. 9.4). For example, if the Broca’s area (the area of cerebral
CHAPTER 9 Alterations of neurological function across the life span
RESEARCH IN F
CUS
Two new warning signs found for impending stroke Prevention of stroke is far more preferable than treatment once a stroke has occurred. Researchers have been searching for ways to identify what signs and individuals may be associated with higher stroke risk. It has been shown that individuals with elevated biochemistry markers of lipoproteinassociated phospholipase A2 (a proinflammatory enzyme secreted by macrophages that binds to low-density lipoprotein), elevated levels of trimethylamine-N-oxide (a gut bacteria byproduct) and highly sensitive C-reactive protein (CRP, a protein produced by the liver during periods of inflammation) have a significantly increased risk for ischaemic stroke. In addition, those with obstructive sleep apnoea also have a greater risk for stroke independent of other risk factors. More research is needed to find the exact reasons for the increased risk.
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motor cortex responsible for the initiation of speech) in the left frontal lobe is affected, then the classical sign of stroke; expressive aphasia (difficulty in speaking) will occur and the patient may say only a couple of short words rather than speak in full sentences. If the blood flow to brain areas involved in speech remains normal, then speech will not be affected. Another classical manifestation of stroke regarding speech involves the Wernicke’s area in the left temporal lobe. This region of the brain contains motor neurons involved in the comprehension of speech. In this case, the person will be able to articulate, but may use words and sentences that do not make sense. Since the patient cannot interpret what they are saying, they will be unaware of their errors. These are examples of receptive aphasia. Other common clinical manifestations of ischaemic stroke include: vision loss or deficit, weakness and impaired coordination (ataxia), which are typically asymmetrical.4,9 HAEMORRHAGIC STROKE
Right-brain damage (stroke on right side of the brain) • Paralysed left side: hemiplegia • Left-sided neglect • Spatial–perceptual deficits • Tends to deny or minimise problems • Rapid performance, short attention span • Impulsive, safety problems • Impaired judgment • Impaired time concepts
Left-brain damage (stroke on left side of the brain) • Paralysed right side:hemiplegia • Impaired speech/language aphasias (loss of language production and interpretation) • Impaired right/left discrimination • Slow performance, cautious • Aware of deficits: depression, anxiety • Impaired comprehension related to language, mathematics
FIGURE 9.4
Manifestations of right-sided and left-sided stroke. The main clinical features of stroke differ, depending on which side of the brain has suffered the stroke.
Individuals experiencing intracranial haemorrhage from a ruptured or leaking aneurysm (discussed in the next section) have one of three sets of symptoms: (1) onset of an excruciating generalised headache with an almost immediate lapse into an unresponsive state; (2) headache but with consciousness maintained; or (3) sudden lapse into unconsciousness. Once in a deep unresponsive state, the person rarely survives. The immediate prognosis is grave, but if the person survives, some recovery of function is often possible. If the haemorrhage is confined to the subarachnoid space, there may be no local signs. If bleeding spreads into the brain tissue, hemiparesis (paralysis on one side of the body), dysphasia or aphasia (difficulty using or understanding language, respectively) or blindness in half of the visual field may occur. Warning signs of an impending aneurysm rupture may be present and include headache and temporary fluctuating unilateral weakness, numbness and tingling and speech disturbance. Rapid worsening of headache is much more common in haemorrhagic stroke than ischaemic stroke due to irritation of the meningeal membranes by blood components.4,9 A ruptured vessel causes a sudden ‘explosive’ headache, accompanied by nausea and vomiting, visual disturbances (including sensitivity to light, known as photophobia), neck stiffness, motor deficits and loss of consciousness related to a dramatic rise in intracranial pressure. Meningeal irritation and inflammation often occur, causing nuchal rigidity (a resistance to flexing the neck forwards due to rigidity of the neck muscles), photophobia (an abnormal intolerance of light causing discomfort of the eyes), blurred vision, irritability, restlessness and low-grade fever. A positive Kernig’s sign (inability to extend the leg at the knee when the thigh is flexed) and Brudzinski’s sign (passive flexion of the neck causes passive flexion of the legs) may appear. No localising signs are present if the bleed is confined completely to the subarachnoid space.
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EVALUATION AND TREATMENT
It is essential to distinguish between ischaemic and haemorrhagic causes of stroke to guide best treatment options. A range of investigations can assist with this definitive diagnosis and most major hospitals have a dedicated stroke care unit to provided efficient evidence-based care; however, these units are less common in rural and remote healthcare settings. The patient’s medical history is important, particularly since hypertension is the main risk factor for haemorrhagic stroke and TIA. Knowing the time that the symptoms commenced is important: if the patient was experiencing stroke on waking, the time that symptoms commenced is assumed to be the time when they were last awake and asymptomatic. Timing is critical as it strongly influences treatment options.10 The lack of pain with ischaemic strokes means these strokes do not usually wake the patient, but haemorrhagic strokes do. The Australian guidelines for predicting those at early risk of stroke after a TIA use an ABCD2 score, which assigns points based on a patient’s symptoms of age, blood pressure, clinical features (unilateral weakness, speech impairment), duration of symptoms and diabetes (see Table 9.2). This allows patients to be classified as low or high risk of subsequent stroke — those at high risk should have a CT scan of the brain within 24 hours.9 A brain scan is essential to confirm the diagnosis of stroke and to eliminate other causes of the symptoms (such as a tumour). The CT scan should be performed as soon as possible but at least within 24 hours of symptoms commencing if the patient is at high risk of stroke (see Fig. 9.5). While an MRI scan is preferable for distinguishing between ischaemic and haemorrhagic stroke, the cost and time involved with this test means that many facilities will rely on a CT scan.9 A cerebral angiograph can be combined
with CT to visualise the blood vessels to identify areas of blockage, abnormal vessel anatomy, arteriovenous malformation or aneurysm. This entails inserting a catheter into an artery (femoral or brachial) and guiding it into the internal carotid artery. Dye is then injected into the intracranial arteries and x-rays are used to determine the vascular anatomy and to identify any abnormalities such as aneurysms. In ischaemic stroke, thrombolytic therapy using a drug that dissolves clots (known as tissue plasminogen activator, commonly abbreviated to tPA) by breaking down fibrin, is given as soon as possible. While neuronal death occurs
A
B
TABLE 9.2 ABCD2 score for predicting early risk of stroke The ABCD2 scoring for predicting those with a TIA at a high risk of early stroke. A score above 4 indicates those at high risk, who require an urgent CT scan. SYMPTOMS
POINTS
A
Age: 60 or older
1
B
Blood pressure: 140/90 mmHg or higher
1
C
Clinical features:
D
D
unilateral weakness
2
speech impairment without weakness
1
Duration: 60 minutes or longer
2
10–59 minutes
1
Diabetes
1
Total: maximum of 7
FIGURE 9.5
A CT scan is essential to confirm the diagnosis of stroke. A CT image of an ischaemic stroke due to blockage in the middle cerebral artery. B CT image of a haemorrhagic stroke (arrow) in a patient due to use of the drug ecstasy.
CHAPTER 9 Alterations of neurological function across the life span
within 5 minutes, administering this medication has the important goal of rescuing the penumbral cells. It is recommended that the thrombolytic tPA (alteplase) be administered at least within 4.5 hours of the stroke,17 but preferably less than 3 hours. Different hospitals have adopted different protocols. This tight time-window requires coordination of services for the patient to ensure quick diagnosis and treatment induction. Brain scans are essential prior to commencement of thrombolytic therapy to confirm an ischaemic stroke: if the stroke is haemorrhagic, it is imperative that thrombolytic therapy not be used, as it will worsen the condition. Treatment is directed at restoration of adequate blood flow, prevention of ischaemic injury and supportive management to control cerebral oedema and increased intracranial pressure. Other treatments include aspirin within 24 hours, and surgical removal of blood clot (endovascular thrombectomy) and, in those patients who have atherosclerosis in the carotid artery, a carotid endarterectomy may be performed to surgically remove material (atheromas) on the inside of an artery (see Fig. 9.6). Arresting the disease process by control of risk factors is critical, and anticoagulant therapy using aspirin is usually instituted to minimise the risk of subsequent stroke.18 The diagnosis of a subarachnoid haemorrhage is based on the clinical presentation, a CT scan, blood test (serum levels for troponin I & INR) and a lumbar puncture (insertion of a needle into the subarachnoid space to sample the CSF). This CSF sample will identify if blood is present. Treatment is directed at controlling intracranial pressure, preventing ischaemia and hypoxia of the neural tissues and preventing rebleeding. Treatment of an intracranial bleed, regardless of the cause, focuses on stopping or reducing the bleeding, cardiopulmonary support (blood pressure
A A
A B B
A B C C
External carotid artery Plaque Shunt
Common carotid artery
FIGURE 9.6
Carotid endarterectomy is performed to prevent stroke. The procedure can be performed by clamping the artery to temporarily prevent blood flow, with the other carotid artery supplying enough blood to the brain, or redirecting blood flow using a vascular shunt. A A shunt (tube) is inserted above and below the blockage to allow blood flow to the brain. B Atherosclerotic plaque in the common carotid artery is removed. C Once the artery is stitched closed, the shunt is removed and blood flow through the artery is restored.
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maintenance, intubation if required, assessment using the Glasgow Coma Scale) controlling the increased intracranial pressure, preventing re-bleeding and preventing vasospasm; a condition where the muscle in artery walls spasms, leading to vasoconstriction and potentially ischaemia. Intravenous administration of a drug that promotes blood clotting (recombinant activated factor VII) within 4 hours of onset of a cerebral bleed is currently under study as a therapy. Some surgeons drain the subarachnoid blood collection, or surgically clip or pack the aneurysm with coils. It has been proposed that patients with TIA or stroke should be treated with the same degree of urgency and attention as those with acute coronary disorders, particularly in the light of the risk of disability in these high-risk patients.10 The risk of recurrence is high — without diagnosis and treatment, 80–90% have a recurrence of symptoms by 1 year.10 Even with adequate treatment, almost 10% suffer a recurring event.2 Preventing stroke recurrence is a balance between education, patient modification of risk factors and improved research. Patient safety is a goal for which nurses assume a major responsibility. These goals include: • maintenance of an adequate airway and oxygenation support to prevent hypoxia • control of fever • swallowing assessment/management • ongoing assessment for cardiac arrhythmia and cardiac ischaemia/infarction • blood pressure management to maximise cerebral perfusion • glycaemia management to maintain glucose less than 6.7 mmol/L to decrease risk of cerebral oedema and haemorrhage • prevention of complications such as aspiration pneumonia, nosocomial infections and device-related infections (urinary tract infections, intravascular line infections) • prevention of deep venous thrombosis and pulmonary embolism • facilitate early mobilisation • fall prevention and patient safety. Many patients will be managed in a stroke unit through close monitoring by nurses with expertise with the stroke population. Some critically ill and unstable patients who may require a ventilator may also require admission to an intensive care unit. Regardless of the setting, nurses work collaboratively with the acute stroke medical team and allied health team to achieve optimal outcomes.
The longer-term consequences of stroke
‘Brain attack’ patients need to be evaluated for dysphagia (difficulty in swallowing). Nasogastric or enteral nutrition (semi-liquid diet infused directly into the stomach via a tube through the nose) may be necessary for the first month or more if swallowing is not functional or puts the patient at risk of aspiration.9 Urinary incontinence (involuntary
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leakage of urine) may require a combination of exercise and medication. Although faecal incontinence (involuntary loss of bowel contents) may occur in one-third of stroke patients, this improves such that only 11% remaining incontinent after several months.9 Stroke patients need to be assessed for depression, anxiety and mood alterations and appropriate medications maybe used to treat these. Allied health professionals will be involved in the rehabilitation of patients post-acute stroke including: • physiotherapist • occupational therapist • speech pathologist • dietitian • social worker • psychologist. Stroke survivors may need to be assessed by Aged Care Assessment Teams (ACATs) or an equivalent service, which can determine those who are eligible for specific assistance programs. A wide range of techniques and equipment are available to assist those with motor difficulties in the longer term. Many patients will require palliative care and almost 20% of stroke survivors require nursing home or other support.18 F OC US O N L E ARN IN G
1 Why is atherosclerosis a risk factor for thrombotic stroke? 2 Why do lacunar strokes involve small infarcts? 3 Compare treatments for thrombotic stroke and embolic stroke.
Cerebral aneurysm
A cerebral aneurysm, also known as intracranial aneurysm, is caused by a weakness in the wall of an artery (or arteriole) supplying the brain that results in a dilated ‘pouch’ filled with blood. This out-pouching gives the vessel a localised swollen, balloon-like appearance. Intracranial aneurysms may result from hypertension, familial connective tissue disorders (Marfan’s syndrome), arteriovenous malformation, trauma, inflammation and localised vasospasm such as that associated with cocaine use. The aneurysm size may vary from 2 mm to 3 cm or greater. Most aneurysms are located at bifurcations (branching points in blood vessel) at the base of the brain in or near the circle of Willis, in the vertebrobasilar arteries or within the carotid vessels. Aneurysms may occur singularly, but in 10% of cases, more than one is present.19 The swollen, stretched and overfilled vessel is prone to rupture and induction of an intracranial bleed. Peak incidence of rupture occurs in persons aged 50 to 60 and the incidence is slightly higher in women than in men.19 Rupture of a cerebral aneurysm usually results in a significant subarachnoid haemorrhage (SAH), or bleeding into the subarachnoid space, and is a main cause of a haemorrhagic stroke.
PATHOPHYSIOLOGY
Aneurysms are classified on the basis of their morphology (shape and form).20 Saccular aneurysms (berry aneurysms) occur frequently (in approximately 2% of the population)20 and probably result from congenital abnormalities in the tunica media of the arterial wall as well as degenerative changes in the vessel wall. The sac gradually grows over time. A saccular aneurysm may be: (1) round, with a narrow stalk connecting it to the parent artery; (2) broad-based without a stalk; or (3) cylindrical (see Fig. 9.7).20 Classification Cerebral aneurysms can be classified by size, according to these categories: • small: to 10 mm • medium: 10 to 15 mm • large: 15 to 25 mm • giant: 25 to 50 mm • super-giant: larger than 50 mm. Cerebral aneurysms can also be classified by shape and aetiology which yields the following categories: • berry aneurysm: most common type; berry or saccular shaped with a neck or stem • fusiform aneurysm: an out-pouching of an arterial wall, without a stem • traumatic aneurysm: any aneurysm resulting from a traumatic head injury (accounts for a small number) • mycotic (infections) aneurysms: rare; caused by septic emboli from infections, such as bacterial endocarditis; may lead to aneurysmal formation • Charcot-Bouchard aneurysm: microscopic aneurysmal formation associated with hypertension; involves the basal ganglia and brainstem • dissecting aneurysm (pseudo-aneurysm): related to atherosclerosis, inflammation, or trauma; an aneurysm
Saccular aneurysm
Saccular aneurysm at bifurcation
Broad-based saccular aneurysm
Fusiform aneurysm
FIGURE 9.7
Types of aneurysms. Aneurysms are localised dilations of blood vessels, with different structural appearance.
CHAPTER 9 Alterations of neurological function across the life span
in which the intimal layer is pulled away from the medial layer and blood is forced between layers.20 Aneurysms rupture through thin areas, causing haemorrhage into the subarachnoid space that spreads rapidly, producing localised changes in the cerebral cortex and focal irritation of nerves. While some ruptured aneurysms are too severe for blood clotting to correct the issue, a less severe bleed may be remedied through blood clotting processes. The bleed undergoes reabsorption through arachnoid villi within 3–4 weeks. CLINICAL MANIFESTATIONS
Aneurysms often are asymptomatic. Of those who undergo routine autopsy, 5% are found to have one or more previously unidentified intracranial aneurysms. Clinical manifestations include headache, and may also arise from cranial nerve compression, but the signs vary, depending on the location and size of the aneurysm. Cranial nerves III (oculomotor), IV (trochlear), V (trigeminal) and VI (abducens) are most commonly affected. Unfortunately, the most common first indication of the presence of an aneurysm is an acute subarachnoid haemorrhage or intracerebral haemorrhage, which may cause a serious haemorrhagic stroke (see previous section). Headaches are a main symptom. EVALUATION AND TREATMENT
The Hunt and Hess classification of subarachnoid haemorrhages is based on a description of the clinical manifestations (see Table 9.3).19 Rebleeding is a significant risk, with a high mortality (up to 70%). The period of greatest risk is within the first month, with the peaks in the incidence of rebleeding occur in the first 24–28 hours and at 7 to 10 days postbleed.19 The onset of rebleeding is typically accompanied by sudden severe headache, severe nausea and vomiting, a decrease in or loss of consciousness, and new neurological deficits linked to increasing intracranial pressure. Death may occur.
TABLE 9.3 Subarachnoid haemorrhage classification scale CATEGORY
DESCRIPTION
Grade I
Neurological status intact; mild headache, slight nuchal rigidity (neck stiffness). Survival 70%.
Grade II
Neurological deficit evidenced by cranial nerve involvement; moderate to severe headache with more pronounced meningeal signs (e.g. photophobia, nuchal rigidity). Survival 60%.
Grade III
Drowsiness and confusion with or without focal neurological deficits; pronounced meningeal signs. Survival 50%.
Grade IV
Stuporous with pronounced neurological deficits (e.g. hemiparesis, dysphasia); nuchal rigidity). Survival 20%.
Grade V
Deep coma state with decerebrate posturing and other brainstem functioning. Poor survival rate (10%).
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Diagnosis before a bleeding episode is made using intracranial angiography. After a subarachnoid or intracerebral haemorrhage, a tentative diagnosis of an aneurysm is made based on clinical manifestations, patient history, CT scanning and/or MRI. The treatment of choice for an aneurysm is typically surgical management. Small coils may be packed into the aneurysm, which encourages blood clotting and tissue growth over the area, reducing the risk of it rupturing (see Fig. 9.8). Results from a meta-analysis clearly show that coiling yields a better clinical outcome than clipping; the benefit being greater in those with a good preoperative grade than in those with a poor preoperative grade. However, coiling leads to a greater risk of rebleeding.19,20 The location and size of the aneurysm and the person’s clinical status determine whether invasive therapy is feasible.
Vascular malformation
An arteriovenous malformation (AVM) describes a tangled mass of dilated blood vessels that create abnormal channels between cerebral arteries and veins. AVMs may occur in any part of the brain and vary in size from a few millimetres to large malformations extending from the cortex to the ventricle. AVMs occur equally in males and females and occasionally occur in families. Although AVMs are usually present at birth, most are asymptomatic, and those who exhibit symptoms generally present after 30 years of age.20 PATHOPHYSIOLOGY
AVMs do not have a normal blood vessel structure (such as arterialised veins) and vessels typically range from hypertrophied to abnormally thin. One or several arteries may feed the AVM and become tortuous and dilated over time. With moderate to large AVMs in high pressure vessels, local arterial hypotension and venous hypertension may occur, which deprives surrounding cells of adequate blood flow, leading to brain ischaemia and hypoxia. CLINICAL MANIFESTATIONS
About 20% of people with an AVM have a set of characteristic symptoms including: a chronic, nondescript headache,
FIGURE 9.8
Coils inserted in aneurysm. Platinum coils attached to a thin wire are inserted into the catheter and then placed in the aneurysm until the aneurysm is filled with coils. Packing the aneurysm with coils prevents the blood from circulating through the aneurysm, reducing the risk of rupture.
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seizures, reduced consciousness and nausea. Bleeding from an AVM into the subarachnoid space causes symptoms identical to those associated with a ruptured aneurysm. If bleeding occurs into the brain tissue, focal signs develop that resemble a stroke-in-evolution; 10% of people experience hemiparesis or other focal signs. Hydrocephalus may also develop where there is a large AVM that extends into the ventricular lining.20
Cluster headaches can last 15 to 180 minutes, come in groups (clusters) between one to eight daily, lasting weeks to months (cluster period). The clinical presentation of a cluster headache includes severe, ipsilateral (same side of body) pain located in the orbital, supraorbital, temporal or any combination of these sites. These headaches can be triggered by alcohol, certain scents, histamine or nitroglycerin and are more prevalent in men between 20 and 40 years of age.
EVALUATION AND TREATMENT
Migraine
It is difficult to know whether a person has an AVM in their cerebral vascular anatomy. A bruit (noise generated by turbulent blood flow as it rushes past an obstruction in an artery) auscultated over the carotid artery in the neck, the mastoid process or the eyeball in a young person is almost diagnostic of an AVM. Confirming diagnosis is made by CT scan (not sensitive for diagnosing AVM but important for revealing intracerebral haemorrhage) and MRI (80–95% sensitive for diagnosing medium to large AVM) followed by MRA (magnetic resonance angiography). Treatment options available for AVMs include surgery, embolisation, radiosurgery and conservative treatment.20 FOCUS O N L E ARN IN G
1 How is an arteriovenous malformation different from a cerebral aneurysm? 2 How are cerebral aneurysms classified? 3 Relate cerebral aneurysm to haemorrhagic stroke.
Headache and migraine Headache
Headaches and migraines are covered within this chapter due to their symptoms mainly affecting cranial structures. Headaches are very common, being experienced by about 90–95% of the population in any given year, and causing 2% of presentations to emergency departments. Headaches can be classified into two main categories; primary or secondary. A primary headache is a headache for which no structural abnormalities can be identified and includes migraine, tension-type headache, cluster and miscellaneous headaches. Secondary headaches are associated with various underlying primary aetiologies attributed to head and neck trauma, infections, substance use or its withdrawal. There is apparently prostaglandin-cytokine involvement in the development of the pain associated with most headaches as they typically respond well to nonsteroidal antiinflammatory drugs (NSAIDs), including paracetamol. Tension-type headaches are the most common type of primary headache reported by over 70% of some populations with an average 1-year prevalence of 42% in adults worldwide.21 Tension headaches have been associated with a muscular origin and can be triggered by stress, mental tension or musculoskeletal neck problems. Pain is bilateral and of mild to moderate intensity with a feeling of tightness and pressure and not accompanied by nausea or vomiting like a migraine.
Migraines are a common, often chronic, neurological condition that include primary disabling headache that may present with or without other neurological abnormality.22 Sensory abnormalities associated with migraine can include visual perceptual abnormality including development of an ‘aura’. An ‘aura’ is a constellation of focal neurological symptoms that initiate or accompany an attack that can last between 5 and 60 minutes. Common auras include visual disturbances such as development of bright spots in the visual field, somatosensory sensations including tingling of the lips, face or hands; paresis of an arm or leg; mild aphasia and confusion. Development of aura is the most common reason patients with headache give for seeking medical assistance. Migraine affects 10–15% of adults worldwide with a three times higher rate in women, which may be hormonally driven.22 The aetiology of migraine is not yet fully understood; however, research supports the view that the brain in migraine suffers from hyperexcitability and is more easily triggered to abnormal activity by a wide range of triggers, from sleep disturbance to hormonal alteration to food sensitivity and altered blood glucose levels. In paediatric patients, migraine triggers often include stress, lack of sleep and duration of exposure to electronic screens.21 Although treatment of an individual by avoiding their triggers may be impractical, the role of triggers in stimulating activation of the painful sensations remains unclear. Researchers debate the origins of migraine; however, it does seem to relate to neurogenic inflammation of the trigeminal nerve (the first division of cranial nerve V) which innervates cerebral vasculature and the meninges.23 Therefore, the ‘head’ pain arising with migraine appears to be caused by hyper-activation of: (1) the meningeal or vascular branches (explains the throbbing pain) of the trigeminal nerve; and (2) its respective nociceptive pathways that pass through the periaqueductal grey system and presumably on to thalamic regions, explaining the sensory abnormality and sensitivity commonly accompanying migraines. This may also explain why NSAIDs are ineffective in some patients in resolving their symptoms.22,23 FOCU S ON L EA RN IN G
1 Compare and contrast various kinds of headaches. 2 Why are some drug therapies effective for some headaches and not so effective for others? 3 How does the symptomatology of migraine differ from headache?
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TABLE 9.4 Causes of brain injury TYPE OF INJURY
MECHANISM
Coup
Injury is directly below site of forceful impact
Contrecoup
Injury is on opposite side of brain from site of forceful impact
Extradural haematoma
Vehicular accidents, falls, sporting accidents
Subdural haematoma
Vehicular accidents or falls, especially in the elderly or those with chronic alcohol abuse
Intracerebral haemorrhage
Contusions caused by forceful impact, usually vehicular accidents or falls from a distance
Compound fracture
Objects strike head with great force or head strikes object forcefully; temporal blows, occipital blows, upward impact of cervical vertebrae (basilar skull fracture)
Penetrating injury
Missiles (bullets) or sharp projectiles (knives, ice picks, axes, screwdrivers) that enter the cranial vault
Diffuse axonal injury
Moving head strikes hard, unyielding surface or moving object strikes stationary head; vehicular accidents (occupant or pedestrian); torsional head motion
Brain injury may be
Brain trauma
Traumatic brain injury is a type of acquired brain injury caused by a blow to the head or by the head being forced to move rapidly usually with some loss of consciousness.24 This may be the result of a motor vehicle accident, fall, assault, sporting accident, gunshot wound or violent shaking.25 In Australia and New Zealand, such injuries are usually caused by a motor vehicle or sporting accident (see Table 9.4). Causes of non-traumatic brain injury include excess alcohol consumption, hypoxia from stroke or cardiac arrest, tumours or lead poisoning.26 As a result of the brain injury, the individual suffers functional impairments, including physical, emotional and/or cognitive deterioration. Males are twice as likely to be hospitalised for traumatic brain injury than females, with most people who are hospitalised being children under 5 years, those in their late teens and early 20s, or the over-60 age group.25 Furthermore, Indigenous Australians have a hospitalisation rate for traumatic brain injury more than double that for non-Indigenous Australians.27 There are two classes of injuries to the brain: • focal brain injuries are localised to a specific region or regions • diffuse axonal injuries are widespread. Focal brain injuries account for most head injury deaths, while the more severely disabled survivors, including those in an unresponsive state or with reduced level of consciousness, are more likely to have primarily diffuse axonal injuries. Focal head injuries are broadly categorised into blunt (closed) traumas and penetrating (open) traumas (see Fig. 9.9). Blunt traumas are more common and involve either the head striking a hard surface (falls) or a rapidly moving object (e.g. baseball bat) striking the head. The dura mater of the meninges (brain covering within the
may be
Traumatic e.g. blow to the head, motor vehicle accident
results in
Haematomas — bleeds that are contained within the skull
results in
OR
Penetrating (open) trauma — dura mater is broken
Blunt (closed) trauma — dura mater remains intact causes
Non-traumatic e.g. alcohol consumption, stroke
causes Diffuse brain injuries – widespread axonal damage – concussion
CONCEPT MAP
Trauma to the central nervous system
causes causes Focal brain injuries – localised neuronal damage – haematomas
FIGURE 9.9
Types of brain injury.
skull) remains intact, so the brain is not exposed to the environment. Blunt trauma may result in both localised, focal, brain injuries and more widespread, diffuse, axonal injuries. Penetration of the dura results in exposure of the cranial contents to the environment, open trauma, and induces focal brain injuries. In recent years, there has been a focus on reducing the severity of head injury (with products such as motor vehicle
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air bags and head protection in contact sport) and improved medical management both at the scene of the injury and in healthcare facilities. As a result, more people are surviving head injuries. Those with severe traumatic brain injuries are being admitted to rehabilitation programs and more successfully managing the longer-term outcomes of cerebral damage. PATHOPHYSIOLOGY
Focal brain injury The force of impact from a focal brain injury typically produces contusions — injury to brain tissue without breaking the inner pia mater. Damage results from compression of the brain against the skull at the point of impact and from a rebound effect of the brain at the opposite side of the skull, classified as coup or contrecoup respectively (see Fig. 9.10). The damage that occurs at the moment of trauma (contusion and blood vessel tearing) is considered the primary brain injury. The inflammatory events, and the brain oedema that forms around the damaged neural tissues, contributing to increasing intracranial pressure, are considered secondary injury events.28 The effects of these injuries typically peak approximately 18–36 hours after severe head injury. Contusions are found most commonly in the frontal and temporal lobes of the cerebral cortex. They can result in changes in attention, memory, emotion and behaviour. Focal damage includes cerebral contusions (involving just the cerebral cortex) and intracranial haematomas. One of the important consequences of focal brain injury is the risk of development of an intracranial haematoma — a clotted mass of blood that is contained within tissues. Intracranial haemorrhage refers to the actual loss of blood from a cranial vessel; however, as blood from a haemorrhage
A
1 Dura (peeled off skull)
Skull fracture Arterial blood
cannot easily exit the cranium, so development of haematoma following an intracranial bleed is likely. A serious complication of development of an intracranial haematoma is that the accumulation of blood inside the cranial vault can increase the intracranial pressure and compress brain tissue (secondary brain injury; see above). This can lead to severe consequences such as brain herniation, whereby the brain is forced downwards towards the brainstem and spinal cord; this is usually fatal (review using Chapter 8). Haematomas may be epidural, subdural, intracranial or intraventricular (see Fig. 9.11). 1 b
a
2
b
a
c
FIGURE 9.10
Coup and contrecoup head injury after blunt trauma. 1 Coup injury: impact against object; a, site of impact and direct trauma to brain; b, shearing of subdural veins; c, trauma to base of brain. 2 Contrecoup injury: impact within skull; a, site of impact from brain hitting opposite side of skull; b, shearing forces through brain. These injuries occur in one continuous motion — the head strikes the wall (coup) and then rebounds (contrecoup).
2 Dura (still attached to skull) Venous blood
B 3
FIGURE 9.11
Types of haematomas. A 1 Epidural, 2 subdural and 3 intracerebral. B Acute subdural haematoma on the right side (arrows) from a 76-year-old man who fell 10 days prior to imaging (MRI). Chronic subdural haematoma (arrowheads) on the left side is also present.
CHAPTER 9 Alterations of neurological function across the life span
• Epidural haematomas (also known as extradural haematoma) develop from bleeds arising from arteries or veins in the potential space between the dura mater and the inner surface of the skull. Epidural haematomas are treated as an emergency, as 85% are arterial in origin, occurring from a tear in a branch of the middle meningeal artery.29 The bleed occurs just exterior to the outer layer of the meninges (the dura mater), inside the skull. As the volume of blood occupying space within the skull increases, it causes pressure on the brain tissue, causing it to herniate (move) into the ventricles or down towards the spinal cord. • Subdural haematomas refers to a collection of blood or blood products between the dura and arachnoid layers surrounding the brain. These may be acute or chronic, and vary significantly in presentation and treatment — the acute form usually presents in the trauma setting develop rapidly (within 48 hours) and affects all age groups, while the chronic form that develops more slowly (weeks to months) is common in the elderly and those who abuse alcohol and have brain atrophy (shrinkage); the resulting increased intracranial pressure eventually compresses the bleeding vessels and reduces frank blood loss.26 • Intracerebral haematomas refers to bleeding into the brain tissue resulting from contusions or blood vessel injury, and causes approximately 16% of traumatic brain injury cases. They are common in the cerebral hemisphere deep white matter in the frontal and temporal lobes. Penetrating forces associated with the speed of head movement (or the colliding object) traumatise small blood vessels. The damage caused by intracerebral haematomas is usually the cumulative effects of the actual haematoma, the increasing intracranial pressure (which can result in herniation) caused by oedema (fluid accumulation in the brain tissue) and the toxic effects of the blood in the brain tissue.30 Delayed traumatic intracerebral haematoma may also occur hours to days after the head trauma. • Intraventricular haematoma occurs secondary to traumatic subarachnoid haemorrhage or as an extension from an intracranial haemorrhage and could be suggestive of severe head injury. It is reported in approximately 10% of severe head injuries. Open trauma produces discrete (focal) injuries. A compound fracture (break in the skull and associated opening of the skin) exposes the brain to the environment and should be investigated whenever there are head lacerations (cuts or wounds). Debris from skull injury can cause damage by penetrating the brain, as well as by stretching nearby blood vessels and nerves. Diffuse brain injury Immediately following concussion (impact resulting in altered consciousness and neuronal function), the majority of cells in the brain send action potentials simultaneously, inducing massive electrical discharges and causing release
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of the neurotransmitter glutamate. This can cause excitotoxicity through alterations in ion flow through potassium, sodium and calcium ion channels.29 Calcium enters the cells and disrupts, amongst other things, mitochondrial function. As mitochondria are involved in cellular energy production, mitochondrial dysfunction can create a cellular energy crisis (severe lack of ATP). This prohibits the cells from restoring electrolyte balance (using the sodium-potassium-ATP pumps) across the cell membrane that is necessary to generate and propagate neuronal action potentials, and therefore neurons are functionally impaired (see Chapter 6). Diffuse brain injury to axons (known as diffuse axonal injury or DAI) results from high levels of acceleration and rotation forces (shearing forces that damage nerve fibres) at the time of the injury, as seen in road traffic crashes. Lesions typically manifest in the white matter tracts, such as the brainstem, corpus callosum and cerebral hemispheres; with the frontal and temporal lobes most commonly affected.30 The most severe DAIs cause extensive cognitive impairments, as seen in survivors of traumatic brain injury resulting from motor vehicle crashes. This damage reduces the speed of information processing and responding and disrupts attention; often, the patient requires lifelong assistance with activities of daily living.26 CLINICAL MANIFESTATIONS
Focal brain injury A contusion may be evidenced by some short-term consequences (immediate to a few minutes) including loss of consciousness, loss of reflexes (the individual falls to the ground, as the muscle reflexes involved in posture become impaired), absence of breathing, slowed heart rate (bradycardia) and/or decreased blood pressure. Increased CSF pressure occurs, as do changes in the electrical activity of the heart and brain (observed by ECG and EEG, respectively). Vital signs may normalise in a few seconds, reflexes return and the person regains consciousness over minutes to days. Residual deficits may persist, often due to damage to the brain nuclei involved in the reticular activating system (see Chapter 6) and some people never regain a full level of consciousness. • Epidural haematomas. Individuals lose consciousness on injury and then many become lucid (47% of cases) for a few minutes to a few days.29 As the haematoma accumulates, clinical deterioration manifests, which includes vomiting, drowsiness, confusion, seizures, a headache of increasing severity; hemiparesis (weakness on one side of the body) may develop. As temporal lobe herniation occurs, level of consciousness and Glasgow Coma Scale (GCS) scores rapidly reduce (refer to Chapter 8), with ipsilateral pupillary dilation (on the same side of the body as the haematoma) and contralateral hemiparesis (opposite side of the body), based on contralateral motor cortex disruption. Signs of increased ICP may include the Cushing reflex (hypertension, bradycardia and respiratory distress). The prognosis can be good if
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intervention is initiated before bilateral dilation of the pupils. Epidural haematomas are almost always treated as medical emergencies. • Subdural haematomas. In acute subdural haematoma, the expanding clots compress the brain and can actually close the broken vessel to help stop the bleeding. However, cerebral compression and displacement of brain tissue can also cause temporal lobe herniation. An acute subdural haematoma classically begins with headache, drowsiness, confusion, restlessness or agitation, slowed cognition and nausea and vomiting. These symptoms worsen over time and progress to loss of consciousness, respiratory pattern changes and pupillary dilation — the symptoms of temporal lobe herniation. Defective vision in either the right or the left visual field and disconjugate gaze — the eyes do not move or track equally — may also occur. Most people affected by chronic subdural haematomas may present with nonspecific symptoms such as chronic headaches, confusion, aphasia and tenderness over the haematoma on palpation. Most people also appear to have a progressive dementia with paratonia (involuntary resistance during passive movement).26 • Intracerebral haematomas. Intracerebral haematomas present clinically with two main elements; those caused by the location of the haematoma in the brain, and symptoms caused by increasing ICP. Symptoms caused by increasing ICP can include decreasing consciousness (decreasing GCS scores), headaches and vomiting. Coma or a confusional state from other injuries, however, can make the cause of this increasing unresponsiveness difficult to detect. The symptoms caused by the haematoma itself will be dependent on its size and anatomical location; however, common manifestations include contralateral hemiplegia, hemisensory impairment, aphasia, visual defects and gaze palsies.29
• Intraventricular haematoma. Signs and symptoms include altered level of consciousness, hemiparesis, ipsilateral pupil dilation and intracranial hypertension. Diffuse brain injury Diffuse brain injury, also known as diffuse axonal injury, results in the following: • physical consequences: spastic paralysis (where the muscles are in a constant state of spasm so that they cannot contribute to function), peripheral nerve injury, dysphagia (difficulty swallowing), dysarthria (difficulty articulating words), visual and hearing impairments, taste and smell deficits • cognitive deficits: disorientation and confusion, short attention span, memory deficits, learning difficulties, dysphasia, poor judgement, perceptual deficits • behavioural manifestations: including, but not limited to, agitation, impulsiveness, blunted affect, social withdrawal, depression. The most common result of diffuse axon injury is concussion resulting in altered consciousness and altered neuronal activity. This may be mild or classical cerebral concussion (see Table 9.5). Mild concussion is characterised by immediate but temporary clinical manifestations including CSF pressure rises and ECG and EEG changes, without loss of consciousness. The initial confusional state lasts for one to several minutes, possibly with amnesia (memory loss) for events prior to the trauma (retrograde amnesia). Short-term anterograde amnesia or forgetting of events after the trauma may also occur. Some people experience headache and complain of nervousness and ‘not being themselves’ for up to a few days.31 In classic cerebral concussion, consciousness is lost for up to 6 hours and reflexes fail. Breathing stops, the heart rate and blood pressure fall temporarily but vital signs
TABLE 9.5 Categories of diffuse brain injury TYPE OF INJURY
MECHANISM
Mild concussion
Temporary axonal disturbance affecting attentional and memory systems; consciousness not lost
Grade I
Confusion and disorientation with amnesia (momentary)
Grade II
Momentary confusion and retrograde amnesia after 5–10 minutes
Grade III
Confusion and retrograde amnesia from impact; also anterograde amnesia
Classic cerebral concussion (Grade IV)
Diffuse cerebral disconnection from brainstem reticular activating system; physiological/neurological dysfunction without substantial anatomical disruption; immediate loss of consciousness lasting less than 6 hours; retrograde and anterograde amnesia (posttraumatic)
Diffuse axonal injury
Prolonged traumatic coma (longer than 6 hours)
Mild
Posttraumatic coma lasts 6–24 hours; death uncommon; persistent residual cognitive, psychological and sensorimotor deficits; rare — only 8% of severe head injuries
Moderate
Widespread physiological impairment throughout the cerebral cortex and diencephalon; actual tearing of axons in both hemispheres; prolonged coma (longer than 24 hours); incomplete recovery among survivors; common — 20% of severe head injuries
Severe
Formerly called primary brainstem injury or brainstem contusion; severe mechanical disruption of axons in both hemispheres, diencephalon and brainstem; 16% of severe head injuries
CHAPTER 9 Alterations of neurological function across the life span
quickly normalise. Amnesia, before and after the incident occurs, along with confusion lasting for hours to days. Headaches, nausea, fatigue, attentional (inability to concentrate) and mood changes (anxiety, depression, irritability, fatigability, insomnia) can occur. A post-concussive syndrome, including headache, nervousness or anxiety, irritability, insomnia, depression, inability to concentrate, forgetfulness and fatigability, may exist. EVALUATION AND TREATMENT
Evaluation of traumatic brain injury includes collecting a comprehensive history and performing a thorough neurological examination. Brain imaging including x-rays, CT and MRI scans are used to distinguish between focal and diffuse injuries, as well as to locate any haematoma/s. The degree of brain injury can be clinically assessed using the Glasgow Coma Scale, using a series of responses to verbal and reflexive stimuli (refer to Chapter 8). The patient may score from 3 (if there are no detectable responses) through to 15 (if no gross abnormalities are detected). Large contusions and lacerations with haemorrhage may be surgically excised (removed). Otherwise, treatment is directed at controlling ICP and managing symptoms. Treatment of haematoma depends on its location. Epidural haematomas are often treated using surgical ligation (tying off), while chronic subdural haematomas require a craniotomy (opening the skull) to remove the clotted blood. Evacuation of a singular intracerebral haematoma occurs relatively infrequently. Otherwise, treatment is directed at reducing ICP and allowing the haematoma to reabsorb slowly (as described in the section on haemorrhagic stroke earlier in the chapter).
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Penetrating injuries often require debridement to remove the necrotic and traumatised tissues to prevent infection and to remove blood clots, further reducing ICP. ICP is managed with hyperosmolar therapy (hypertonic saline or mannitol), corticosteroids and diuretics (drugs that cause fluid excretion). Broad-spectrum antibiotics are typically administered to prevent infection. Early and late seizures must be prevented where possible or controlled — phenytoin (an antiepileptic drug) is effective in preventing early seizures (within 7 days), but prevention of later seizures is more difficult.2,4
Spinal cord trauma
The incidence of significant spinal cord trauma in Australia is quite low relative to other developed nations, with 362 new cases each year, the majority of which were due to trauma (285) and 77 due to other causes. 84% of these cases are males, with the highest incidence being in the 15–24 age group (30%), followed by those over 65. Over half of all cases are traffic-related, followed by falls, which account for one third of cases.32 PATHOPHYSIOLOGY
Spinal cord injuries most commonly occur from trauma to the vertebral column (spine), which contains the spinal cord (refer to Chapter 20). Vertebral injuries in adults occur most often at the cervical vertebral region and the thoracolumbar junction (between the last few thoracic and first few lumbar vertebrae), which are the most mobile portions of the vertebral column. Injuries to the cord are summarised in Table 9.6. Quadriplegia (or tetraplegia) involves the paralysis of all limbs through an injury to the
TABLE 9.6 Spinal cord injuries INJURY
DESCRIPTION
Cord concussion
Results in a temporary disruption of cord-mediated functions
Cord contusion
Bruising of the neural tissue causing swelling and temporary loss of cord-mediated functions
Cord compression
Pressure on the cord causing ischaemia to tissues; must be relieved (decompressed) to prevent permanent damage to the spinal cord
Laceration
Tearing of the neural tissues of the spinal cord; may be reversible if only slight damage is sustained by the neural tissues; may result in permanent loss of cord-mediated functions if the spinal tracts are disrupted
Transection
Severing of the spinal cord, causing permanent loss of function
Complete
All tracts in the spinal cord are completely disrupted; all cord-mediated functions below the transection are completely and permanently lost
Incomplete
Some tracts in the spinal cord remain intact, together with functions mediated by these tracts; has the potential for recovery, although function is temporarily lost
Preserved sensation only
Some demonstrable sensation below the level of injury
Preserved motor nonfunctional
Preserved motor function without useful purpose; sensory function may or may not be preserved
Preserved motor functional
Preserved voluntary motor function that is functionally useful
Haemorrhage
Bleeding into the neural tissue as a result of blood vessel damage; usually no major loss of function
Damage or obstruction of spinal blood supply
Causes local ischaemia
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cervical region of the spine, while paraplegia involves paralysis of the torso and lower limbs, which occurs if the injury is lower than T1. With injury, microscopic haemorrhages appear in the central grey matter and the pia mater; these increase tissue volume causing compression and necrosis (cell death). Oedema in the white matter occurs, impairing the microcirculation within the cord. The haemorrhaging and oedema obstruct local blood flow and may lead to tissue ischaemia. Transient cord swelling causes functional impairment, which makes it difficult to distinguish temporary dysfunction from permanent. In the higher cervical region (C1–C3), cord swelling may be life threatening if it impairs phrenic nerve function, and thus diaphragm innervation, or vital homeostatic functions mediated by the medulla oblongata. CLINICAL MANIFESTATIONS
Normal activity of cells within the spinal cord, at and below the level of injury ceases after cord injury; causing AA
spinal shock. Reflex function is completely lost in all segments below the lesion, including all skeletal muscles; bladder, bowel and sexual function; and autonomic control. Severe impairment below the level of the lesion is obvious and it includes impairment or paralysis of skeletal muscles and decreased sensation of skin. The condition also results in disturbed thermal control by the hypothalamus, because the sympathetic nervous system is damaged and cannot direct blood vessels to constrict to conserve body heat; therefore, the patient develops poikilothermia (unable to regulate body temperature which fluctuates according to that of the surroundings). Spinal shock generally improves after a few days to months and reflex activity, such as emptying the bladder and bowel, will return. Autonomic hyperreflexia may occur after spinal shock resolves. It is caused by an excessive sympathetic nervous system response to noxious stimuli below the level of lesion (distended bowel or full bladder) (see Fig. 9.12 and Chapter 6). The condition is life threatening 3 Brain interprets sensory inputs; course of action determined Empty bladder Remove painful stimulus
4 Corticospinal tracts carry motor impulses to appropriate muscles
2 Spinothalamic tracts carry the impulses to the brain
Spinal ganglion Grey ramus White ramus
Splanchnic nerve Vagus nerve
Spinal ganglion
STIMULUS 5 Motor output Empty bladder Remove painful stimulus Eliminates stimulus to sensory nerve
FIGURE 9.12
Autonomic hyperreflexia. A Normal response pathway.
1 Visceral distension Bowel Bladder Abdomen Pain receptors Skin Glans penis Uterus Continues
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5 Ninth cranial nerve stimulated by carotid; receptors send message to vasomotor centre of medulla, vagus nerve stimulated; impulse sent to SA node; results in bradycardia
B B
Carotid sinuses Glossopharyngeal nerve (IX)
4 Increased blood pressure stimulates carotid sinus receptors
Carotid sinus nerve Vagus nerve (X)
Medulla 6 Autonomic response to hypertension down to level of cord lesion Arterial dilation Flushed skin Headache Sweating
SA node
3 Reflex stimulus to major sympathetic outflow resulting in: Vasospasm Hypertension Pallor of skin Pilomotor spasms 2 Spinothalamic tracts carry sensory impulses to level of lesion (T6 and above)
Lesion
STIMULUS
1 Visceral distension Bowel Bladder Abdomen Pain receptors Skin Glans penis Uterus
FIGURE 9.12
Autonomic hyperreflexia continued. B Autonomic hyperreflexia pathway. SA = sinoatrial.
and requires immediate treatment. Individuals most likely to be affected have lesions at the T6 level or above. Clinical manifestations include hypertension (up to 300 mmHg systolic), pounding headache, blurred vision, sweating above the level of the lesion with flushing of the skin, nasal congestion, nausea, piloerection caused by pilomotor spasm and very slow heart rate (bradycardia, 30–40 beats/minute).
In autonomic hyperreflexia, also known as autonomic dysreflexia, sensory receptors below the level of the cord lesion are stimulated. The intact autonomic nervous system reflexively responds with an arteriolar spasm that increases blood pressure. Baroreceptors in the cerebral vessels, the carotid sinus and the aorta sense the hypertension and stimulate the parasympathetic system. The heart rate decreases, but the visceral and peripheral vessels do not
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dilate because efferent impulses cannot pass through the cord. The most common cause of autonomic hyperreflexia is a distended bladder (such as due to blocked catheter) or impacted rectum (constipation), but any sensory stimulation can elicit autonomic hyperreflexia. Stimulation of the skin or pain receptors may cause autonomic hyperreflexia. Bladder or bowel emptying usually relieves the syndrome and drugs such as phenoxybenzamine (to block α-adrenergic receptors) may facilitate relief. EVALUATION AND TREATMENT
Diagnosis of spinal cord injury is based on physical examination, CT scan, MRI, myelography (x-ray of the spinal cord using dye) and electromyography (monitors changes in cord innervation to muscles). The first step in the treatment of spinal cord injury is to assess whether the injury is stable or not.33 For a suspected and confirmed unstable vertebral injury, immediate immobilisation of the spine is essential to limit further cord trauma. Decompression and surgical fixation may also be necessary to maintain cord integrity. If the injury is stable, rehabilitation can be commenced. Corticosteroids can be used to decrease additional cord injury that may result from local inflammation. Nutrition, lung function, skin integrity and bladder and bowel management must be addressed. In cases of autonomic hyperreflexia, intervention must be prompt because cerebrovascular accident is possible. Antihypertensive medications may be used if blood pressure remains elevated. Support and counselling for patients is essential.33
F OC US O N L E ARN IN G
1 Explain how a concussion is different from a contusion. 2 Discuss why epidural, subdural and intracerebral haematomas present with different clinical scenarios. 3 Describe why head motion is the principal causative mechanism of diffuse brain injury. 4 Compare spinal shock and autonomic hyperreflexia.
Degenerative disorders of the central nervous system Until this point, we have explored conditions that cause acute damage to the central nervous system (CNS). Patients with these conditions may experience significant neurological impairment, but many have the capacity to recover some, if not all, neurological function. However, there are many neurological disorders that can significantly incapacitate individuals, although this may occur over several years or even decades. The most prevalent of
these in Australia and New Zealand, especially in the older population, are the neurodegenerative disorders — those that cause a progressive, irreversible decline in neurological function. The most common neurodegenerative disorder is Alzheimer’s disease, followed by Parkinson’s disease.34
Alzheimer’s disease
Alzheimer’s disease is one of the most common causes of severe cognitive dysfunction in older people. In Australia, Alzheimer’s disease accounts for approximately 50–75% of all cases of dementia.34 To put this in perspective, dementia is the most prevalent condition for people aged 65 years and older: almost 1 in 10 (9%) people aged over 65 are diagnosed with dementia, and this rises to 3 in 10 (30%) for those aged over 85.34 Furthermore, the number of people with dementia is projected to triple, with estimations that by 2050, 900 000 Australians will have dementia.36 Similar rates are reported in New Zealand. In 2016, 62 287 New Zealanders were estimated to have Alzheimer’srelated dementia — 1.3% of the New Zealand (NZ) population.35 PATHOPHYSIOLOGY
The exact cause of Alzheimer’s disease is unknown, but it is characterised by a decreased brain size — 100–200 g less than average and there is evidence that the cerebral cortex (grey matter) shrinks in Alzheimer’s disease (see Fig. 9.13). In addition to loss of grey matter (neurons), there is also a loss of neuronal synapses (or connections between neurons). Synapses are the key to the formation and retention of memories, so loss of synapses causes loss of the memories that were stored in affected regions.36 There are differences in neurotransmitter levels in the brains of people with Alzheimer’s disease, typically including increased levels of glutamate (excitatory neurotransmitter) and decreased levels of acetylcholine.37 At the cellular level, there are two key changes that develop in the neurons that can be observed microscopically (see Fig. 9.13): 1 neurofibrillary tangles: intracellular clumping of proteins in the microtubules (cytoskeletal filaments) surrounding the nucleus, leading to neuron cell death 2 senile plaques: extracellular accumulations (beta-amyloid) that occur when groups of nerve cells degenerate, that are not broken down but allowed to accumulate and harden; this disrupts nerve-impulse transmission. Senile plaques and neurofibrillary tangles are more concentrated in the cerebral cortex — the area of most apparent brain shrinkage — and in the hippocampus and amygdala. The decline in memory, cognitive processes and personality change is directly related to the number of these microscopic abnormalities seen in postmortem examination, with plaque development being strongly associated with early symptoms.37 (See also Research in Focus: Alzheimer’s disease and type 2 diabetes?)
CHAPTER 9 Alterations of neurological function across the life span
Neuritic plaques
A
213
B
Neurofibrillary tangles
Neuron
C
FIGURE 9.13
Pathological changes in Alzheimer’s disease. A Schematic representation of neuritic plaque and neurofibrillary tangle. B The gross brain of an Alzheimer’s patient: note the reduced size, narrow gyri and wide sulci, mainly in the frontal and temporal lobes. C An age- and sex-matched brain of an individual without Alzheimer’s disease.
RESEARCH IN F
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Alzheimer’s disease and type 2 diabetes? The aetiology of Alzheimer’s disease, the most common cause of dementia, remains unknown; however more and more evidence is pointing towards a relationship with poor blood glucose control such as that found in people with type 2 diabetes. Research has shown strong links between the development and severity of Alzheimer’s disease and poor glycaemic control. Moreover, pathophysiological evidence links persons with type 2 diabetes with greater amounts of a defective protein (tau) in their CSF, which is commonly found in patients with Alzheimer’s disease, and other types of dementia. Clinical evidence has shown improvement in cognitive function and memory in Alzheimer’s disease models given glycaemic control medications.
Abstraction, problem solving, nominal dysphasia (word finding) and judgement gradually deteriorate. Behavioural changes can include irritability, agitation and restlessness. Mood changes can result and the person may become anxious, depressed, hostile and/or increasingly prone to mood swings. Interestingly, the mood changes may also seem more positive, so someone who previously was difficult to get along with may become more compliant. Motor changes may occur if the posterior frontal lobes are involved, causing paratonia (rigidity) with flexion posturing. There is great variability in the age of onset, intensity and sequence of symptoms, and also in the location and extent of brain abnormalities. For example, those who develop Alzheimer’s at a younger age often deteriorate more quickly than those who develop the condition at a much older age. EVALUATION AND TREATMENT
CLINICAL MANIFESTATIONS
The onset of clinical manifestations is insidious and often attributed to increasing age, forgetfulness, emotional upset or other illness. These vague manifestations mean that Alzheimer’s disease cannot be conclusively diagnosed in the early stages. The individual becomes progressively more forgetful over time, particularly in relation to recent events. Memory loss increases as the disorder advances, and the person becomes increasingly disoriented, confused and loses the ability to concentrate.
The diagnosis of Alzheimer’s disease is primarily made by ruling out other possible causes of neurological change. The diagnosis of Alzheimer’s disease is made clinically, exploring the history and course of the illness, which may span 5 years or more. The patient undergoes a mental status examination, which includes a number of questions such as the date, calculations and contextual recall. Brain imaging using CT, MRI or PET is used to assist in excluding other causes (see Fig. 9.14). The disease takes decades to manifest clinically and so it is usually at a relatively advanced stage when diagnosed.37 Olfactory testing is an increasingly common component of the diagnostic tests for Alzheimer’s
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A
B Normal
Advanced Alzheimer’s disease
young as 15, with the average age at diagnosis between 55 and 65.41 It is slightly more common in males. This disease is one of the most prevalent of the primary CNS disorders and is a leading cause of neurological disability in individuals older than 60 years. There were an estimated 64 044 individuals diagnosed with Parkinson’s disease in Australia in 2011 and this number is projected to grow to 115 300 by 2031 (80% increase).42 This equates to 283 per 100 000 in the total Australian population, or 857 per 100 000 among the population aged over 50.34,42 PATHOPHYSIOLOGY
FIGURE 9.14
Positron emission tomography (PET) used in the diagnosis of Alzheimer’s disease. Radioactive fluorine is applied to glucose, which is taken up by metabolically active cells (yellow areas). A Normal brain. B Advanced Alzheimer’s disease is recognised by hypometabolism in many areas of the brain.
disease, as olfactory function is lost early in the development of many neurodegenerative diseases.38 Genetic testing for substances with key roles in the senile plaques is possible (test for amyloid precursor protein and apolipoprotein E), but has poor diagnostic power.39 These genetic factors cannot be used as a predictor of who will get the disease, as not all people with the genetic abnormalities have Alzheimer’s disease. Treatment should be individualised and directed at using devices to compensate for the impaired cognitive function, such as memory aids; maintaining the remaining unimpaired cognitive function; and maintaining or improving the general state of hygiene, nutrition and health. There are a few drugs available that increase the concentration of acetylcholine (mainly by limiting its breakdown) and these have had a modest effect on cognitive function in the early stage of Alzheimer’s disease (donepezil, galantamine, rivastigmine). Memantine is a drug that interacts with the other main neurotransmitter activity — it blocks glutamate activity and is used to slow progression of disease in moderate to severe Alzheimer’s disease.37,40 No therapy is currently available that is able to correct damage to the neurons.
Parkinson’s disease
Parkinson’s disease is a commonly occurring degenerative disorder of the basal nuclei (previously known as basal ganglia) involving the selective loss of the neurons that secrete dopamine. Parkinson’s disease typically begins after the age of 40, although some familial forms are diagnosed in patients as
The cause of Parkinson’s disease is unknown. Loss of neurons in the substantia nigra is a key feature. These neurons release dopamine into the basal nuclei, hence Parkinson’s is characterised by loss of neurons with depletion of dopamine, an inhibitory neurotransmitter in this brain region (see Fig. 9.15A). Dopamine depletion in the basal nuclei results in a relative excess of cholinergic activity in the feedback circuit. This is manifested by the classic Parkinson’s disease triad: bradykinesia (slow and delayed movements, rigidity), resting tremor and postural tremor. CLINICAL MANIFESTATIONS
The classic manifestations of Parkinson’s disease are tremor at rest, rigidity (muscle stiffness) and bradykinesia (slow movements) or akinesia (loss of spontaneous movement). Others symptoms can include postural instability, difficulty speaking (dysarthria) and difficulty swallowing (dysphagia). As the disease progresses, all symptoms are usually present. Because the onset is insidious, the development of symptoms is difficult to document. Early in the disease, reflex status, sensory status and mental status usually are normal. Postural abnormalities (flexed, forward leaning; see Fig. 9.16), difficulty walking and weakness develop. Depression is also common. Other difficulties due to autonomic nervous system imbalance include inappropriate diaphoresis (sweating), orthostatic hypotension, gastric retention, constipation and urinary retention. Disorders of equilibrium result from postural abnormalities; where sufferers cannot make the appropriate postural adjustment to tilting and falls are subsequently common. The consequential festinating gait (short, accelerating steps) of the individual with Parkinson’s disease is an attempt to maintain an upright position while walking. Individuals are also unable to right themselves when changing from a reclining or crouching position to a standing position and when rolling over from a supine to a lateral or prone position. Excessive daytime sleepiness is experienced in more than 50% of cases.41 Postural instability, sleep disturbance and difficulty in concentrating are some of the most depressing symptoms for persons with the disease.42 Progressive dementia may be associated with the disease and is more common in those older than 70 years. The person’s mental status may be further compromised by the side effects of the medication taken to control symptoms.
CHAPTER 9 Alterations of neurological function across the life span
215
Substantia nigra
A Basal nuclei Dopamine Acetylcholine
Akinesia, rigidity
Skeletal muscle
Substantia nigra
B
GABA
Globus pallidus
Dopamine Acetylcholine
Basal nuclei
Skeletal muscle
Hyperkinesia FIGURE 9.15
Neurotransmitter imbalances in Parkinson’s disease and Huntington’s disease. A In Parkinson’s disease, loss of neurons from the substantia nigra results in less dopamine transmission; as a result, the amount of acetylcholine is increased and the muscle movement becomes increased, resulting in rigidity. B In Huntington’s disease, loss of neurons from the globus pallidus results in loss of the inhibitory neurotransmitter GABA; as a result, the amount of dopamine is effectively increased, resulting in excessive movements.
EVALUATION AND TREATMENT
The diagnosis of Parkinson’s disease is based on the history and physical examination; MRI may highlight neurodegenerative brain changes,43 and single photon emission computed tomography (SPECT) imaging has demonstrated promise in supporting the diagnosis of Parkinson’s disease, but is not commonly used at this time. Olfactory testing is an increasingly common component
FIGURE 9.16
The stooped posture of Parkinson’s disease. A patient with Parkinson’s may exhibit characteristic postural changes, such as this stooped forward position.
of the tests for Parkinson’s disease, as olfactory function is lost early in the development of many neurodegenerative diseases.44 Treatment of Parkinson’s disease is symptomatic, involving drug therapy to increase dopamine levels such as levodopa (which the body uses to produce dopamine inside the brain) together with a drug that limits peripheral interconversion of levodopa into dopamine, such as carbidopa. Because of troublesome side effects and a progressive loss of effectiveness over 5 to 10 years use, drug therapy may not be started until the symptoms become debilitating.41 However, advanced Parkinson’s disease is often unresponsive to these dopamine-related agents. Surgical interventions include neurostimulation, thalamotomy and pallidotomy to surgically inactivate the globus pallidus (see Research in Focus: Surgery or stem cell therapy for Parkinson’s disease).41,42 Parkinson’s disease is the subject of many clinical trials examining the use of stem cell therapy. Parkinson’s disease progresses slowly for 15–20 years before producing severe immobility and dependence. Maintaining quality of life and managing symptoms of Parkinson disease with a chronic disease management approach including speech therapy, physiotherapy and occupational therapy in collaboration with education, counselling and social support from friends and family is essential. 42
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RESEARCH IN F
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Surgery or stem cell therapy for Parkinson’s disease Deep brain stimulation (DBS) from implanted electrodes to reduce parkinsonian motor symptoms has been shown to be an effective treatment procedure, providing relief for individuals with advanced disease. It is recommended that DBS be used on patients with debilitating motor symptoms without cognitive changes, therefore, in Australia DBS is only available for patients whose symptoms can no longer be managed medically. The Australian Government has provided funding since 2006: 91 DBS procedures were administered to patients in 2006–07 and 224 in 2009–10. However, increasingly, researchers are looking towards stem cell therapies to restore dopamine production in patients with degenerative diseases such as Parkinson’s disease. Gene therapy to promote dopaminergic neurons and implantation of genetically engineered stem cells is also being explored and currently a number of clinical trials are underway and showing promise. Progress towards the use of both embryonic and adult neural stem cells for neuroprotective and regenerative interventions holds much promise for the future. Of particular interest is the move to use autologous cell transplants, transplants of cells taken from a patient, grown, differentiated and returned to the same patient, removing the issues of immune rejection and embryonic cell therapies.
abnormality.46 Regardless of reproductive decisions, an individual who is asymptomatic but has family members affected may opt for genetic testing to ascertain their own status of carrying the altered gene. PATHOPHYSIOLOGY
Huntington’s disease is inherited as an autosomal dominant trait, which means that offspring only need to inherit one copy of this abnormal gene in order to exhibit symptoms of the disease (see Chapter 5). The principal pathological feature of Huntington’s disease is severe degeneration within the basal nuclei of the neurons that send inhibitory signals (using the neurotransmitter gamma-aminobutyric acid, GABA) in control of motor function; therefore, degeneration in this area allows excessive motor output and more abnormal movements. Neuronal loss removes the inhibitory pathway, thereby causing decreased inhibitory GABA activity on dopaminergic neurons in the substantia nigra. As a consequence, there is a relative excess of dopaminergic activity in the basal nuclei feedback circuit with the cerebral cortex. In some ways, Huntington’s disease is the opposite of Parkinson’s in terms of neurotransmitters — whereas Parkinson’s is characterised by a deficiency of dopamine, Huntington’s has excess dopamine (see Fig. 9.15B). However, there are multiple pathological changes in cortical and subcortical structures too.47 CLINICAL MANIFESTATIONS
F OC US O N L E ARN IN G
1 Describe the clinical manifestations of Alzheimer’s disease. Indicate why diagnosis of this condition may be difficult. 2 Discuss the neurotransmitter alterations in Parkinson’s disease. Outline the types of treatments that are used. 3 List the clinical manifestations of Parkinson’s disease.
Huntington’s disease
Huntington’s disease, also known as Huntington’s chorea (from the Greek word for ‘dancing’, because the movements can appear dance-like) is a relatively rare, dominant hereditary disorder. In Australia, Huntington’s disease affects approximately 6–7 people per 100 000.45 The disease affects several brain areas, mainly the basal nuclei. There is a gradual onset from the age of 30–50 years with uncontrollable movements (chorea), which progresses to a general lack of coordination. Other symptoms include difficulty in decision making, irritability and mood fluctuations. As the disease continues, further debilitating symptoms arise, such as a decrease in intellectual capacity, until death, usually 20 years after onset of the disease. Offspring of an individual with Huntington’s disease have a 50% chance of inheriting the disease. Those at high risk of the disease may choose to undergo prenatal genetic testing to ascertain the likely genetic inheritance of their offspring; although the overall usage of this testing is low, some people use alternative reproductive options to avoid passing on the genetic
The classic manifestations of Huntington’s disease are abnormal movement and progressive dysfunction of intellectual and thought processes (dementia). Any one of these features may mark the onset of the disease. Chorea, the most common type of abnormal movement affecting these individuals, begins in the fingers, toes and face, eventually affecting the entire body. A range of neurological deficits develop including loss of working memory and reduced capacity to plan, organise and sequence. Thinking is slow and patients may experience apathy, irritability and/ or depression.47 EVALUATION AND TREATMENT
The diagnosis of Huntington’s disease is based on a thorough physical examination and positive family history of the disorder. No known treatment is effective in halting the degeneration or progression of symptoms. However, patients will benefit from a combination of pharmacological and non-pharmacological therapies. Depression or psychosis is treated with drug therapy. The patient requires adequate support and palliative care; the dependency on multidisciplinary and family care increases as the disease progresses, leading to a long-term requirement for palliative care.48 One important drug treatment is tetrabenazine, which depletes the stores of dopamine in the brain. However, the dosage must be slowly titrated (altered) to produce the desired effect on movements; too high a dose can result in a Parkinson’s-like syndrome. Another adverse effect of this therapy is depression,49 so caution must be taken to avoid exacerbating the patient’s psychological status.
CHAPTER 9 Alterations of neurological function across the life span
Multiple sclerosis
Multiple sclerosis (MS) is a relatively common disorder involving inflammation and destruction of previously normal myelin of axons within the CNS (brain, spinal cord and optic nerves). The age of onset of multiple sclerosis is usually between 20 and 50 years. It affects three times more females than males50 and is a leading cause of neurological disability in early adulthood. Although the disorder does not exhibit a defined inheritance pattern, 15% of those with MS have an affected relative. The prevalence in Australia is approximately 2.4 per 100 000 people.50,51 PATHOPHYSIOLOGY
Multiple sclerosis involves an autoimmune process, which may be initiated by an environmental factor (virus, toxin, UV light) in genetically susceptible individuals. This results in some inflammatory processes that lead to the destruction of oligodendrites, the myelin-forming cells.52 Pathological features of this process are: (1) interaction between the immune system and the CNS; and (2) demyelination of the white matter. The acute (early) stage of plaque formation is characterised by demyelination with inflammatory oedema. Symptoms usually remit, partially or completely, weeks after the onset of an early episode. The chronic stage of demyelination and plaque formation is characterised by gliosis (glial scarring with late degeneration of axons). Progressive loss of function leads to permanent disability, usually after 20 years or more. Vitamin D deprivation during gestation also seems to increase the risk of developing MS, with distinctive seasonal and latitude-based incidence distributions.50 CLINICAL MANIFESTATIONS
Various events occur immediately before the onset or exacerbation of symptoms and are regarded as precipitating factors. Infection, trauma and pregnancy are the least debated. Most of the pregnancy-related exacerbations occur 3 months postpartum, suggesting a relation to the stresses of labour and the increased fatigue during the postpartum period rather than to the pregnancy itself. The major manifestations of MS start in the initial syndromes (see Table 9.7), followed by remissions (apparent absence of disease) and established syndromes with no remissions. While symptoms initially result from the demyelination, symptoms may improve if some re-myelination occurs. However, eventually the axon is permanently damaged, leading to loss of myelin and permanent symptoms. Short-lived attacks of neurological deficits are the temporary appearance or worsening of symptoms. The mechanism of these attacks is complete, reversible conduction block in partially demyelinated axons. Conditions that cause short-lived attacks include: (1) minor increases in body temperature or serum calcium concentration; and (2) functional demands exceeding the conduction capacity of the neurons. An increase in body temperature or serum calcium level increases current leakage through demyelinated neurons, so action potentials become transmitted less effectively.
217
TABLE 9.7 Symptoms of multiple sclerosis 1 Loss of coordination/clumsiness 2 Speech difficulties 3 Hand shaking/tremor 4 Loss of bladder/bowel control 5 Extreme fatigue 6 Sight impairments 7 Memory lapses 8 Vertigo 9 Weakness 10 Impaired sensation
Paroxysmal attacks (sudden recurrence) include development of sensory or motor symptoms with abrupt onset and of short duration (a few seconds to minutes) and include dysarthria (difficulty speaking) and ataxia (lack of coordination) and tonic head turning. The mechanism invoking these symptoms is a functional ‘short-circuiting’ of motor neurons — with nerve impulses being directly transmitted between adjacent demyelinated axons, akin to the short-circuiting of a circuit made up of non-insulated wires. A classical paroxysmal symptom, called Lhermitte’s sign, is the momentary paraesthesia (shock-like or tingling sensation) that shoots down the trunk or limbs during flexion of the neck. Paroxysmal attacks tend to persist for weeks or months and may be followed by progressive symptoms of multiple sclerosis. EVALUATION AND TREATMENT
The diagnosis of MS is based on a thorough neurological history and physical examination, supported by findings from CSF examination, visual evoked potentials (testing the conduction efficiency of the optic nerves) and MRI.50 Persistently elevated CSF immunoglobulin G (IgG; discussed in Chapter 12) is found in most people with MS due to the inflammatory response. MRI is the most sensitive method available of detecting the disease. Signs of two separate attacks or flares with demyelination in the CNS support the diagnosis. Multiple sclerosis is treated for three purposes: (1) acute managing of relapses to prevent disability; (2) reducing the frequency of relapses and disease progression; and (3) managing symptoms to improve quality of life.52 Drugs with anti-inflammatory properties (corticosteroids) are used to treat acute episodes. Other drugs may be useful in slowing progression of the disease by modulating the immune system through suppressing the T lymphocyte responses (which may be involved in myelin destruction) — these include interferons and glatiramer. Symptom management is also part of treatment plans. Special problems requiring preventive and symptomatic management are: fatigue;
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weakness; spasticity; bladder, bowel and sexual dysfunction; pain; tremor and ataxia; depression; vertigo; sensory sensations; and heat intolerance. Supportive and rehabilitative management is directed towards relieving specific symptoms and preventing the complications of immobility — especially pressure sores and infections of the pulmonary and genitourinary systems.
A
Motor neuron disease
Motor neuron disease (also known as amyotrophic lateral sclerosis or Lou Gehrig’s disease) is a degenerative disorder involving lower and upper motor neurons and resulting in progressive muscle weakness. The term amyotrophic (progressive muscle wasting) refers to the predominant lower motor neuron component of the syndrome. Lateral sclerosis, scarring of the corticospinal tract (refer to Fig. 6.19A) in the lateral column of the spinal cord, refers to the upper motor neuron component of the syndrome. It usually begins in the early 50s, with males affected slightly more than females. Stephen Hawking (the British physicist) was one of the most famous people living with motor neuron disease, although the disease was named after Lou Gehrig; a famous American baseball player who died from the disease. The disease affects approximately 1200 people in Australia, with 400 new cases being diagnosed each year.53
B
PATHOPHYSIOLOGY
The cause of motor neuron death is unknown. Current data suggest that a genetic factor is involved: 20% of people with familial motor neuron disease have a genetic mutation in the glial cells surrounding the motor neuron.54 The principal pathological feature of motor neuron disease is the degeneration of motor neurons in the cortex (frontotemporal), brainstem (pons, medulla) and spinal cord. Death of the motor neuron results in axonal degeneration and secondary demyelination with glial proliferation and sclerosis (scarring). Lower motor neurons, adjacent to degenerating neurons, attempt to compensate for neuronal loss by distal intramuscular sprouting, re-innervation and enlargement of motor units. CLINICAL MANIFESTATIONS
Weakness and wasting may begin in any or all muscles of the body (see Fig. 9.17). Dyspraxia (problems with movement and coordination) precede paralysis associated with the progressive muscle atrophy. No associated mental, sensory or autonomic symptoms are evident. Sensory functions are sustained until death. EVALUATION AND TREATMENT
Diagnosis of the syndrome is based predominantly on the history and physical examination. Electromyography and muscle biopsy verify lower motor neuron degeneration and denervation. There is no cure for motor neuron disease so treatment focusses on symptom management. The drug riluzole can delay the disease progression and will
FIGURE 9.17
Motor neuron disease. A This patient has progressive muscular atrophy and presented with wasting of the muscles between the thumb and index finger on the dorsal (arrow) and palmar surfaces. B Another patient with motor neuron disease showing tongue atrophy.
prolong survival by a number of months.55 Supportive management and rehabilitative management are directed towards preventing complications of immobility. The average duration of life is approximately 2–3 years from the appearance of symptoms, but the course of the disease may run from a few months to more than 20 years.53
FOCU S ON L EA RN IN G
1 Describe the underlying pathophysiology in Huntington’s disease. 2 Discuss the uses of genetic testing in Huntington’s disease. 3 List common symptoms of multiple sclerosis. Explain how the immune system affects this disorder. 4 Briefly discuss motor neuron disease.
CHAPTER 9 Alterations of neurological function across the life span
Peripheral nervous system and neuromuscular junction disorders Some disease processes may injure neuronal axons travelling to and from their respective cell bodies in the CNS. Other diseases may injure a distinct anatomical area of whole spinal nerves or at the larger plexus level (group of spinal nerves). The cranial nerves do not have plexuses like spinal nerves and thus are generally affected individually. Autonomic nerve fibres may be injured as they travel in certain cranial nerves or as they emerge through a root or plexuses to travel into the periphery of the body.
Guillain-Barré syndrome
Guillain-Barré syndrome is an acute, inflammatory autoimmune disease whereby the myelin sheath (Schwann cells) surrounding peripheral nerves is destroyed by the person’s immune system. Although the myelin destruction is the main concern, the damage may even include the actual axons as well. An autoimmune disease is caused by the immune system actually targeting and destroying a normal component of the healthy body, in the same way that it might destroy something foreign, such as bacteria that infect the body (see Chapter 14).56 The reasons why autoimmune diseases occur are complex and more research is needed to understand these causes of disease. The incidence of Guillain-Barré syndrome in Australia is approximately 1–2 per 100 000 people.57 PATHOPHYSIOLOGY
Guillain-Barré is often associated with bacterial (C. jejuni 3–39%) and viral (cytomegalovirus 5–22%) infection, where the antibodies which are produced during that infection begin to destroy the myelin sheath around neurons. Interestingly, a vaccine for swine influenza that was used in the 1970s was related to the development/recognition of Guillain-Barré syndrome and the recent epidemic of swine flu in 2009 caused this issue to resurface. Importantly, the vaccine that was used for the 2009 outbreak was different from that used in the 1970s and there was no expected risk of Guillain-Barré with the more developed swine flu vaccinations.58 CLINICAL MANIFESTATIONS
The lack of myelination around the nerves means that fewer action potentials reach the skeletal muscles; without receiving the signal from the neurons, the muscles are unable to contract, which leads to muscle weakness and paralysis. Weakness and paralysis of the respiratory muscles can become life threatening. Other symptoms include paraesthesias (abnormal sensation) in the hands and feet, pain and bladder or bowel dysfunction, due to demyelination of the sensory receptors. Guillain-Barré is described as an ‘ascending paralysis’, because the loss of muscle function and sensory deficit usually begins
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in the feet and then progresses up the body to affect more areas.56 TREATMENT
Treatment using plasmapheresis is effective for autoimmune disorders. This procedure takes a quantity of the patient’s blood and the plasma goes through a process whereby substances such as antibodies are removed from the plasma; the ‘washed’ plasma, which no longer contains the autoimmune antibodies, is returned to the patient. Most people recover within weeks or years,57 but most of this time will be spent hospitalised. Steroid therapy is also effective to reduce antibody production.56
Myasthenia gravis
Myasthenia gravis is a chronic autoimmune disease that affects the neuromuscular junction and is characterised by rapid and severe fatigue and muscle weakness. Myasthenia gravis affects approximately 3 in every 100 000 people in Australia, with about twice as many women affected as men.59 Generalised autoimmune myasthenia involves the proximal musculature throughout the body and has several courses: (1) a course with periodic remissions; (2) a slowly progressive course; (3) a rapidly progressive course; and (4) a fulminating course. In neonatal myasthenia, some signs of myasthenia gravis are present in 10–15% of infants born to mothers with myasthenia gravis, as the antibodies from the mother’s immune system can cross the placenta. Usually, the newborn recovers in the first weeks after birth. PATHOPHYSIOLOGY
Myasthenia gravis results from a defect in nerve impulse transmission at the neuromuscular junction. The postsynaptic acetylcholine receptors on the muscle’s cell membrane are no longer recognised as normal components of the person’s own body; because they are recognised as foreign, the immune response causes production of antibodies, which results in destruction of the receptors for acetylcholine receptors. This causes diminished transmission of the nerve impulse across the neuromuscular junction and lack of muscle depolarisation (see Fig. 9.18), which manifests as skeletal muscle weakness.60 CLINICAL MANIFESTATIONS
Myasthenia gravis typically has an insidious onset. The foremost complaints are muscle fatigue and progressive weakness. The first muscles to be affected are usually the eyes, including diplopia (double vision, due to eye muscles not working equally) and ocular palsies (paralysis), as well as the face, mouth (chewing), throat (dysphagia — difficulty swallowing and dysarthria — slow or slurred speech) and face (see Fig. 9.19). The person often complains of fatigue after exercise and has a recent history of recurring upper respiratory tract infections. The muscles of facial expression are also affected resulting with facial droop and an expressionless face; difficulty chewing and swallowing associated with dietary changes
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Intestinal motility increases, with episodes of diarrhoea and complaints of cramping, fasciculation (muscle twitches just below the skin), bradycardia (slow heart rate), pupillary constriction, increased salivation and increased sweating. These are caused by the smooth muscle hyperactivity secondary to excessive accumulation of acetylcholine at the neuromuscular junctions and excessive parasympatheticlike activity (refer to Chapter 6 for the parasympathetic nervous system neurotransmitters). As in myasthenic crisis, the individual is in danger of respiratory arrest.61 EVALUATION AND TREATMENT
FIGURE 9.18
Pathophysiology of myasthenia gravis. A Normally, acetylcholine is released from the neuron, which travels across the synapse and binds with acetylcholine receptors on the skeletal muscle. In response, the skeletal muscle contracts. B With myasthenia gravis, there is destruction of the acetylcholine receptors, so that there is very little acetylcholine binding on the skeletal muscle. As a result, the muscle does not receive a significant signal to undergo contraction.
FIGURE 9.19
‘Peek’ sign in myasthenia gravis. During sustained forced eyelid closure this patient with myasthenia gravis is unable to bury his eyelashes (left), and after 30 seconds he is unable to keep the lids fully closed (right).
and weight loss; drooling and episodes of choking and aspiration; and a nasal, low-volume but high-pitched monotonous speech pattern. The muscles of the neck, shoulder girdle and hip flexors are less frequently affected. The respiratory muscles of the diaphragm and chest wall become weak and ventilation is impaired. In the advanced stage of the disease, all muscles are weak. Myasthenic crisis occurs when severe muscle weakness causes extreme quadriplegia, respiratory insufficiency with shortness of breath and extreme difficulty in swallowing. The individual in myasthenic crisis is in danger of respiratory arrest.61 Cholinergic crisis may arise from anticholinesterase drug toxicity (related to usual treatment, see next section).
The diagnosis of myasthenia gravis is based on history, physical examination and laboratory testing including: antibody levels for acetylcholine receptors, repetitive nerve stimulation and single-fibre electromyography. The single-fibre electromyogram can detect delay or failure of neuromuscular transmission in pairs of muscle fibres. Four treatment options should be considered for myasthenia gravis: 1 anticholinesterase drugs such as edrophonium (Tensilon), which enhances neuromuscular transmission as it limits the breakdown of the neurotransmitter by acetylcholinesterase, thereby allowing more acetylcholine to be available at synapses for muscle contraction 2 immunosuppressive therapy (such as corticosteroids, tacrolimus) 3 plasmapheresis to remove antibodies from plasma or intravenous (IV) immunoglobulin 4 thymectomy if the patient has a thymoma (tumour in the thymus gland).60 The progression of myasthenia gravis varies, appearing first as a mild case that spontaneously remits, with a series of relapses and symptom-free intervals ranging from weeks to months. Over time the disease can progress, leading to death. For individuals with cholinergic crisis, anticholinergic drugs are withheld until blood levels fall out of the toxic range, while ventilatory support is provided and respiratory complications are prevented. FOCU S ON L EA RN IN G
1 Discuss why plasmapheresis is a treatment option for both Guillain-Barré and myasthenia gravis. 2 Describe the clinical manifestations of myasthenia gravis.
Infection and inflammation of the central nervous system Meningitis
Meningitis is inflammation of the meninges, usually caused by an infection, which involves the pia mater and arachnoid,
CHAPTER 9 Alterations of neurological function across the life span
subarachnoid space, ventricular system and CSF. Meningitis may be caused by a number of different microorganisms, with the most common types in Australia being bacterial and viral causes. A systemic or bloodstream infection or a direct extension from an infected area is the access route to the subarachnoid space. Most cases of bacterial meningitis in Australia are due to meningococcus (Neisseria meningitidis), with approximately 1–3 people affected per 100 000 per year.62 Fatality rates are approximately 6% of affected people.62 This is also the most common organism to cause bacterial meningitis in children, accounting for approximately 60% of all paediatric cases of meningitis.63 Approximately 2–4% of healthy children are carriers of N. meningitidis. The risk of developing meningitis from daycare centres through contact with children with meningococcal disease is 1 per 1000.64 Meningococcal meningitis occurs predominantly in males, with epidemics predominantly affecting children and adolescents. Young people are at high risk due to their high amount of social activities and close personal contact.65 Other causes of bacterial meningitis are less common in Australia now that the childhood immunisation program includes a vaccination for N. meningitidis type C.64 However, type B is still prevalent — of the 241 Australians confirmed with N. meningitidis in one year, 179, or 75%, were type B.64 Vaccinations for other bacterial meningitis are also included in the childhood immunisation program for Haemophilus influenzae and Streptococcus pneumoniae. In New Zealand, a national immunisation program for N. meningitidis type B was implemented after an epidemic which reached its peak in 2001. Most of the New Zealand population under the age of 20 has received this vaccination, although it has no longer been on the childhood immunisation schedule since nearing the end of the epidemic.66 Viral causes of meningitis include human enteroviruses (such as coxsackieviruses), herpes simplex virus type 2, as well as varicella zoster virus (which causes chickenpox) and the viruses that cause measles and mumps. In the case of herpes infection, there is usually genital herpes associated with the meningitis. Viral meningitis is not a reportable disease in Australia, so exact population statistics are not available. However, although it is more common than the bacterial form, it usually causes a less severe meningitis and hence is not usually life threatening.67 It may resolve within approximately 1 week. PATHOPHYSIOLOGY
The bacteria that usually cause meningitis are common inhabitants of the nasopharynx (the back of the nasal cavity; see Chapter 24), but a predisposing factor such as a prior upper respiratory infection is typically present before the bacteria become blood-borne. The bacteria function as irritants and induce an inflammatory reaction by the meninges, CSF and ventricles. Blood cells (neutrophils) migrate into the subarachnoid space, producing an exudate that thickens the CSF and interferes with normal CSF flow around the brain and spinal cord — this is key in diagnosing
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the type of meningitis.65 This can obstruct arachnoid villi and lead to increasing intracranial pressure). Further inflammation occurs as the purulent exudate (pus containing bacterial and immune cells) increases rapidly, especially around the base of the brain, and extends into the sheaths of the cranial and spinal nerves and into the perivascular spaces of the cortex. Meningeal cells become oedematous and the combined exudate and oedematous cells further increase intracranial pressure. Small and medium-sized subarachnoid arteries, veins and choroid plexuses become engorged, disrupting blood flow and potentially producing thrombosis. Secondary infection of the brain may occur.68 For viral meningitis, the infection usually begins in the lining of the respiratory or gastrointestinal tract. From there, the virus enters the lymphatic system and travels to the blood, finally crossing the blood–brain barrier to reach the meninges.65 CLINICAL MANIFESTATIONS
Meningitis is characterised by severe headache and fever. The clinical manifestations of bacterial meningitis can be grouped into meningeal signs, infectious signs and neurological signs. The clinical manifestations of the systemic infection include rapid onset of fever, tachycardia, chills and a petechial rash. Importantly, the rash mainly appears with associated septicaemia, so meningitis without septicaemia would not usually produce the rash. Clinical manifestations that are more specific to meningeal irritation include a generalised throbbing headache that becomes very severe, photophobia (inability to tolerate light) and nuchal rigidity (neck stiffness, which results in inability to flex the head forwards). The neurological signs include a decrease in consciousness, cranial nerve palsies, seizures and focal neurological deficits that include weakness (hemiparesis) or paralysis (hemiplegia) on one side of the body and ataxia (abnormal coordination of movements). Often the vomiting centre is irritated, causing projectile vomiting. With meningococcal meningitis, a non-blanching petechial or purpuric rash covers the skin and mucous membranes (see Fig. 9.20). As intracranial pressure increases, papilloedema develops and delirium may progress to unconsciousness.68 The clinical manifestations of viral meningitis are similar although mild compared with those associated with bacterial meningitis. Mild, generalised throbbing headache, mild photophobia, mild neck pain, stiffness, fever and malaise typically accompany viral meningitis.67 EVALUATION AND TREATMENT
Diagnosis of meningitis is based on physical examination, nasopharyngeal smear and blood tests to determine the cause. CSF cultures (obtained through lumber puncture) may be needed to confirm the cause. One of the distinguishing features discriminating between bacterial and viral causes of meningitis is determined by laboratory analysis of the leucocytes (white blood cells) in the CSF — in bacterial meningitis, the neutrophils predominate, whereas lymphocytes predominate in viral meningitis.69 Head CT
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encephalitis than meningitis.72 There may be widespread nerve cell degeneration. Oedema, necrosis with or without haemorrhage and increased intracranial pressure develop. Infectious encephalitis may result from a postinfectious autoimmune response to the virus or from direct invasion of the CNS. Non-infectious encephalitis may account for up to 30% of cases, which are usually immune mediated.73 CLINICAL MANIFESTATIONS
FIGURE 9.20
Skin lesions with meningitis. Characteristic purpura with petechiae and ecchymoses in a patient who has severe sepsis and meningitis due to Neisseria meningitidis.
Encephalitis ranges from a mild infectious disease to a life-threatening disorder. Dramatic clinical manifestations include fever, delirium or confusion progressing to unconsciousness, seizure activity, skin rash, cranial nerve palsies, paresis and paralysis, involuntary movement and abnormal reflexes. Signs of intracranial pressure including headache, visual disturbances, decreased level of consciousness, papillary changes, Cushing’s triad (hypertension, bradycardia and irregular respiratory pattern), motor dysfunction (hemiparesis or hemiplegia) or aphasia (disorder of language affecting the generation of speech and its understanding) may be present. EVALUATION AND TREATMENT
or MRI should be considered for diagnosis and to investigate the extent of complications. Until the causative bacteria has been identified, broad-spectrum antibiotics should be given parentally.69 Antibiotic therapy (refer to Chapter 14) for bacterial causes includes rifampicin or ciprofloxacin and other supportive measures — treatment for those exposed to meningococcal meningitis involves using these for prevention (prophylaxis) and vaccination.69 Corticosteroids may be useful in minimising inflammation.70 There are no specific treatments for viral causes, other than supportive care and rest.67
Encephalitis
Encephalitis is an acute febrile illness, usually of viral origin, which causes an inflammation of the nervous tissue. If inadequately treated it can be fatal and, for the survivors, there are long-term health alterations.71 It differs from meningitis, which is inflammation of the meninges rather than of neural tissue. The most common forms are caused by mosquito-borne (arthropod) viruses, such as Murray Valley encephalitis, West Nile virus, and herpes simplex type 1 (which is associated with lesions around the mouth, such as cold sores). Encephalitis may occur as a complication of systemic viral diseases such as poliomyelitis or mononucleosis, or it may arise after recovery from viral infections such as rubella. Encephalitis may also follow vaccination with a live attenuated virus vaccine if the vaccine has an encephalitis component — for example, the measles, mumps and rubella vaccine; however, it is important to emphasise that encephalitis after this vaccine is quite rare. PATHOPHYSIOLOGY
Meningeal involvement is present in all types of viral encephalitis. Altered consciousness is more common with
Diagnosis is made by the history and clinical presentation aided by CSF examination and culture, serology, white blood cell count, CT scan or MRI. Encephalitis due to herpes simplex virus or varicella zoster virus is now being treated with antiviral agents, such as aciclovir.71 Encephalitis is a medical emergency; patients require intensive care, and instigation of measures to control intracranial pressure and ventilation is critical.
Abscesses
Brain abscesses are localised collections of pus within the tissue of the brain and spinal cord. Men experience brain abscesses twice as often as women. The median age for abscess formation is 30–40 years. Abscesses can occur: (1) after open trauma and during neurosurgery; (2) in association with infection near the CNS, such as the middle ear, nasal cavity and nasal sinuses; and (3) through spread from a distant site, such as the heart, lungs, pelvic organs, skin, tonsils, abscessed teeth, osteomyelitis (infection and inflammation of the bone or bone marrow) and dirty needles (especially in compromised hosts). Streptococci, staphylococci and Bacteroides are the most common bacteria that cause abscesses; however, yeast and fungi have also been found. Brain abscesses are classified as extradural or intracerebral. Extradural brain abscesses are associated with osteomyelitis in a cranial bone. Unlike intracerebral brain abscesses, they rarely arise from a vascular source. Spinal cord abscesses are classified as epidural or intramedullary. Individuals with diabetes mellitus show an increased incidence of spinal epidural abscesses (within the epidural space between dura mater and spinal cord), whereas debilitated individuals with sepsis more often develop intramedullary spinal cord abscesses (within the spinal cord). Epidural spinal abscesses
CHAPTER 9 Alterations of neurological function across the life span
usually originate as osteomyelitis in a vertebra; the infection then spreads into the epidural space.74 PATHOPHYSIOLOGY
Brain abscesses evolve through four stages: 1 early cerebritis (days 1–3) with localised inflammation with presence of inflammatory cells (neutrophils) surrounding a core of necrosis, marked cerebral oedema is present, with activation of glial cells 2 late cerebritis (days 4–9) with necrotic centre surrounded by macrophages, lymphocytes, microglia and fibroblasts, new blood vessels form rapidly around abscess, thin capsule develops, oedema still persists 3 early capsule formation (days 10–13) with necrotic centre decreasing in size, more fibroblasts and macrophages are present, mature collagen evolves forming a capsule 4 late capsule formation (days 14 and longer) with well-formed necrotic centre surrounded by a dense collagen capsule. Existing abscesses also tend to spread and form multiple abscesses in the nearby area.74 CLINICAL MANIFESTATIONS
Clinical manifestations of brain abscesses are associated with an intracranial infection or expanding intracranial mass. Early manifestations include headache (the most common symptom), low-grade fever, vomiting, neck pain and stiffness with mild nuchal rigidity, confusion, drowsiness, sensory deficits and communication deficits. Later clinical manifestations include inattentiveness (distractibility), memory deficits, decreased visual acuity and narrowed visual fields, ocular palsy, ataxia and dementia. The development of symptoms may be insidious, often making an abscess difficult to diagnose. Extradural brain abscesses are associated with localised pain, purulent drainage from the nasal passages or auditory canal, fever, localised tenderness and neck stiffness. Occasionally the individual experiences a focal seizure. Clinical manifestations of spinal cord abscesses have four stages: (1) spinal aching; (2) severe root pain, accompanied by spasms of the back muscles and limited vertebral movement; (3) weakness caused by progressive cord compression; and (4) paralysis. EVALUATION AND TREATMENT
The diagnosis is suggested by clinical features and confirmed by CT scan or MRI. Aspiration (obtaining a biopsy or removing the abscess) through a burr hole (small circular area of bone removed from the cranium) is used, although excision through an open craniotomy may be unavoidable. Antibiotic therapy is used, preferably after obtaining the biopsy to guide the choice of antibiotic drug. In addition, intracranial pressure may have to be managed, and the corticosteroid dexamethasone is often used.68 As decompression is necessary, spinal cord abscesses are treated with surgical excision or aspiration. Antibiotic therapy and support therapy also are instituted.74
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FOCU S ON L EA RN IN G
1 Compare and contrast the clinical manifestations and treatment of meningitis and encephalitis. 2 List the most common causes of meningitis in Australia and New Zealand. 3 Describe the 4 stages of brain abscess development.
Tumours of the nervous system Tumours are abnormal growths that may be benign or malignant — malignant tumours are usually referred to as cancers. A complete discussion of the genetic basis of cancer, cancer growth and spread, and cancer treatments can be found in Chapter 37. Here we examine some specific information relating mainly to CNS cancers.
Cranial tumours
Tumours within the cranium can be either primary or secondary (metastatic), as follows: • Primary. Intracerebral tumours originate from brain structures such as neuroglia, cells of blood vessels and connective tissues. Extracerebral tumours originate outside substances of the brain and include meningiomas, acoustic nerve tumours, cranial nerves and tumours of the pituitary and pineal glands. Primary tumours may undergo metastasis, or spread, within the brain. Although many brain tumours remain relatively benign, they can be life threatening due to direct compression of brain tissue. • Secondary or metastatic. The cancer originates outside the brain, but has spread to the brain. The concept of cancer spread by metastasis is discussed in Chapter 37. Brain tumours are fatal for more than 1200 Australians per year.75 The incidence of cranial tumours increases to age 70 years and then decreases. Interestingly, CNS tumours are the second most common group of tumours occurring in children, affecting more than 100 children per year.75 These cancers have a low survival rate, meaning that a relatively small percentage of those diagnosed will be alive in the years following diagnosis. The percentage of those surviving 5 years after diagnosis of brain cancer in Australia is less than 20%.76 Local effects of cranial tumours are caused by the destructive action of the tumour itself on a particular site in the brain and by compression causing decreased cerebral blood flow and decreased neural function. Effects include seizures, visual disturbances, speech deficit, ataxia (unstable gait) and cranial nerve dysfunction. Generalised effects result from increased intracranial pressure caused by obstruction of the ventricular system, haemorrhages in and around the tumour, or cerebral oedema (see Fig. 9.21). Intracranial brain tumours do not metastasise as readily
CONCEPT MAP
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Neoplasm
Diminished cognitive functioning
causes
Compression of Invasion of brain structures the brain tissue causes causes results in Focal deficits depending on location
Cerebral oedema
Headache
Increased intracranial pressure
results in
Behavioural alteration
Vomiting
leads to
Seizures Papilloedema Unsteady gait
contributes to
Loss of sphincter control
FIGURE 9.21
Origin of clinical manifestations associated with an intracranial neoplasm.
as tumours in other organs because there are no lymphatic channels within the brain tissue. Medulloblastomas, ependymomas, astrocytomas, brainstem gliomas, craniopharyngiomas and optic nerve gliomas make up approximately 75–80% of all paediatric brain tumours. The types and characteristics of childhood brain tumours are summarised in Table 9.8.
Primary intracerebral tumours
Primary intracerebral tumours may be benign and encapsulated or non-encapsulated and invasive tumours. Gliomas are tumours of the glial cells (which support the neurons) and represent 42% of all primary brain tumours and 77% of malignant brain tumours.77 Typically, these tumours invade and destroy adjacent normal CNS tissue, and more distal neural and vascular tissues are displaced and compressed, causing ischaemia (inadequate oxygen delivery to the cells), oedema and increased intracranial pressure. Surgery to fully excise the growth, surgical decompression (surgery to decrease intracranial pressure), chemotherapy and radiotherapy are used for these tumours. Supportive treatment is directed at reducing oedema. ASTROCYTOMAS
Astrocytomas are the most common glioma (about 40% of all tumours of the brain and spinal cord)78 and are graded I–IV (see Table 9.9). Developed from astrocytes, astrocytomas expand and infiltrate into the normal surrounding brain tissues. One-third of astrocytomas are classified at diagnosis as grade I or grade II, which are slow-growing. These tumours are generally located in the cerebrum, hypothalamus or pons. Headache and seizures may be early signs. Onset of a focal seizure disorder between the second and sixth decades of life suggests an astrocytoma. Other general or focal
neurological manifestations develop gradually, with increased intracranial pressure occurring late in the tumour’s course. Grade I astrocytomas are treated with surgery and follow-up CT scans. Grade II astrocytomas are treated surgically if accessible or by conventional external radiation, local radiation or radiosurgery. Some 25% of people survive 5 years following surgery alone, while 55% survive 5 years when surgery is followed by radiation therapy.79 Grade I and II astrocytomas commonly progress to a higher grade tumour. However, radiation therapy is often accompanied by the development of progressive localised dysfunction including development of dementias. Grades III and IV astrocytomas are found predominantly in the lobes and cerebral hemispheres. Men are twice as likely to have them as women and those 45–55 years old have the highest incidence. Grade IV astrocytomas, glioblastoma multiforme, are highly vascular and extensively infiltrative. They may become large enough to extend from the meningeal surface through the ventricular wall and half of them occupy more than one lobe at the time of death. The typical clinical presentation for grade IV astrocytomas is that of diffuse, nonspecific clinical signs, such as headache, irritability and ‘personality changes’ that progress to more clear-cut manifestations of increased intracranial pressure such as headache on position change, visual changes, seizures or vomiting. Symptoms may progress to include definite focal signs, such as hemiparesis, dysphasia, cranial nerve palsies and visual field deficits. Diagnosis of high-grade astrocytoma most commonly takes several months from the onset of the first clinical manifestations because the person does not recognise the need to consult a healthcare provider. Grade III astrocytomas are treated surgically if they are accessible and with radiotherapy and chemotherapy. With treatment, 55–60% of people survive 1 year, 30–35% survive 2 years and 10%
CHAPTER 9 Alterations of neurological function across the life span
TABLE 9.8 Brain tumours in children TYPE
CHARACTERISTICS
Astrocytoma
• Arises from astrocytes, often in the cerebellum or lateral hemisphere • Slow-growing, solid or cystic • Often very large before diagnosed • Varies in degree of malignancy
Optic nerve glioma
• Arises from optic chiasm or optic nerve • Slow-growing, low-grade astrocytoma
Medulloblastoma (infiltrating glioma)
• Often located in the cerebellum, extending into the fourth ventricle and spinal fluid pathway • Rapidly growing malignant tumour • Can extend outside the CNS
Brainstem glioma
• Arises from the pons or myelencephalon • Numerous cell types • Compresses cranial nerves V to X
Ependymoma
• Arises from ependymal cells lining the ventricles • Circumscribed, solid, nodular tumours
Craniopharyngioma
• Arises near the pituitary gland, optic chiasm and hypothalamus • Cystic and solid tumours that affect vision, pituitary and hypothalamic functions
TABLE 9.9 Classification systems for astrocytomas GRADE
DESCRIPTION
Astrocytomas Grade I
Well-differentiated astrocytoma
Least malignant, grow slowly, near normal appearance
Grade II
More cellular and anaplastic astrocytoma
Abnormal appearance under a microscope, infiltrated and may recur at a higher grade
Glioblastomas Grade III Poorly differentiated astrocytoma
Malignant, many cells undergoing mitosis, infiltrated and may recur at a higher grade
Grade IV Poorly differentiated astrocytoma (glioblastoma multiforme)
Increased number of cells undergoing cell division, bizarre appearance under a microscope, widely infiltrated, neovascularisation, central necrosis
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survive longer than 5 years. Grade IV astrocytomas are also treated with surgery, radiotherapy and chemotherapy, but average survival time is only about 1 year.79 If a young child complains of repeated and worsening headache, a thorough investigation should take place because headache is uncommon in young children. Headache caused by increased intracranial pressure is usually worse in the morning and gradually improves during the day when the child is upright and venous drainage is enhanced. The frequency of headache and other symptoms worsens as the tumour grows. Irritability and increased somnolence (drowsiness) may also result. Like headache, vomiting occurs more commonly in the morning. Often it is not preceded by nausea and may become projectile, differing from a gastrointestinal disturbance in that the child may be ready to eat immediately after vomiting. OLIGODENDROGLIOMAS
Oligodendrogliomas constitute about 4% of all primary brain tumours and approximately 10–15% of gliomas.78 They are typically slow growing. The majority are found in the frontal and temporal lobes, often in the deep white matter, but they are found also in other parts of the brain. Most oligodendrogliomas occur in adults 50–60 years old and are found more often in men and in young adults with a history of epilepsy. Approximately half of tumours classified as oligodendrogliomas are actually a mixed type of oligodendroglioma and astrocytoma. Malignant degeneration occurs in approximately one-third of those with oligodendrogliomas and the tumours are then referred to as oligodendroblastomas. If there is extension to the pia mater or ependymal wall, oligodendrogliomas may metastasise to distant CNS sites through the ventricular and arachnoid spaces. More than 50% of individuals experience a focal or generalised seizure as the first clinical manifestation. Half of those with an oligodendroglioma have increased intracranial pressure at the time of diagnosis and surgery, and one-third develop focal manifestations. The time from the first clinical manifestation to surgical intervention ranges from 2 to 6 years. Survival time is approximately 5–10 years.79 EPENDYMOMAS
Ependymomas are gliomas that arise from ependymal cells in the walls of the ventricles and grow either into the ventricle or into adjacent brain tissue; they are not encapsulated (see Fig. 9.22). They constitute about 3% of all primary brain tumours in adults and 10% in children (sixth most common brain tumour in children) and adolescents. Most are in the fourth ventricle, with others found in the third ventricle, lateral ventricles and spinal cord. Patients with fourth ventricle ependymomas present with difficulty with balance, unsteady gait, uncoordinated muscle movement and dysfunctional fine motor movement. The clinical manifestations of a lateral and third ventricle ependymoma that involves the cerebral hemispheres are seizures, visual changes and contralateral weakness of
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NERVE SHEATH TUMOURS
FIGURE 9.22
Ependymoma. This tumour is the large reddish growth at the left hand side of the photograph. It is large and filling into the fourth ventricle.
a body part. Blockage of the CSF pathway by the tumour results clinically in the development of headache, nausea and vomiting arising from the resulting hydrocephalus (refer to Chapter 8). The course of ependymomas may be short or long. The interval between the first manifestations and surgery may be as short as 4 weeks or as long as 7 or 8 years. Ependymomas are treated with radiotherapy, radiosurgery and chemotherapy: 20–50% of people survive 5 years. Some people benefit from a shunting procedure to treat hydrocephalus by draining the CSF.79
Primary extracerebral tumours MENINGIOMAS
Meningiomas constitute about 30% of all primary intracranial tumours. They are considered benign because they are encapsulated and usually do not invade the surrounding brain; interestingly, although benign, it is possible to develop several meningiomas. These tumours usually originate from the dura mater or arachnoid membranes. Small meningiomas (less than 2 cm in diameter) are often found on postmortem examination in middle-aged and elderly individuals who experienced no clinical manifestations and died of totally unrelated causes. The meningioma may extend to the dural surface or exhibit malignant qualities. Focal seizures are often the first manifestation, as well as headaches and limb weakness. Because of the extremely slow-growing nature of these tumours, increased intracranial pressure is uncommon. There is a 20% recurrence rate, even with complete surgical excision. Radiation therapies are also used to slow growth.
Nerve sheath tumours are either neurofibromas or schwannomas (neuromas, neurolemmas). Some 5% of all neuromas are attributable to neurofibromatosis (an inherited disorder);80 the remainder are benign tumours that arise from the myelin sheath of the Schwann cells surrounding the axons of the cranial nerves. These tumours most commonly affect people in their 20s and 30s. The vestibular division of cranial nerve VIII is most commonly affected, with cranial nerves V, VIII and IX also affected. The tumour generally originates just distal to the junction between the nerve root and brainstem (junction of cerebellum and pons). As it grows, it compresses adjacent nerves and eventually the brainstem is displaced and CSF flow is obstructed. Initial clinical manifestations include headache, tinnitus (ringing in the ears), hearing loss, impaired balance, unsteady gait, facial pain and loss of facial sensations. Later, vertigo with nausea and vomiting, a sense of pressure in the ear and moderate to severe unsteadiness with rapid position changes may appear. CT scan or MRI can establish the diagnosis. Treatment is by surgical excision and radiotherapy of the neuroma.
Secondary (metastatic) brain carcinomas
Metastatic brain tumours that originate from systemic cancers are the most common type of brain tumour and an estimated 10–15% of people with cancer develop metastasis to the brain.79 Some 50% of metastatic brain tumours arise from the lung, 13% from melanomas, 6% from the breast and 4% from the kidneys.81 Carcinomas are disseminated to the brain through the circulation. In more than three-quarters of cases, the metastases are multiple and found scattered throughout the cerebrum and cerebellum. Metastatic tumours are often located in the meninges and near the brain surface in the grey matter and subcortical white matter. Metastatic brain tumours produce signs resembling those of glioblastomas and often of stroke or brain attack. Metastatic brain tumours carry a poor prognosis. If a solitary tumour is found, surgery or radiation therapy is used, but if multiple tumours exist, treatment varies widely.
FOCU S ON L EA RN IN G
1 Describe the general symptoms of cranial tumours. 2 Describe the stages of astrocytoma development. 3 Explain how primary extracerebral tumours develop. 4 Discuss the clinical significance of secondary brain tumours.
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Central nervous system malformations are responsible for 75% of fetal deaths and 40% of deaths during the first year of life. During the perinatal period, CNS malformations account for one-third of all apparent congenital malformations, and 90% of CNS malformations are defects of neural tube closure. Other injury to the developing brain, such as occurs with cerebral palsy, appears to occur before birth, but the causes of this are poorly understood. Defects of neural tube closure Neural tube defects occur in approximately 4.6 out of 10 000 live births in Australia each year, with about 25% of these babies dying within the first month after birth. Fetal death often occurs prior to birth as a result of the neural defects, thereby reducing the actual prevalence of neural defects at birth. These defects include anencephaly (an = without; enkephalos = brain), whereby a major part of the brain is missing; encephalocele, where part of the brain or meninges protrudes through an abnormal opening with the cranial bones; and spina bifida (see the next section). The cause of neural tube defects is believed to be multifactorial — a combination of genes and environment. No single gene has been found to cause neural tube defects. Folic acid (folate) appears to be important, particularly in the very early stages of pregnancy. Folic acid is essential for healthy DNA replication, particularly for rapidly dividing cells. The early stages of nervous system growth and development for the fetus occur shortly after conception, and folic acid deficiency during the early stages of pregnancy increases the risk for neural tube defects. Preconception supplementation assures adequate folate levels, and in Australia it is now mandatory for folate to be added to bread flour to further lessen the risk of neural tube defects. Voluntary codes of folate supplementation have been implemented in many EU countries and New Zealand. Other risk factors include heredity, maternal blood glucose concentrations, use of anticonvulsant drugs (particularly valproic acid) and maternal hyperthermia. Spina bifida When defects of neural tube closure occur, an accompanying vertebral defect allows the protrusion of the neural tube contents. This is called spina bifida and it is present in 3.4 per 10 000 births in Australia. Although the cause of spina bifida is unknown, periconception maternal folate deficiency and genetic alterations are commonly associated with the defect. It may also occur without any visible exposure of the meninges or neural tissue, for which the term spina bifida occulta (occult = unseen) is used. In spina bifida occulta, the posterior vertebral laminae do not fuse. This is a more mild form of the condition where the extent of the defect is relatively
small. It is extremely common occurring to some degree in 10–25% of infants. Approximately 80% of these vertebral defects are located in the lumbosacral regions, most commonly in the fifth lumbar vertebra and the first sacral vertebra; they may be detected prenatally with ultrasonic scanning and amniotic fluid alpha-fetoprotein (AFP) testing. About 3% of normal adults have spina bifida occulta of the atlas (cervical vertebra 1). Certain cutaneous or subcutaneous abnormalities suggest underlying spina bifida, including the following (see Fig. 9.23): • abnormal growth of hair along the spine, which often is either very coarse or very silky
A
B
C
FIGURE 9.23
Cutaneous and subcutaneous markers of occult spina bifida. A Note the hairy patch over the lumbar region. B The soft subcutaneous mass seen overlying the sacrum of this infant was determined to be a lipoma. C Sacral sinus tract associated with intraspinal dermoid tumour. Continued
PAEDIATRICS
Paediatrics and developmental disorders
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• a midline dimple with or without a sinus tract • a cutaneous angioma (benign tumour of the blood vessels), usually of the ‘port wine’ variety • a subcutaneous mass, usually representing a lipoma (a benign tumour of fatty tissue) or dermoid cyst. Spina bifida occulta usually causes no serious neurological dysfunctions. When dysfunctions occur, the common lumbosacral defects cause gait abnormalities, positional deformities of the feet as a result of muscle weakness, or sphincter disturbances of the bladder and bowel. These dysfunctions become evident during periods of rapid growth. Surgical closure is usually completed in the neonatal period and techniques are being developed for intrauterine closure. Cerebral palsy Cerebral palsy is the term given to a diverse group of non-progressive syndromes that affect the brain and cause motor dysfunction beginning in early infancy. The cause was thought to include prenatal cerebral hypoxia or trauma; however, there is also evidence that hypoxia and other injuries during childbirth are not associated. There is evidence that genetic factors, specific inflammatory processes and maternal infection with viruses such as herpes simplex virus, varicella zoster virus and EpsteinBarr virus that can cross the placenta may be all associated with the development of cerebral palsy. Cerebral palsy can be classified on the basis of neurological signs and symptoms and the types of muscle movements that result. The different types of cerebral palsy are due to different brain regions being affected. A range of neurological and cognitive processes are altered, as well as difficulty moving due to the damage to motor pathways. Cerebral palsy affects 1 in 400 births and is one of the most common crippling disorders of childhood. One of the distinguishing features of cerebral palsy is the inability to walk with the foot flat on the floor due to stiffness of muscles in the lower leg (gastrocnemius) (see Fig. 9.24). Spastic cerebral palsy is associated with increased muscle tone, causing stiffness and difficulty with movements (including reflexes). This accounts for approximately 70–80% of cerebral palsy cases. Dyskinetic cerebral palsy is associated with extreme difficulty in fine motor coordination and purposeful movements. Movements are jerky and uncontrolled. This form of cerebral palsy accounts for approximately 10–20% of cases. Ataxic cerebral palsy manifests with gait disturbances and instability. The infant with this form of cerebral palsy may have hypotonia (low muscle tone) at birth, but stiffness of the trunk muscles develops by late infancy. Persistence of this increased tone in truncal muscles affects the child’s gait and ability to maintain equilibrium. This form of cerebral palsy accounts for approximately 5–10% of cases. A child may have symptoms of each of these cerebral palsy types, which leads to a mixed disorder accounting for approximately 13% of cases.
FIGURE 9.24
Toe-walking. A 4-year-old child with cerebral palsy cruises on furniture. Notice that the child is crouched because of hamstring tightness and is toe-walking because of gastrocnemius tightness.
Children with cerebral palsy often have associated neurological disorders, such as seizures (about 50%) and intellectual impairment ranging from mild to severe (about 67%). Other complications include visual impairment, communication disorders, respiratory problems, bowel and bladder problems, and orthopaedic disabilities. Although the brain injury is static (unchanging), the chemical picture of cerebral palsy may change with growth and development. Therefore, a fundamental component of an effective treatment regimen includes ongoing assessment, evaluation and revision of the child’s overall management plan. The use of baclofen (a muscle relaxant drug) and botulinum toxin (Botox) has shown some improvement in some children with cerebral palsy (see Box 9.2). Family-focused interdisciplinary team management provides the best treatment outcomes. Neuroblastomas Neuroblastoma is a common childhood tumour originating in tissues that normally give rise to the sympathetic ganglia and the adrenal medulla (part of the adrenal gland, involved with the sympathetic nervous system). It is most commonly diagnosed during the first 2 years of life and 75% of neuroblastomas are found before the child is 5 years old. Occasionally, these tumours are diagnosed at birth with metastasis actually apparent in the placenta. Although it accounts for only 8–10% of paediatric malignancies, neuroblastoma causes 15% of cancer deaths in children. The most common location of neuroblastoma is in the adrenal medulla. The tumour is evident as an abdominal
CHAPTER 9 Alterations of neurological function across the life span
BOX 9.2
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Botox and cerebral palsy
In recent years, there has been a surge in the awareness and usage of Botox for cosmetic procedures. ‘Botox’ is an abbreviation of botulinum toxin, which is produced by the bacteria Clostridium botulinum. These bacteria cause severe illness and may be fatal in the case of food poisoning. The toxin blocks the release of acetylcholine at the neuromuscular junction, so it should be no surprise that it may be detrimental if ingested in food, as in high levels it can produce muscle paralysis, including those involved in respiration. When Botox is used cosmetically, a controlled dosing system is followed, so that it decreases muscle activity in a dosedependent manner — for example, a small dose decreases muscle activity by a small amount, while a larger dose results in a more substantial decrease in muscle contractions. Botox is injected into facial muscles to lessen the wrinkles associated with ageing (brow furrow or glabellar lines, and crow’s feet). It paralyses the muscles that contract and pull on the skin and cause wrinkles — relaxing these muscles makes the wrinkles less obvious. Perhaps less well-known is the value of Botox in the treatment of cerebral palsy, by injecting the toxin into the spastic muscles to allow them to become partially relaxed. Muscle tightness can render the muscles ineffective, but partially relaxing them using Botox provides the way for more controlled usage of muscle contractions. After the toxin is injected, splinting is used at night to maximise the benefit of the drug in maintaining muscle elongation. Botox is also used in combination with other therapies, such as occupational therapy, and other drugs. This important drug is increasing muscle function not only with cerebral palsy, but also with other conditions associated with muscle contraction.
mass and may cause anorexia, bowel and bladder alteration and sometimes spinal cord compression. Neuroblastoma is also found in the mediastinum (the area separating the lungs). There the tumour may cause dyspnoea or infection related to airway obstruction. A number of systemic signs and symptoms are characteristic of neuroblastoma, including weight loss,
irritability, fatigue and fever. Intractable diarrhoea occurs in 7–9% of children. More than 90% of children with neuroblastoma have increased amounts of adrenaline and noradrenaline and associated metabolites in their urine; higher levels of these are associated with a poorer prognosis.
chapter SUMMARY Cerebrovascular disorders • Cerebrovascular disease is the most frequently occurring neurological disorder. Any abnormality of the circulation of blood to the brain is referred to as a cerebrovascular disease. The main types of cerebrovascular disease are stroke, aneurysm and vascular malformation. • While strokes (‘brain attacks’) occur mainly in the elderly, one-fifth of sufferers are actually younger than 60 years of age. • Cerebrovascular accidents or strokes are classified according to pathophysiology and include ischaemic (85%: thrombotic or embolic) and haemorrhagic (15%: intracranial haemorrhage).
• Thrombotic stroke is caused by a blockage inside the blood vessels which obstructs the blood supply to brain tissue. Alterations in neuronal function occur and last for more than 24 hours. Permanent damage to the affected area of the brain occurs and the stroke may be fatal. • Less severe types of ischaemic stroke are transient ischaemic attacks (TIAs), which are temporary decreases in brain blood flow, and lacunar infarcts, in which the thrombosis is particularly small and localised. • An embolic stroke occurs when a fragment from elsewhere in the body becomes lodged within a cerebral vessel. A subsequent stroke is likely after embolic stroke.
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• Symptoms of ischaemic stroke depend on the blood vessels involved. Classical symptoms of difficulty speaking occur if the Broca’s speech area or Wernicke’s area for speech interpretation is affected. • Haemorrhagic stroke is caused by rupturing of a cerebral blood vessel. An intracerebral haemorrhage is strongly related to hypertension. A subarachnoid haemorrhage can cause a substantial haematoma that increases cerebral pressure. • Symptoms of haemorrhagic stroke — including subarachnoid haemorrhage — include severe headache (which may be rapidly worsening) and unconsciousness. Paralysis of one side of the body, difficulty speaking or understanding language or blindness may occur. • Distinguishing the type of stroke is essential to guide treatments. A CT scan is most commonly used and MRI, cerebral angiograph or lumbar puncture may also be used. In the case of thrombotic stroke, tissueplasminogen activator (or tPA) is administered in the form of alteplase within 6 hours of the onset of symptoms. For subarachnoid haemorrhage, limiting the bleeding is essential. • Intracranial aneurysms result from defects in the vascular wall and are classified on the basis of form, shape and size. They are often asymptomatic, but the signs vary depending on the location and size of the aneurysm. Surgical procedures may be an appropriate treatment. • A vascular malformation known as an arteriovenous malformation (AVM) is a tangled mass of dilated blood vessels. Although sometimes present at birth, AVM exhibits a delayed age of onset.
Trauma to the central nervous system • Motor vehicle accidents or sporting injuries are the major cause of traumatic CNS injury. Traumatic injuries to the head are classified as closed-head trauma (blunt) or open-head trauma (penetrating). Closed-head trauma is the more common type of trauma. • Different types of focal brain injury include contusion (injury or bruising of the brain without breaking the pia mater), laceration (tearing of brain tissue), epidural haematoma (accumulation of blood above the dura mater), subdural haematoma (blood between the dura mater and arachnoid membrane), intracerebral haematoma (bleeding into the brain) and open-head trauma (skull fracture with exposure of the cranial vault to the environment). • Diffuse brain injury (diffuse axonal injury) results from the effects of head rotation. The brain experiences shearing stresses resulting in axonal damage ranging from concussion to fatal. • Spinal cord trauma is mainly transport-related or due to falls. Those with this type of trauma are most commonly young males and older adults. • Spinal cord injury involves damage to vertebral or neural tissues by compressing tissue, pulling or exerting tension on tissue or shearing tissues so that they slide into one another.
• Spinal cord injury may cause spinal shock with cessation of all motor, sensory, reflex and autonomic functions below any transected area. Loss of motor and sensory function depends on the level of injury. • Paralysis of the lower half of the body with both legs involved is called paraplegia. Paralysis involving all four extremities is called quadriplegia (tetraplegia). • Return of spinal neuron excitability occurs slowly and may occur in weeks to months. Eventually, reflex emptying of the bladder and other reflexes return.
Degenerative disorders of the central nervous system • Alzheimer’s disease is characterised by decreased size (atrophy) of the brain, loss of the number of neurons and a decreased number of neuronal synapses. Disturbances of memory are common. Mood alterations and motor changes may also occur. • Diagnosis of Alzheimer’s disease includes the history and course of the illness, mental status examination and brain imaging. There is some evidence of genetic involvement. Management involves support and therapeutic agents, but neuronal damage cannot be corrected. • Neurodegenerative diseases are typically accompanied by a diagnostic preclinical loss of olfactory function (smell). • Parkinson’s disease is prevalent in our community and is associated with loss of neurons that secrete dopamine in the basal nuclei. This lack of dopamine leads to alterations in motor function, such as hypertonia and bradykinesia. Tremor at rest, rigidity and postural disturbances are also common. Pharmacological agents that increase the level of dopamine are useful. • Huntington’s disease is characterised by uncontrolled movements, with an average age of onset at 30–50 years. The disease progresses to dysfunction of cognition. There is degeneration of neurons within the brain that control motor function, due to a relative excess of dopamine. • Multiple sclerosis (MS) is a relatively common degenerative disorder of myelin of the CNS. Although the pathogenesis is unknown, the demyelination and inflammation is thought to result from an immunogenetic-viral cause — a previous viral insult to the nervous system in a genetically susceptible individual yields a subsequent abnormal immune response in the CNS. • Symptoms of multiple sclerosis include visual disturbances, loss of coordination, muscle spasticity, extreme fatigue and bladder or bowel dysfunction. Management is supportive. • Motor neuron disease is a degenerative disorder diffusely involving lower and upper motor neurons. The pathogenesis is not fully known; however, there is lower and upper motor neuron degeneration. It causes progressive disability (motor) and ultimately death (usually from respiratory failure).
CHAPTER 9 Alterations of neurological function across the life span
Peripheral nervous system and neuromuscular junction disorders • Guillain-Barré syndrome is a demyelinating disorder caused by an immunological reaction directed at the peripheral nerves. The clinical manifestations may vary from paresis of the legs to complete quadriplegia, respiratory insufficiency and autonomic nervous system instability. Plasmapheresis is used during the acute phase. • Myasthenia gravis is a disorder of the neuromuscular junction characterised by muscle weakness and fatigability. It is an autoimmune disease that destroys acetylcholine receptors, causing decreased transmission of the nerve impulse across the neuromuscular junction. This leads to defects in nerve impulse transmission at the neuromuscular junction.
Infection and inflammation of the central nervous system • Meningitis (infection of the meninges) may be due to a number of different microorganisms, with the most common cause being bacterial. Bacterial meningitis is primarily an infection of the pia mater and arachnoid and increased CSF in the subarachnoid space. • An inflammatory reaction occurs with bacterial meningitis and exudate is formed and increases rapidly. CSF flow is impaired. These changes lead to an increase in intracranial pressure and cerebral oedema. • Symptoms of meningitis include decreased consciousness, fever, neck stiffness, severe headache, seizure, muscle weakness or paralysis, vomiting and a distinct skin rash. • Encephalitis is an acute, febrile illness of viral (usually) origin with nervous system involvement. The most common causes of encephalitis are arthropod-borne (mosquito-borne) viruses and herpes simplex. Meningeal involvement appears in all with all causes of encephalitis. • Altered consciousness is a distinct sign of encephalitis. Clinical manifestations include fever, delirium, confusion, seizures, abnormal and involuntary movement and increased intracranial pressure. • Herpes encephalitis is treated with antiviral agents. No definitive treatment exists for the other causes of encephalitis.
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• Brain abscesses often originate from infections outside the CNS. Organisms gain access to the CNS from adjacent sites or spread along the wall of a vein. A localised inflammatory process develops with formation of exudate, thrombosis of vessels and degenerating leucocytes. After a few days, the infection becomes delimited with a centre of pus and a wall of granular tissue. • Clinical manifestations of brain abscesses include headache, nuchal rigidity, confusion, drowsiness, and sensory and communication deficits. Treatment includes antibiotic therapy and surgical excision or aspiration.
Tumours of the central nervous system • Two main types of tumours occur within the cranium: primary and metastatic. Primary tumours are classified as intracerebral tumours (astrocytomas, oligodendrogliomas and ependymomas) or extracerebral tumours (meningiomas or nerve sheath tumours). Metastatic tumours can be found inside or outside the brain substance. • CNS tumours cause local and generalised manifestations. The effects are varied and local manifestations include seizures, visual disturbances, loss of equilibrium and cranial nerve dysfunction. • Astrocytomas are relatively common types of tumour, although the diagnosis may take a long time due to the nonspecific nature of the clinical signs such as headache and personality changes.
Paediatrics and developmental disorders • CNS disorders are main causes of fetal and newborn mortality. • Neural tube defects are related to factors such as insufficient maternal folate; hence fortification of bread flour can be preventative for the population. • Spina bifida arises from defects in the neural tube that allow it to protrude from the vertebral column. Neurological defects may not always result. • Cerebral palsy results in significant motor dysfunction due to muscle stiffness. Botox treatments can be useful to partially paralyse the spastic muscles.
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CASE STUDY
A DU LT Aroha is 62 years old and lives alone. She receives assistance with physical chores such as shopping and cleaning, but is still able to do light tasks such as tidying the house and cooking her own meals. She is not overweight, but does not exercise. She has a history of hypertension and her blood pressure today was 145/90. She has no other comorbidities. Aroha presented to the emergency department today after experiencing an episode of blurred vision, difficulty speaking and dizziness. She did not lose consciousness and did not experience any muscle weakness. The episode commenced about an hour ago and lasted for approximately 20 minutes. She was not asleep when the symptoms commenced. After arriving at hospital, a CT scan was performed, where no tumour was observed. An MRI scan is about to be performed.
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Based on the information provided, which type of stroke is Aroha most likely to have suffered? Identify which features from Aroha’s case notes (the information provided) are risk factors for the development of stroke. Using the information provided, give Aroha a score using the ABCD2 system (as per Table 9.2). What does this score mean for the patient? Would it be appropriate to consider treating Aroha with tissue plasminogen activator (tPA, alteplase)? How does this drug work? After Aroha has been stabilised and is ready to be discharged home, what type of information should she be given to assist in preventing further stroke?
CASE STUDY
A GEING Tangaroa is 89 years old and lives with his daughter in a lowset home. He has a history of Alzheimer’s disease, alcohol use and frequent falls. His daughter attends to daily chores including shopping, cleaning and cooking meals with help from Blue Care nurses. Tangaroa had been complaining of a headache over the last few weeks, which was relieved with paracetamol. At 0800 hours Tangaroa had worsening confusion, complained of a severe headache and was drowsy. On arrival to ED a CT scan was performed.
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Based on the information given above, which type of haematoma is Tangaroa most likely to have suffered? What key factors from Tangaroa’s history helps to identify the type of haematoma Tangaroa may have developed over time? Why didn’t Tangaroa neurologically deteriorate immediately post his fall 4 weeks ago after he bumped his head? What type of surgery may Tangaroa require if clinically indicated? What do you need to consider regarding Tangaroa’s discharge planning?
REVIEW QUESTIONS 1 Why do the signs and symptoms associated with transient ischaemic attack resolve quickly? 2 What changes occur in the blood vessel with an aneurysm? 3 Discuss how haematomas resulting from brain trauma lead to complications in the brain. 4 Describe concussion as a manifestation of brain trauma. 5 Explain physiologically what occurs with autonomic hyperreflexia. 6 Discuss the changes in physical appearance in the patient with Parkinson’s disease.
7 Compare chorea, hypertonia and bradykinesia. 8 Compare the pathophysiology of Guillain-Barré with (a) myasthenia gravis and (b) multiple sclerosis. 9 Explain the progression of meningitis to the point where the patient may become unconscious. 10 What are the differences between primary and secondary cranial tumours?
Key terms adrenal cortex, 247 adrenal glands, 246 adrenal medulla, 247 aldosterone, 249 androgens, 250 anterior pituitary, 237 cortisol, 248 down-regulation, 235 euglycaemia, 246 first messenger, 236 glucagon, 245 glycaemic control, 243 glycogen, 244 hormone receptors, 235 hormones, 234 hyperglycaemia, 244 hypoglycaemia, 244 hypothalamus, 237 insulin, 244 negative feedback, 235 oestrogens, 250 ovaries, 252 pancreas, 243 parathyroid glands, 241 pineal gland, 251 pituitary gland, 237 posterior pituitary, 240 second messenger, 236 target cell, 235 testes, 252 thymus gland, 252 thyroid gland, 241 up-regulation, 235
CHAPTER
The structure and function of the endocrine system
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Sarah List Chapter outline Introduction, 234 Mechanisms of hormonal regulation, 234 Regulation of hormone release, 235 Mechanisms of hormone action, 235 The structure and function of the endocrine glands, 237 The hypothalamic–pituitary system, 237
The thyroid and parathyroid glands, 241 The pancreas, 243 The adrenal glands, 246 The pineal gland, 251 The thymus gland, 252 The testes and ovaries, 252 Ageing and the endocrine system, 252
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Introduction The easiest example of the power of the endocrine system is that seen during puberty, when hormones elicit some very obvious physical changes. However, this is only a small part of the endocrine system as every cell of the body is influenced by hormones. A substantial number of processes are controlled by the endocrine system; examples of such diverse functions include regulation of blood pressure, control of the sleep–wake cycle, maintenance of adequate calcium in the blood and bones, and even assisting with the long-term stress response. The endocrine system is composed of various glands located throughout the body (see Fig. 10.1). The main endocrine glands are the pancreas, adrenals, hypothalamus, pituitary, thyroid and parathyroid (other glands that secrete hormones are considered throughout this textbook). The endocrine glands produce and release hormones as chemical messengers. The endocrine system has four general functions: 1 Homeostasis. The endocrine system has an important role in maintaining an optimal internal environment throughout life. 2 Stress response. Hormones assist with the adaptive responses when emergency demands occur. 3 Growth and development. Hormones have a pivotal role in differentiation of tissues in the developing fetus and stimulation of sequential growth and development during childhood and adolescence. 4 Sexual maturation. The onset of puberty is characterised by surges in hormone levels, which allow for maturation of the reproductive system and make sexual reproduction possible. Hormones convey specific regulatory information among cells and organs and are integrated with the nervous system to maintain communication and control. The main mechanism of communication by hormones is the endocrine system, where hormones are released and travel through the bloodstream to reach their target cells. The endocrine system works with the nervous system in the control and regulation of body processes: the endocrine system is involved in long-term control (such as regulation of growth), while the nervous system is mainly responsible for control of activities that require a quick response (such as coordination of muscle activity so that you can walk smoothly and effortlessly; see Chapter 6). The endocrine and nervous systems work together to regulate responses to the internal and external environments. The endocrine cells release hormones into the bloodstream and therefore are able to reach every cell of the body. The hormones then cause an intracellular response at their target cells. Some hormones are trophic hormones, which means that their function is to increase or decrease the secretion of another hormone. In contrast, the remaining hormones (which are non-trophic) have direct effects on the body’s cells. In the following section we explore the factors involved in stimulating the release of hormones from the endocrine cells.
Hypothalamus Pineal Parathyroids
Pituitary
Thyroid Thymus
Adrenals Pancreas (islets)
Testes (male)
Ovaries (female)
FIGURE 10.1
The principal endocrine glands. Main endocrine glands include the hypothalamus and pituitary glands, the thyroid and parathyroid glands, the adrenal glands, pancreas and reproductive structures.
Mechanisms of hormonal regulation There are specific rates and rhythms of hormonal secretion. The three basic secretion patterns are: 1 diurnal patterns, which fluctuate around a 24-hour cycle 2 pulsatile and cyclic patterns, which fluctuate around other cycles, such as the female menstrual cycle of 28 days
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patterns that depend on levels of substances circulating within the bloodstream (e.g. calcium, sodium or potassium, or circulating levels of the hormone itself). Diurnal, pulsatile and cyclic patterns of hormone release involve consistent patterns of secretion. All hormones share certain general characteristics: • They operate within feedback systems, either positive or negative, to maintain an optimal internal environment. We know this concept as homeostasis (you may wish to review your understanding of homeostasis by referring to Chapter 2). • They affect only target cells with specific receptors for the hormone and then act on these cells to initiate specific cell functions or activities. • They are excreted by the kidneys or are deactivated by the liver.
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AA Up-regulation Hormone
Target cell
Hormone receptor Time
B Down-regulation
Hormone
Regulation of hormone release
Hormones are released either in response to an altered cellular environment or in the maintenance of a regulated level of another hormone or substance. One or more of the following mechanisms regulates hormone release: (1) chemical factors (such as blood glucose or calcium levels); (2) endocrine factors (a hormone from one endocrine gland controls another endocrine gland); and (3) neural control. For example, insulin is secreted in response to increased glucose levels (a chemical stimulus), to direct stimulation of the insulin-secreting cells of the pancreas by the autonomic nervous system (a neural stimulus) and to the secretion of cortisol by the adrenal cortex, a form of endocrine regulation. Feedback systems provide precise monitoring and control of the cellular environment. The most common feedback system, negative feedback, occurs because the rising hormone level negates the initiating change that triggered the release of the hormone (refer to Chapter 2 to revise negative feedback). Negative-feedback systems are important in maintaining hormones within physiological ranges. The lack of negative-feedback inhibition on hormonal release often results in pathological conditions. As discussed in Chapter 11, various hormonal imbalances and related conditions are caused by excessive hormone production, which is the result of failure to ‘turn off ’ the system.
Mechanisms of hormone action
The sensitivity of the target cell to a particular hormone is related to the total number of receptors per cell: the more receptors, the more sensitive the cell. Low concentrations of hormone increase the number of receptors per cell; this is called up-regulation. High concentrations of hormone decrease the number of receptors; this is called down-regulation (see Fig. 10.2). Thus, the cell can adjust its sensitivity to the concentration of the signalling hormone. The receptors on the cell membrane are continuously produced and degraded, so that changes in receptor concentration may occur within hours. Various conditions
Target cell
Hormone receptor Time
FIGURE 10.2
Regulation of target cell sensitivity. A Low hormone level and up-regulation, or an increase in number of receptors. B High hormone level and down-regulation, or a decrease in number of receptors.
can affect both the receptor number and the affinity (attraction) for which the hormone binds to its receptor.
Hormone receptors
Although a hormone is distributed throughout the body via the bloodstream, only those cells with appropriate receptors for that hormone are affected (see Fig. 10.3). Hormone receptors of the target cell have two main functions: (1) to recognise and bind specifically and with high attraction (or affinity) to their particular hormones; and (2) to initiate a signal to appropriate intracellular effectors. Some hormone receptors are located in the cell membrane of the target cell. Hormones that are protein-based (consist of proteins) are water soluble and therefore they cannot easily diffuse through the lipids of the cell membrane. The receptors for these types of hormones are on the cell surface, where the hormone can bind with the receptor (see Fig. 10.4A). Most of the hormones in the human body are these protein-based hormones. Other hormone receptors are located inside the target cell. This means that the hormone actually diffuses through the cell membrane, where it binds to receptors located within the cell. This process applies to the lipid-based or steroid-based hormones, which are derived from cholesterol, such as the sex hormones as well as those from the adrenal
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ENDOCRINE CELL
Nucleus Hormones Hormone secreted into bloodstream
Receptor
Blood vessel
Receptor
Nucleus
Nucleus TARGET CELL
NON-TARGET CELL
FIGURE 10.3
Hormone release and target cell specificity. The hormone (represented by triangles) is released from the endocrine cell into the bloodstream. It travels through the blood and can bind to receptors on the target cells. The hormone cannot bind to cells without receptors for that particular hormone (nontarget cells).
cortex. These can diffuse through the lipids of the cell membrane and bind with receptors in the cytoplasm or on the nucleus (see Fig. 10.4B). The hormone-receptor complex then binds to a specific region in the DNA and stimulates the expression of a specific gene. Types of hormones are summarised in Table 10.1. PROTEIN-BASED HORMONES
Receptors for the protein-based (water-soluble) hormones are located in the cell membranes. The hormone is the first messenger secreted into the bloodstream and carries the message from the endocrine gland to the target cell. At the target cell it interacts with the receptor on the cell membrane. As the protein-based hormones cannot get into the cell, they must pass the message on by using a second messenger (see Fig. 10.4A). The hormone–receptor interaction initiates a signal that generates this second messenger inside the cell, which takes the signal from the receptor (at the cell membrane) to the cytoplasm and nucleus of the cell. The second messenger controls the effect of the hormone on the target cell — for example, membrane transport, contractile proteins, enzyme activation, production of proteins (protein synthesis) and cellular growth. Consequently, the second messenger directs the actions or products of specific cells. STEROID-BASED HORMONES
The lipid-soluble hormones are steroid-based hormones and are produced from cholesterol. They include androgens, oestrogens, progestins, glucocorticoids, mineralocorticoids
FIGURE 10.4
The signalling process for protein- and steroid-based hormones. A Protein-based hormones bind to receptors located on the cell membrane, activate a second messenger and alter cellular processes. B Steroid-based hormones readily diffuse across the cell membrane and attach to a receptor in the cytosol (1) or in the nucleus (2).
and thyroid hormones. Because they are relatively small, lipophilic (lipid-loving), hydrophobic molecules, they can cross the lipid cell membrane by simple diffusion (see Chapter 3). Receptors for steroid-based hormones are in the cytoplasm and nucleus (see Fig. 10.4B). Their role is to trigger events that increase or decrease the expression of specific genes. This modulation of gene expression can take hours to days.
CHAPTER 10 The structure and function of the endocrine system
TABLE 10.1 Classification of the major hormones PROTEIN-BASED HORMONES
STEROID-BASED HORMONES
Pituitary hormones
Adrenal cortex hormones
Growth hormone
Cortisol
Prolactin
Aldosterone
Thyroid-stimulating hormone
Androgens
Luteinising hormone
Reproductive hormones
Follicle-stimulating hormone
Oestrogen
Adrenocorticotrophic hormone
Progesterone
Antidiuretic hormone
Testosterone
Oxytocin Pancreatic hormones Insulin Glucagon Thyroid hormones Thyroxine (note: although protein-based, it is actually lipid soluble) Calcitonin Parathyroid hormone Adrenal medulla hormones Adrenaline Noradrenaline Melatonin
F O CUS O N L E A R N IN G
1 Describe how hormones are used in communication and explain the mechanisms by which they function. 2 Discuss how first messengers differ from second messengers. 3 Compare the location of receptors for protein-based and steroid-based hormones.
The structure and function of the endocrine glands In this section, we explore the names and functions of specific hormones. For each hormone, we also consider the specific stimulus that causes the hormone to be secreted, as well as the signal that limits further hormone secretion when adequate levels have been reached — in this way, homeostasis of hormone levels is maintained.
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The hypothalamic–pituitary system
The hypothalamic–pituitary system (or hypothalamic– pituitary axis) produces a number of hormones that affect a diverse variety of body functions. The hypothalamic– pituitary axis forms the structural and functional basis for central integration of the neurological and endocrine systems. The hypothalamus controls the function of the pituitary gland. The hypothalamus is located at the base of the brain; just inferior to it (below it) is the pituitary gland, connected to the hypothalamus by the infundibulum (pituitary stalk). The cells of the hypothalamus are like other neurons in that they have similar electrical properties, membranes and synapses (refer to Chapter 6). However, the hypothalamus also contains neurosecretory cells — these are specialised neurons that produce and secrete hormones. The pituitary gland is located in a depression of the sphenoid bone at the base of the skull. It weighs approximately 0.5 g, except during pregnancy when its weight approaches 1 g. It is composed of two distinctly different lobes: (1) the anterior pituitary; and (2) the posterior pituitary (see Fig. 10.5). These two lobes differ in their cell types and functional relationship to the hypothalamus.
The anterior pituitary
The anterior pituitary (adenohypophysis) accounts for 75% of the total weight of the pituitary gland. Blood vessels known as the hypophyseal portal system link the hypothalamus to the anterior pituitary, so the hypothalamus secretes hormones into the blood to reach target cells within the anterior pituitary, thereby controlling this part of the pituitary gland (see Fig. 10.6). The hypophyseal portal system is the primary blood supply to the pituitary gland. It is known as a portal system because the capillary bed from the hypothalamus drains into the capillary bed of the anterior pituitary — an unusual arrangement, as capillaries generally drain into a venous system returning towards the heart (see Chapter 22). The major hypothalamic hormones that control the secretion from the anterior pituitary are listed in Table 10.2. In response to each of these hypothalamic hormones, the anterior pituitary secretes growth hormone (GH), prolactin (PRL), adrenocorticotrophic hormone (ACTH), thyroidstimulating hormone (TSH), follicle-stimulating hormone (FSH) and luteinising hormone (LH). Each hormone affects the physiological function of the specific target organ (see Fig. 10.7). GROWTH HORMONE
Function of growth hormone Growth hormone is secreted by the anterior pituitary and, as its name suggests, it is important for growth and development of muscles and bones. It causes the cells to increase in size and divide, resulting in increased mass of bones and muscles. The highest levels of growth hormone are found throughout adolescence, when growth is at its peak. In addition, growth hormone actually targets nearly
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Optic chiasm Thalamus Optic chiasm Infundibulum Pituitary diaphragm
Third ventricle
Hypothalamus
Pineal gland
Mammillary body
Hypothalamus
Pituitary stalk
Brainstem Neurohypophysis (posterior)
Pituitary (hypophysis)
Sphenoid bone
Nasal cavity
Pars intermedia Pars anterior
Adenohypophysis (anterior)
FIGURE 10.5
Location and structure of the pituitary gland (hypophysis). The pituitary gland is located within the sella turcica of the skull’s sphenoid bone and is connected to the hypothalamus by a stalk-like infundibulum. The pituitary stalk passes through a gap in the portion of the dura mater that covers the pituitary (the pituitary diaphragm). The inset shows that the pituitary is divided into an anterior portion, the adenohypophysis, and a posterior portion, the neurohypophysis.
Hypothalamic neurosecretory cell
Superior hypophyseal artery
Releasing hormones
Target cells in adenohypophysis
Anterior hypophyseal vein FIGURE 10.6
The relationship of the hypothalamus and anterior pituitary. Neurons in the hypothalamus secrete releasing hormones into veins that carry them directly to the vessels of the adenohypophysis, thus bypassing the normal circulatory route.
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TABLE 10.2 Major hormones of the hypothalamus and anterior pituitary HYPOTHALAMUS RELEASES
ANTERIOR PITUITARY RELEASES
TARGET
Growth hormone–releasing hormone (GHRH)
Growth hormone (GH)
Bones, muscle, liver, other
Prolactin-releasing hormone (PRH)
Prolactin (PRL)
Breasts
Corticotrophin-releasing hormone (CRH)
Adrenocorticotrophic hormone (ACTH)
Adrenal gland (hormone release)
Thyrotrophin-releasing hormone (TRH)
Thyroid-stimulating hormone (TSH)
Thyroid gland (hormone release)
Gonadotrophin-releasing hormone (GnRH)
Follicle-stimulating hormone (FSH) Luteinising hormone (LH)
Reproductive organs
Hypothalamic nerve cell Bone Growth hormone
Adrenal cortex
Anterior pituitary
Antidiuretic hormone
Adrenocorticotrophic hormone
Kidney tubules
Thyroidstimulating hormone Thyroid gland
Posterior pituitary
Oxytocin
Gonadotrophic hormones Prolactin (LH, FSH, and ICSH)
Uterus smooth muscle
Testis Mammary glands
Ovary
Mammary glands FIGURE 10.7
Pituitary gland hormones and their targets. The anterior pituitary gland produces and releases growth hormone, adrenocorticotrophic hormone, thyroid-stimulating hormone, gonadotrophic hormone, and prolactin. The posterior pituitary releases antidiuretic hormone and oxytocin; these are actually produced by the hypothalamus, and then travel to the posterior pituitary for their release. LH = luteinising hormone; ICSH = interstitial cell-stimulating hormone (male); FSH = follicle-stimulating hormone (female).
every body cell, where it is necessary for normal metabolism. Growth hormone also targets the liver to increase blood glucose and fatty acid levels, making these fuels available for working cells.
from the hypothalamus. In addition, growth hormone secretion has a daily cycle, with high peaks seen during sleep (see Fig. 10.8). High levels of secretion also occur during exercise.
Regulation of growth hormone secretion The regulation of growth hormone secretion from the anterior pituitary is by growth hormone–releasing hormone
OTHER ANTERIOR PITUITARY HORMONES
The anterior pituitary releases adrenocorticotrophic hormone, which targets the cells of the adrenal cortex
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Sleep
Growth hormone (ng/mL plasma)
30 20
Strenuous exercise
10 0 8am 12 4pm 8pm 12 4am 8am Noon Midnight
Supraoptic nucleus
Paraventricular nucleus
FIGURE 10.8
Typical variations in growth hormone secretion throughout the day. The graph demonstrates the high rate of growth hormone secretion that occurs during the first few hours of deep sleep, as well as the especially powerful effect of strenuous exercise on growth hormone secretion.
(adrenal gland); the effects of this are discussed later in the section on the adrenal gland; similarly, thyroid-stimulating hormone is discussed in the section on the thyroid gland. The remaining anterior pituitary hormones — follicle-stimulating hormone, luteinising hormone and prolactin — have several functions specific to the reproductive system and are discussed in Chapter 31.
Neurosecretory cells
Hypothalamus
Optic chiasma Anterior pituitary (adenohypophysis)
Posterior pituitary (neurohypophysis)
The posterior pituitary
The posterior pituitary (neurohypophysis) is a neural extension of the hypothalamus and the hypothalamus controls this part of the gland with action potentials (neural signals; see Fig. 10.9). These neurons have their cell bodies within the hypothalamus and the axons of those neurons extend through the infundibulum to the axon terminals in the posterior pituitary. Hormones are stored in these axon terminals. When signals (action potentials) come from the hypothalamus, they travel through the infundibulum on the neurons and, on reaching the axon terminal in the posterior pituitary, cause the release of those hormones from the neurons. The posterior pituitary secretes two protein-based hormones: antidiuretic hormone (discussed next) and oxytocin (discussed in Chapter 31 on the reproductive system). These hormones are structurally very similar. They are produced in the hypothalamus, packaged in secretory vesicles and moved down the axons to the posterior pituitary for storage. The posterior pituitary can be seen as a storage and releasing site for hormones produced in the hypothalamus. ANTIDIURETIC HORMONE
Function of antidiuretic hormone The major homeostatic function of the posterior pituitary is the control of plasma osmolality (concentration) as regulated by antidiuretic hormone (ADH). Antidiuretic
FIGURE 10.9
The relationship of the hypothalamus and the posterior pituitary. Neurosecretory cells have their cell bodies in the hypothalamus and their axon terminals in the posterior pituitary. Thus, hormones produced in the hypothalamus are actually released from the posterior pituitary.
hormone released into the bloodstream travels to the kidneys, where its effect is to increase the permeability of the distal renal tubules and collecting ducts (see Chapter 28). This increased permeability leads to increased water reabsorption and more concentrated urine. As a result, more water is retained in the bloodstream, rather than being excreted in the urine (see Fig. 10.10). The name antidiuretic hormone describes its function: diuresis is the production of urine, hence antidiuretic hormone decreases the production of urine. Antidiuretic hormone was originally named vasopressin because in extremely high doses it causes vasoconstriction and increased arterial blood pressure. These levels are not
CHAPTER 10 The structure and function of the endocrine system
Increased total plasma concentration of solutes sensed by the Hypothalamus (osmoreceptors) stimulates the Posterior pituitary to release antidiuretic hormone which targets the Kidney tubules to retain water resulting in Less water excreted in urine
hypothalamic osmoreceptors no longer sense increased plasma concentration posterior pituitary no longer secretes antidiuretic hormone
More water remains in bloodstream
negative feedback
CONCEPT MAP
so that Water is retained
241
hormone has no direct effect on electrolyte levels, but by increasing water reabsorption, the serum electrolyte concentrations may decrease because of a dilutional effect. Antidiuretic hormone secretion is also increased by changes in intravascular volume, which are monitored by baroreceptors in the left atrium, the carotid and aortic arches. A volume loss of 7–25% stimulates antidiuretic hormone secretion. Stress, trauma, pain, exercise, nausea, nicotine, exposure to heat and drugs such as morphine also increase its secretion. Antidiuretic hormone secretion decreases with decreased plasma osmolality, when the blood is already sufficiently diluted (see Fig. 10.10). Its release is also inhibited by increased intravascular volume and hypertension. In addition, ingestion of alcohol inhibits antidiuretic hormone, which results in loss of fluid via the urine. This can lead to dehydration, worsening the effects of intoxication and hangover. FOCU S ON L EA RN IN G
1 Describe the anatomical relationship between the hypothalamus and pituitary gland. 2 Discuss the secretion of growth hormone. 3 Explain the action of antidiuretic hormone.
which leads to Plasma concentration returns to normal
FIGURE 10.10
Secretion of antidiuretic hormone. In response to insufficient water in the blood, detected by an increasing concentration of solutes, antidiuretic hormone is released from the posterior pituitary into the blood. Once it reaches its target organ, the kidneys, it promotes the retention of water (and hence a corresponding decrease in urine volume).
reached physiologically, but high doses of antidiuretic hormone (as the drug vasopressin) may be administered to promote vasoconstriction during haemorrhage and in the management of shock or sepsis. Additionally, ADH production increases with the trauma of surgery which can result in oliguria, a very common postoperative side effect. Interestingly, it is also used in clinical trials as an alternative to adrenaline for the management of cardiac arrest (refer to Chapter 23). Regulation of antidiuretic hormone secretion The secretion of antidiuretic hormone is regulated primarily by the osmoreceptors of the hypothalamus. These osmoreceptors are specialised neurons that can sense the concentration of body fluids and they become activated by increased osmolality. As plasma osmolality increases, the rate of antidiuretic hormone secretion increases. This
The thyroid and parathyroid glands
The thyroid gland, located in the anterior part of the neck just below the larynx, produces hormones that control the rates of metabolic processes throughout the body. The four parathyroid glands are near the posterior side of the thyroid and function to control serum calcium levels (see Fig. 10.11). Epiglottis Hyoid bone Larynx Superior parathyroid gland Thyroid gland Inferior parathyroid gland Trachea Anterior view
Posterior view
FIGURE 10.11
The thyroid and parathyroid glands. The thyroid gland is located on the anterior curve of the trachea. The parathyroid glands are located on the posterior side of the thyroid gland.
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The thyroid gland
The two lobes of the thyroid gland lie on either side of the trachea, inferior to the thyroid cartilage and joined by the isthmus, giving it a ‘butterfly-shaped’ appearance (see Fig. 10.11). The normal thyroid gland is not visible on inspection, but it may be palpated on swallowing, which causes it to be displaced upwards. The internal structure of the thyroid gland is organised into follicles. These contain follicular cells that surround a viscous substance called colloid (see Fig. 10.12). The follicular cells produce and secrete the thyroid hormones. Neurons terminate on blood vessels within the thyroid gland and on the follicular cells themselves, so neurotransmitters may directly affect the secretory activity of follicular cells. THYROID HORMONE
Function of thyroid hormone Thyroid hormone is available in the body as either thyroxine (T4, 90% of thyroid hormone) or triiodothyronine (T3, 10% of thyroid hormone). The thyroid gland produces thyroid hormone using iodide (which is converted to iodine) and thyroglobulin. Either three or four molecules of iodine may be needed for production of thyroid hormones: triiodothyronine (T3) has three iodine molecules and thyroxine (T4) has four. Although most hormone produced by the gland is thyroxine, at the target tissues it becomes converted to triiodothyronine, which acts on the target cell. Thyroid hormone affects most body tissues by increasing the rate of protein, fat and glucose metabolism; this increases the metabolic rate and as a result increases heat production and body temperature. Normal growth requires thyroid hormone, as do the central and autonomic nervous systems1
— normal neural tissue growth and function require thyroid hormone, so it is important across the life span. Thyroid hormone also increases the sympathetic nervous system response by increasing the number of adrenergic receptors present on the surface of cells. In this way, thyroid hormone enhances the sympathetic response. Regulation of thyroid hormone secretion The thyroid gland produces thyroid hormone when stimulated by pituitary thyroid-stimulating hormone (TSH), low serum iodide levels or drugs interfering with the thyroid gland’s uptake of iodide from the blood. Thyrotrophin-releasing hormone levels from the hypothalamus increase in response to increased energy requirements, such as with exposure to cold, stress and pregnancy, as well as when there are decreased levels of thyroxine. Thyrotrophin-releasing hormone promotes the release of thyroid-stimulating hormone from the anterior pituitary. Thyroid-stimulating hormone’s effects include: (1) an immediate increase in the release of stored thyroid hormone; (2) an increase in iodide uptake and conversion to iodine; (3) an increase in thyroid hormone production; and (4) growth of the thyroid gland. Thyroid gland hormones and their regulation and function are summarised in Table 10.3. Thyroid hormone is regulated through a negative-feedback loop involving the hypothalamus, anterior pituitary and thyroid gland. Thyrotrophin-releasing hormone, which is produced and stored within the hypothalamus, initiates this loop. Thyrotrophin-releasing hormone is released into the hypothalamic–pituitary portal system and circulates to the anterior pituitary, where it stimulates the release of thyroid-stimulating hormone (see Fig. 10.13).
Calcitonin
Also found in the thyroid gland are parafollicular or C cells (see Fig. 10.12). C cells secrete various polypeptides, including calcitonin and somatostatin. Calcitonin (also called thyrocalcitonin) lowers serum calcium levels by stimulating calcium uptake from the blood into the bones, as well as by inhibiting bone-resorbing osteoclasts (bone resorption is explained in Chapter 20). Calcitonin and parathyroid hormone together regulate calcium balance (see Fig. 10.14).
Colloid
The parathyroid glands Follicular cell Parafollicular cell (C cell)
Capillary
Normally two pairs of small parathyroid glands are present behind the upper and lower poles of the thyroid gland (see Fig. 10.11). However, their number may range from two to six. PARATHYROID HORMONE
FIGURE 10.12
Thyroid follicle cells. Thyroid follicles consist of a centre of colloid, surrounded by follicular cells, also known as C cells. Between the thyroid follicles are the parafollicular cells.
Function of parathyroid hormone The parathyroid glands produce parathyroid hormone, which is the single most important factor in the regulation of serum calcium. The overall effect of parathyroid hormone secretion is to increase serum calcium and decrease serum
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TABLE 10.3 Regulation and functions of thyroxine (T4) and triiodothyronine (T3) REGULATION
FUNCTIONS
Thyroxine and triiodothyronine levels are controlled by thyroidstimulating hormone
• Released in response to metabolic demand
Influences on amount secreted: Sex Pregnancy Gonadal- and adrenocortical-increased steroids increase levels Exposure to extreme cold increases levels Nutritional state Chemicals Catecholamines (adrenaline and noradrenaline) increase levels
• Regulates protein, fat and carbohydrate usage in all cells • Regulates metabolic rate of all cells • Controls body heat production • Increases blood glucose levels • Maintains growth hormone secretion, skeletal maturation • Affects central nervous system development • Necessary for muscle tone and vigour • Maintains cardiac rate, force and output • Maintains secretions of gastrointestinal tract • Affects respiratory rate and oxygen utilisation • Maintains calcium mobilisation • Affects erythrocyte (red blood cell) production • Stimulates lipid turnover, free fatty acid release and cholesterol production
phosphate. Parathyroid hormone increases calcium levels in the blood by stimulating breakdown of the bone matrix, calcium reabsorption (and a corresponding decrease in phosphate reabsorption) at the kidney and increased intestinal absorption of calcium from food (see Fig. 10.14). Furthermore, parathyroid hormone stimulates the kidneys to activate vitamin D, which further increases intestinal absorption of calcium. Regulation of parathyroid hormone secretion Parathyroid hormone is released in response to low serum calcium. The relationship between serum calcium and serum phosphate means that an increase in serum phosphate decreases serum calcium by causing calcium-phosphate deposition into soft tissue and bone. As this will lower the calcium in the blood, it will stimulate parathyroid hormone secretion. When calcium levels in the blood are adequate, parathyroid hormone secretion is inhibited.
Homeostasis of blood calcium levels
Maintaining homeostasis of calcium in the blood is achieved by a balance between parathyroid hormone and calcitonin. Of these two hormones, parathyroid hormone has the main control (see Fig. 10.14). While you are no doubt aware that calcium is necessary for bones, it is actually essential that neurons can obtain sufficient calcium from the blood in order to function correctly — neurons require calcium for synaptic transmission (see Chapter 6), so insufficient calcium in the blood can be detrimental.
FOCU S ON L EA RN IN G
1 Discuss how the anterior pituitary regulates the thyroid gland. 2 State what form of thyroid hormone is biologically active. 3 Explain the functions of thyroid hormone. 4 Compare and contrast the functions of calcitonin and parathyroid hormone in homeostasis of blood calcium levels.
The pancreas
The pancreas produces hormones that are involved in glycaemic control (control of blood glucose levels) — the main ones being insulin and glucagon. The importance of the pancreas cannot be emphasised strongly enough, as one of the major health crises of our time — diabetes mellitus — is linked to abnormal secretion or function of insulin. The pancreas is located behind the stomach, between the spleen and duodenum. It houses the islets of Langerhans (see Fig. 10.15). The islets of Langerhans have two main types of hormone-secreting cells: alpha cells, which secrete glucagon; and beta cells, which secrete insulin. Other hormones secreted by this organ include somatostatin and pancreatic polypeptide. These hormones regulate most carbohydrate, fat and protein metabolism. Nerves from both the sympathetic and the parasympathetic divisions of the autonomic nervous system innervate the pancreatic islets. (The pancreas also functions as an exocrine gland, producing
Part 2 Alterations to regulation and control
Increased energy requirements, stress sensed by the hypothalamus Hypothalamus releases levels of thyroid thyrotrophin-releasing hormone hormone sufficient for the body’s which needs, hypothalamus causes the no longer secretes Anterior pituitary to thyrotrophin-releasing release thyroidhormone stimulating hormone anterior pituitary no longer secretes causing the thyroid-stimulating hormone Thyroid gland to release thyroid hormone resulting in Thyroid hormone targetting most body cells
negative feedback
CONCEPT MAP
244
leading to Adequate levels of thyroid hormone in the blood
FIGURE 10.13
Secretion of thyroid hormone. In response to a stress response from the hypothalamus, the anterior pituitary releases thyroid-stimulating hormone, which in turn stimulates the thyroid glands to release more thyroid hormone. Thyroid hormone has an effect on most cells of the body.
and secreting pancreatic juice and digestive enzymes into ducts. This is not part of the endocrine system and is discussed in Chapter 26.) INSULIN
Function of insulin The beta (β) cells of the pancreas produce and secrete insulin from peptides (small proteins made of a few amino acids). During the production of insulin, C peptide is released. C peptide can be measured in the blood as an indirect measure of serum insulin production.2 This can be used clinically to assist with determining the function of the pancreatic beta cells, as the presence of C peptide in the blood indicates the active production of insulin. At the target cell, insulin binds with the insulin receptor on the cell surface. When insulin binds to the receptor, it
causes signals within the cell that result in glucose transporters being available in the cell membrane. The glucose transport molecules are stored in the cell cytoplasm and are only inserted into the cell membrane in the presence of insulin. These glucose transport molecules allow glucose to be taken from the blood stream into body cells, thereby lowering blood glucose levels (see Fig. 10.16). After a meal has been digested and the glucose molecules absorbed into the bloodstream, the blood glucose level will rise. The main function of insulin is promoting glucose uptake into body cells, particularly into liver and muscle tissue. In this way, glucose that is not required immediately is taken out of the bloodstream and stored in the form of glycogen (many molecules of glucose attached together). If the blood glucose levels are higher than normal, then hyperglycaemia may result. This can occur when blood glucose levels are in excess of 7 mmol/L3 and may indicate diabetes (refer to Chapter 36). Insulin also causes these tissues to manufacture molecules for storing excess proteins, carbohydrates and lipids. Table 10.4 summarises the actions of insulin. The net effect of insulin in these tissues is to stimulate protein and fat storage and decrease blood glucose. The brain, red blood cells, kidney and lens of the eye do not require insulin for glucose transport. Glucose is able to enter these cells on a continual basis from the bloodstream. Because the brain is dependent on glucose as an energy source, yet does not store any glucose, it must be able to continually obtain adequate glucose from the bloodstream. This is an important reason why glycaemic control is so critical. Regulation of insulin secretion Secretion of insulin is regulated by chemical, hormonal and neural control. The main stimulus for the pancreas to secrete insulin into the bloodstream is hyperglycaemia. Increased levels of amino acids in the bloodstream will also stimulate insulin secretion. Both glucose and amino acids are usually increased in the bloodstream following meals, when those nutrients have been absorbed from the food. Other hormones of the gastrointestinal system can also stimulate the release of insulin — these are gastrin, cholecystokinin and secretin (see Chapter 26). Finally, the parasympathetic nervous system responsible for control of ‘rest and digest’ functions stimulates secretion of insulin, which allows glucose to be taken into cells and stored as part of the body’s restoration process. Insulin secretion diminishes in response to hypoglycaemia (blood glucose levels below 3 mmol/L), when there is no further requirement for insulin to move glucose out of the blood and into cells for storage. Similarly, high levels of insulin switch off further insulin secretion. Finally, the sympathetic nervous system, which mediates the stress response, inhibits secretion of insulin, as adequate or high blood levels of glucose are necessary to facilitate the stress response — this will also occur during exercise, when the sympathetic nervous system is activated, thereby allowing glucose and fatty acids to remain in the blood as fuels for
CHAPTER 10 The structure and function of the endocrine system
C cells of thyroid gland negative feedback, so C cells are no longer stimulated
rising blood calcium
Normal level of calcium in blood = calcium homeostasis dropping blood calcium Parathyroid gland releases parathyroid hormone
which causes the Bones’ uptake of calcium
blood calcium is lowered to normal
blood calcium is raised to normal
CONCEPT MAP
Release of calcitonin
245
negative feedback so no further parathyroid hormone is released
which causes Bone breakdown
Increased intestinal absorption of calcium from food
Kidneys activate vitamin D
Kidneys reabsorb calcium
which enhances
Increasing blood levels of calcium FIGURE 10.14
Calcium homeostasis. In response to rising blood calcium levels, calcitonin is released by the thyroid gland, which promotes deposition of calcium in bone to lower blood calcium to normal levels. On the other hand, in response to a decline in blood calcium levels, a complex series of events is initiated by the release of parathyroid hormone from the parathyroid gland. Parathyroid hormone increases blood calcium through the breakdown of bone, activation of vitamin D and increased absorption of calcium in the digestive tract, and the increased reabsorption of calcium by the kidneys.
working muscles.4 These mechanisms, sympathetic suppression of insulin secretion, are thought to explain the hyperglycaemia observed in acute, critical illness which is a significant clinical challenge. GLUCAGON
Function of glucagon Glucagon is produced by the alpha cells of the pancreas (as well as by cells lining the gastrointestinal tract). Glucagon acts primarily in the liver and increases blood glucose by stimulating the breakdown of the glycogen stores (glycogenolysis), thereby releasing glucose into the bloodstream. It is easy to confuse the words glucagon and glycogen due to their similar spelling — you can remember that glucagon is the hormone, as glucagon ends in the letters
‘on’, also found in the word ‘hormone’. Glucagon can also signal the liver and muscle to use other non-carbohydrate sources (such as amino acids) to make glucose (this process is known as gluconeogenesis, as glucose is produced from a non-glucose source). In addition to increasing blood glucose levels, glucagon also promotes release of fatty molecules to the blood from stores in adipose cells (a process known as lipolysis). Regulation of glucagon secretion The main stimulus for glucagon release by the pancreas is hypoglycaemia, a decline in blood glucose levels. Some amino acids also stimulate glucagon secretion. The sympathetic nervous system stimulates glucagon release to cause an increase in blood glucose levels, which assists in dealing with stressful circumstances.
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Common bile duct
AA A
Accessory pancreatic duct
Body of pancreas Tail of pancreas
Duodenum Lesser duodenal papilla Hepato-pancreatic ampulla Pancreatic duct Greater duodenal papilla Jejunum
Plicae circulares
Head of pancreas
BBA Alpha cells (secrete glucagon)
Beta cells (secrete insulin)
Pancreatic islet Acini cells (secrete enzymes) Vein
Pancreatic duct (to duodenum)
FIGURE 10.15
The pancreas. A Pancreas dissected to show main and accessory ducts. The main duct may join the common bile duct, as shown here, to enter the duodenum by a single opening at the major duodenal papilla, or the two ducts may have separate openings. The accessory pancreatic duct is usually present and has a separate opening into the duodenum. B Exocrine glandular cells (around small pancreatic ducts) and endocrine glandular cells of the pancreatic islets (adjacent to blood capillaries). Exocrine pancreatic cells secrete pancreatic juice, alpha endocrine cells secrete glucagon and beta cells secrete insulin.
Glucagon release is inhibited by high glucose levels, when there is no requirement to further increase blood glucose levels.
Homeostasis of blood glucose levels
In euglycaemia, blood glucose levels are normal. In someone who has been fasting, euglycaemia occurs from 3.0 to 5.4 mmol/L, whereas after eating up to 7.7 mmol/L is still considered normal.5 Insulin and glucagon have opposing effects on blood glucose levels: • insulin lowers blood glucose levels by facilitating glucose uptake and storage in cells • glucagon increases blood glucose levels by releasing glucose into the bloodstream. There is a constant balancing between levels of insulin and glucagon to maintain homeostasis of blood glucose levels. Insulin is the only hormone responsible for lowering blood glucose levels. While glucagon is usually considered
the main hormone for increasing blood glucose levels, other hormones that contribute to this function include adrenaline, cortisol, growth hormone and thyroid hormone (see Table 10.5). Because the brain depends on a constant supply of glucose from the blood, it is necessary to have alternative hormones that can raise blood glucose if necessary. FOCU S ON L EA RN IN G
1 Discuss the functions of insulin. 2 Describe the role of glucagon. 3 Explain the factors involved in homeostasis of blood glucose levels.
The adrenal glands
The adrenal glands are paired, pyramid-shaped organs behind the peritoneum and close to the upper pole of each
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kidney. Each adrenal gland consists of two separate portions: an inner medulla and an outer cortex. These two portions have different structures and hormonal functions. In effect, each adrenal gland functions like two separate glands (see Fig. 10.17). The adrenal cortex, or outer region of the gland, accounts for 80% of the weight of the adult gland. The cortex is subdivided into the following three zones: 1 zona glomerulosa, the outer layer, which constitutes about 15% of the cortex and primarily produces the mineralocorticoid aldosterone 2 zona fasciculata, the middle layer, which constitutes 78% of the cortex and secretes the glucocorticoid cortisol 3 zona reticularis, the inner layer, which constitutes 7% of the cortex and secretes androgens and oestrogens. The adrenal medulla, which accounts for the remaining 20% of the gland’s total weight, secretes the catecholamines adrenaline and noradrenaline. Both sympathetic and parasympathetic cholinergic fibres innervate the adrenal medulla (see Chapter 6 on the neurological system).
The adrenal cortex
The adrenal cortex secretes several steroid hormones, including cortisol (a glucocorticoid), aldosterone (a mineralocorticoid) and the adrenal androgens and oestrogens (gonadocorticoids). These hormones are all produced from
TABLE 10.5 Hormones directly involved in the regulation of blood glucose levels Hormones that decrease blood glucose levels Insulin Hormones that increase blood glucose levels Adrenaline FIGURE 10.16
The effects of insulin on glucose uptake. A Insulin binds to its receptors on the target cells, mainly skeletal muscle and liver cells. B In the presence of insulin, glucose transport molecules become available in the cell membrane. C Glucose is now able to enter the cell through the glucose transport molecules.
Cortisol Glucagon Growth hormone Thyroxine
TABLE 10.4 Insulin actions SITES OF INSULIN ACTION ACTIONS
LIVER CELLS
MUSCLE CELLS
ADIPOSE CELLS
Glucose uptake
Increased
Increased
Increased
Storage of glucose by the production of glycogen (glycogenesis)
Increased
Increased
—
Other
Increased fatty acid production and storage
Increased amino acid uptake and storage
Increased production of triglycerides
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Adrenal gland Kidney Capsule Cortex Medulla
Capsule Zona glomerulosa Zona fasciculata Zona reticularis Medulla
FIGURE 10.17
The structure of the adrenal gland showing cell layers (zonae) of the cortex. Zona glomerulosa secretes aldosterone. Zona fasciculata secretes abundant amounts of glucocorticoids, chiefly cortisol. Zona reticularis secretes minute amounts of sex hormones and glucocorticoids. A portion of the medulla is visible at the bottom of the drawing, although the medulla is associated with the sympathetic nervous system rather than the endocrine system.
cholesterol — although cholesterol can increase the risk of heart disease if too much is present in the blood, it is important that you realise that some cholesterol is essential for the normal structure and function of the body. The cells of the adrenal cortex are stimulated by adrenocorticotrophic hormone from the pituitary gland. CORTISOL
Functions of cortisol The adrenal cortex produces the glucocorticoid cortisol. Cortisol is the main secretory product of the adrenal cortex and it is needed to maintain life and protect the body from stress (see Chapter 34 for a focus on the stress response). Cortisol is a steroid hormone that has metabolic, anti-inflammatory and growth-suppressing effects and influences levels of awareness and sleep patterns. These functions are summarised in Fig. 10.18. In the liver, cortisol acts primarily to stimulate glucose formation — this increase in blood glucose levels assists with the stress response. In extrahepatic tissues (those outside of the liver), cortisol stimulates the breakdown of proteins to assist with glucose production. Cortisol acts at several sites to influence immune and inflammatory reactions. One major immune suppressant effect is the decrease in the proliferation of T lymphocytes, primarily T helper lymphocytes. There is a greater effect on T helper 1 cytokine production (including antiviral interferons) than there is T helper 2 cytokine production and therefore greater depression of cell-mediated immunity than humoral immunity (see Chapter 12). Cortisol also has anti-inflammatory effects related to decreased natural killer cell function, suppression of inflammatory cytokines
and stabilisation of lysosomal membranes, which decreases the release of proteolytic enzymes. Other effects of cortisol include inhibition of bone formation, inhibition of antidiuretic hormone secretion and stimulation of gastric acid secretion. Cortisol appears to potentiate the effects of adrenaline and noradrenaline (catecholamines), thyroid hormone and growth hormone on adipose tissue. A metabolite of cortisol may act like a barbiturate and depress nerve cell function in the brain, accounting for the noted effects on mood associated with steroid fluctuation in disease or stress. Pathologically high levels of cortisol increase circulating erythrocytes (leading to polycythaemia), increase the appetite, promote fat deposition in the face and cervical (neck) areas, increase uric acid excretion, decrease serum calcium levels (possibly by inhibiting gastrointestinal absorption of calcium), suppress the production and secretion of adrenocorticotrophic hormone, and interfere with the action of growth hormone so that growth is inhibited. They also have important ‘permissive’ effects, sensitising arterioles to the vasoconstrictive effects of noradrenaline. Regulation of cortisol secretion Cortisol secretion is regulated primarily by the hypothalamus and anterior pituitary (see Fig. 10.19). Corticotrophin-releasing hormone is produced by the hypothalamus. Once released, it travels through the portal vessels to stimulate the production and secretion of adrenocorticotrophic hormone by the anterior pituitary. Adrenocorticotrophic hormone is the main regulator of cortisol secretion and adrenocortical growth. Once adrenocorticotrophic hormone stimulates the cells of the adrenal cortex, cortisol production and secretion occur immediately. In the healthy person, the secretory patterns of adrenocorticotrophic hormone and cortisol are nearly identical. Adrenocorticotrophic hormone is rapidly inactivated in the circulation, and the liver and kidneys remove the deactivated hormone. Three factors appear to be primarily involved in regulating the secretion of adrenocorticotrophic hormone: 1 High circulating levels of cortisol (and synthetic glucocorticoids) suppress both corticotrophin-releasing hormone and adrenocorticotrophic hormone, whereas low cortisol levels stimulate their secretion (see Fig. 10.19). 2 Stress increases adrenocorticotrophic hormone secretion, leading to increased cortisol levels. (Stress is discussed in Chapter 34.) A form of immunoreactive adrenocorticotrophic hormone is produced by the cells of the immune system and may account, in part, for integration of the immune and endocrine systems. 3 Diurnal rhythms affect adrenocorticotrophic hormone and cortisol levels, with similar patterns seen for both hormones. In people with regular sleep–wake patterns, cortisol has a peak in the morning around the time of waking (see Fig. 10.20). As it has been so many hours since eating, this surge of cortisol is necessary to raise blood glucose levels until breakfast has been eaten.
CHAPTER 10 The structure and function of the endocrine system
Inflammatory and immune
Anti-inflammatory • Decrease numbers of eosinophils • Decrease number of fibroblasts • Decrease inflammatory cytokines (interleukins, bradykinin, serotonin and histamine) • Stimulate anti-inflammatory cytokines (interleukin-10, transforming growth factor beta) • Stabilise lysosomal membranes
Decrease cellular immunity • Decrease T lymphocyte proliferation • Decrease natural killer cell activity • Decrease macrophage activity
Increase blood glucose • Increase hepatic glucose production (gluconeogenesis) • Decrease glucose use in muscle, adipose and lymphatic tissue • Antagonise insulin’s effects
Other • Inhibit bone formation • Inhibit antidiuretic hormone and adrenocorticotrophic hormone secretion • Stimulate gastric acid secretion • Potentiate the effects of catecholamines (adrenaline and noradrenaline), thyroid hormone and growth hormone on adipose tissue • Affect nerve function in the brain (affects mood and sleep)
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Metabolic
Protein metabolism • Stimulate protein breakdown (catabolism) • Decrease protein production
FIGURE 10.18
Major functions of glucocorticoids. Cortisol is the main glucocorticoid. Its main functions can be divided into metabolic (such as increasing blood glucose level and breakdown of protein), inflammatory and immune (such as anti-inflammatory and decreases in some immune functions), and various other functions.
Because cortisol stimulates the breakdown of proteins to increase blood glucose levels, it is critical that breakfast be consumed to prevent unnecessary destruction of protein from muscle and bones. ALDOSTERONE
Functions of aldosterone Aldosterone is the most potent naturally occurring mineralocorticoid. Its target is the kidneys — it causes the kidneys to retain sodium and water in the blood, rather than being lost in the urine. As a result, potassium is excreted from the body in the urine. Aldosterone maintains extracellular volume by acting on the kidney cells to increase sodium reabsorption, and potassium and hydrogen excretion. This renal effect takes 90 minutes to 6 hours. Other effects of aldosterone include
enhancement of cardiac muscle contraction, stiffening of blood vessels and increased vascular resistance. Regulation of aldosterone secretion Aldosterone production and secretion are regulated primarily by the renin-angiotensin-aldosterone system; this is a highly important system in terms of regulation of blood volume, and it is described in detail in the context of its fundamental role in kidney function (described in Chapter 28). Briefly, the renin-angiotensin-aldosterone system is activated by sodium and water depletion, increased potassium and a diminished blood volume (see Fig. 10.21). Angiotensin II is the primary stimulant of aldosterone production and secretion; however, sodium and potassium levels may also directly affect aldosterone secretion. Adrenocorticotrophic hormone may transiently stimulate aldosterone production but does not appear to be a major regulator of secretion.
Part 2 Alterations to regulation and control
Diurnal rhythms
Hypothalamus
Corticotrophin-releasing hormone (CRH)
Stress
Anterior pituitary
Hypoxia Hypoglycaemia Hyperthermia Exercise Cortisol insufficiency
negative feedback
CONCEPT MAP
250
Adrenocorticotrophic hormone (ACTH)
Adrenal cortex
Glucocorticoids (especially cortisol) FIGURE 10.19
Feedback control of glucocorticoid production and secretion. The hypothalamus, hypoxia, exercise and low cortisol stimulate the anterior pituitary to produce and release adrenocorticotrophic hormone. In response, the adrenal cortex releases glucocorticoids, particularly cortisol.
550
Cortisol (mmol/L)
Sleep
Cortisol
440
Awake
330 220 110 0 12 Midnight
4
8
12 Noon Time elapsed (hr)
4
8
12 Midnight
FIGURE 10.20
Rhythm of cortisol. Throughout the 24-hour cycle, cortisol undergoes regular peaks and troughs in its secretion. In particular, note that level of cortisol peaks in the morning around the time of waking up, in order to increase the blood glucose level adequately.
OESTROGENS AND ANDROGENS
The healthy adrenal cortex secretes minimal amounts of oestrogens and androgens. Adrenocorticotrophic hormone appears to be the major regulator. Some of the weakly androgenic substances secreted by the cortex (dehydroepiandrosterone, androstenedione) are converted
by peripheral tissues to stronger androgens, such as testosterone, thus accounting for some androgenic effects initiated by the adrenal cortex. Peripheral conversion of adrenal androgens to oestrogens is enhanced in some cases, including ageing, obesity, liver disease and hyperthyroidism. The biological effects and metabolism of the adrenal sex
CONCEPT MAP
CHAPTER 10 The structure and function of the endocrine system
Corticotrophin-releasing hormone from hypothalamus stimulates Adrenocorticotrophic hormone from anterior pituitary
Hyperkalaemia
Hyponatraemia which stimulates
stimulates
stimulates Renin-angiotensin system stimulates
Aldosterone secretion from adrenal cortex which targets and causes
Retention of sodium
Kidneys
Retention of water
and causes
Excretion of potassium
resulting in Increased blood volume and blood pressure, increased sodium in blood FIGURE 10.21
Secretion of aldosterone. The main stimulus for aldosterone secretion is from the reninangiotensin system (see Chapter 28).
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the other 70% is released from nerve terminals of neurons. The medulla is only a minor source of noradrenaline, as most of this substance is released from neurons too. The adrenal medulla functions to enhance the stress response mediated by the neurons of the sympathetic nervous system. Catecholamines have diverse effects on the entire body. Their release and the body’s response have been characterised as the fight-or-flight response (see Chapter 6). Adrenaline is 10 times more potent than noradrenaline in exerting metabolic effects. The metabolic effects of catecholamines promote hyperglycaemia through a variety of mechanisms including interference with the usual glucose regulatory feedback mechanisms. Regulation of adrenaline and noradrenaline secretion Stimuli to adrenal medullary secretion include sympathetic nerve stimulation, hypoglycaemia (low blood glucose), hypoxia (low tissue oxygen), hypercapnia (high tissue carbon dioxide), acidosis, haemorrhage, glucagon, nicotine, histamine and angiotensin II. In addition, adrenocorticotrophic hormone and cortisol increase adrenal catecholamine secretion.
Neuroendocrine response to stressors
The endocrine system acts together with the nervous and immune systems to respond to stressors. Perception that an event is stressful may be essential to emotional arousal and initiation of the stress response. Some events, such as bacterial invasion, activate the stress response without emotional arousal. The stress response characterised by the sympathetic nervous system is discussed in Chapter 6. As stress is so commonplace in modern-day Australia and New Zealand and it increases the likelihood of developing some chronic diseases, we focus on stress in Chapter 34.
FOCU S ON L EA RN IN G
steroids do not vary from those produced by the gonads (see Chapter 31).
The adrenal medulla
The adrenal medulla is located deep in the adrenal gland and receives inputs from the sympathetic nervous system (the fight-or-flight or stress response). It mainly produces adrenaline and noradrenaline, which are secreted to enhance the actions of the sympathetic nervous system. ADRENALINE AND NORADRENALINE
Function of adrenaline and noradrenaline The adrenal medulla works together with the sympathetic division of the autonomic nervous system. The major hormones secreted by the adrenal medulla are the catecholamines adrenaline and noradrenaline, which are produced from the amino acid phenylalanine. Only 30% of circulating adrenaline comes from the adrenal medulla;
1 Briefly describe the anatomical arrangement within the adrenal gland. 2 Describe the main functions of cortisol. 3 Discuss how aldosterone influences fluid and electrolyte balance. 4 Explain the secretion of adrenaline and noradrenaline from the adrenal medulla.
The pineal gland
The pineal gland secretes melatonin, which is an important hormone in the regulation of circadian rhythm, whereby fluctuations in body function and hormone levels occur around a 24-hour cycle. As such, it is a regulator of the sleep–wake system (sleep is discussed in Chapter 6). Peak levels of melatonin occur during night-time, as they induce drowsiness.
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The thymus gland
The thymus gland is located within the thoracic cavity near the chest. This gland has a role in the normal development of T lymphocytes as part of the immune system (see Chapter 12). The thymus gland is most active in childhood when the immune system is undergoing extensive development.
The testes and ovaries
The testes (in males) and ovaries (in females) secrete hormones that have specific roles in the reproductive system. These are discussed in Chapter 31.
Ageing and the endocrine system involved in many functions), which leads to decreased production of androgen-derived oestrogen and testosterone, decreased metabolic clearance of cortisol, decreased cortisol secretion and decreased levels of aldosterone. After menopause, women have decreased levels of oestrogen and progesterone, increased levels of folliclestimulating hormone and relative increases in androgen levels; these changes have numerous physiological and pathophysiological consequences (see Chapter 32); in men, there is a gradual decrease in serum testosterone levels leading to decreased sexual activity, decreased muscle strength and decreased bone mineralisation. In the posterior pituitary, a decrease in size is seen, accompanied by reduced antidiuretic hormone secretion. In the anterior pituitary, there is increased fibrosis and a moderate increase in the size of the gland, as well as a decline in growth hormone release.
chapter SUMMARY Mechanisms of hormonal regulation • The endocrine system has diverse functions, including sexual differentiation, growth and development, and continuous maintenance of the body’s internal environment. • Hormones are chemical messengers produced by endocrine glands and released into the circulation. • Most hormone levels are regulated by negative feedback, in which hormone secretion raises the level of a specific hormone, ultimately causing secretion to subside. • Hormones affect only target cells with appropriate receptors and then act on these cells to initiate specific cell functions or activities. • Receptors for hormones may be located on the cell membrane or in the intracellular compartment of a target cell.
• Protein-based hormones act as first messengers, binding to receptors on the cell membrane. The signals initiated by hormone-receptor binding are then transmitted into the cell by the action of second messengers. • Steroid-based hormones cross the cell membrane by diffusion. These hormones diffuse directly into the cell nucleus and bind to nuclear receptors. Rapid responses of steroid hormones may be mediated by cell membrane receptors.
The structure and function of the endocrine glands • The hypothalamus is an endocrine gland that exerts control over the hormone production of most of the other endocrine glands of the body. It controls their function by releasing hormones into the blood, which bind with receptors on the target gland cells.
AGEING
In general, with ageing there is atrophy (shrinkage) of endocrine organs, which can result in decreased secretion of hormones. In addition, there is often decreased clearance or removal of hormones by the liver. Pancreatic alterations with ageing include the development of glucose intolerance or diabetes (refer to Chapter 36). The thyroid gland is prone to fibrosis and infiltration by inflammatory processes, which disrupts thyroid function. Possible changes in thyroid hormone are difficult to determine because of concurrent disease in the elderly: there may be decreased thyroxine secretion and turnover, a decline in triiodothyronine (especially in men), diminished thyroid-stimulating hormone secretion and reduced response of plasma thyroid-stimulating hormone concentration to thyroid-releasing hormone administration (especially in men). The declining function of the adrenal glands leads to decreased levels of dehydroepiandrosterone (a steroid
CHAPTER 10 The structure and function of the endocrine system
• The pituitary gland, consisting of anterior and posterior portions, is connected to the central nervous system through the hypothalamus. • The hypothalamus regulates anterior pituitary function by secreting hormones into the hypophyseal portal circulation, a network of blood vessels. • Hormones of the anterior pituitary are mainly regulated by secretion of hypothalamic-releasing hormones or by negative feedback from hormones secreted by target organs. • The hormones of the anterior pituitary are adrenocorticotrophic hormone, growth hormone, prolactin, follicle-stimulating hormone, luteinising hormone and thyroid-stimulating hormone. • Growth hormone is secreted by the anterior pituitary for growth during childhood and adolescence and normally fluctuates throughout the day. • The posterior pituitary is connected to the hypothalamus through neurons, whose cell bodies are in the hypothalamus and axons extend into the posterior pituitary. Hormones are manufactured in the hypothalamus, travel down the axon and are released from the posterior pituitary. • Hormones released from the posterior pituitary are antidiuretic hormone and oxytocin. • Antidiuretic hormone controls serum osmolality (total concentration of solutes in the plasma), increases permeability of the renal tubules to water and thereby causes water to be retained in the body by the kidneys rather than lost through urine. • The thyroid gland contains follicles that secrete the thyroid hormones thyroxine (T4) and triiodothyronine (T3). It also contains C cells, which secrete calcitonin. • Thyroid hormone secretion is regulated by thyroidreleasing hormone through a negative-feedback loop that involves the anterior pituitary and hypothalamus. • Thyroid-stimulating hormone, which is produced and stored in the anterior pituitary, stimulates secretion of thyroid hormone by activating intracellular processes, including uptake of iodine necessary to make thyroid hormone. • Thyroid hormones alter protein production (or synthesis) at target cells and have a wide range of metabolic effects on proteins, carbohydrates, lipids and vitamins. Thyroid hormone also affects heat production and cardiac function. • Calcitonin stimulates calcium uptake from the blood into the bones, thereby lowering blood calcium levels. • The paired parathyroid glands are normally located behind the upper and lower poles of the thyroid. These glands secrete parathyroid hormone, an important regulator of serum calcium levels. • In bone, parathyroid hormone causes bone breakdown and resorption. In the kidneys, parathyroid hormone increases reabsorption of calcium, so that less is lost from the body in urine.
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• The pancreas contains islets of Langerhans, which secrete hormones responsible for controlling blood glucose levels. • Beta cells of the pancreas secrete insulin, which is critical for lowering blood glucose concentrations and also has a role in overall body metabolism of fat, protein and carbohydrates. • Pancreatic alpha cells produce glucagon, which is secreted when blood glucose concentrations are low. • Insulin and glucagon work together to maintain homeostasis of blood glucose levels, known as euglycaemia. • The paired adrenal glands are situated superior to (above) the kidneys. Each gland consists of an adrenal medulla, which secretes catecholamines, and an adrenal cortex, which secretes steroid hormones. • The steroid hormones secreted by the adrenal cortex are produced from cholesterol. These hormones include cortisol, aldosterone and adrenal androgens and oestrogens. • Cortisol directly affects carbohydrate metabolism by increasing blood glucose concentration through causing the liver to release glucose into the blood. Cortisol also inhibits immune and inflammatory responses. • Cortisol is necessary for the maintenance of life and for protection from stress. • Secretion of cortisol is regulated by corticotrophinreleasing hormone from the hypothalamus and adrenocorticotrophic hormone from the anterior pituitary. Cortisol levels fluctuate throughout the day. • Aldosterone is a steroid hormone that directly affects the kidneys, where it causes sodium reabsorption into the blood and potassium and hydrogen excretion with urine. • Aldosterone secretion is regulated primarily by the reninangiotensin system and serum sodium concentration. • Androgens and oestrogens secreted by the adrenal cortex act in the same way as those secreted by the gonads. Most of these hormones are secreted by the gonads. • The adrenal medulla secretes the catecholamines adrenaline and noradrenaline. Adrenaline is 10 times more potent than noradrenaline in exerting metabolic effects. Their release is stimulated by sympathetic nervous system stimulation and cortisol. • Catecholamines cause a range of metabolic effects characterised as the fight-or-flight response and include hyperglycaemia and immune suppression. • The response to stressors involves (a) activation of the sympathetic division of the autonomic nervous system and (b) activation of the endocrine system.
Ageing and the endocrine system • The general changes in the endocrine glands that occur with older age include atrophy and weight loss with vascular changes, decreased secretion and metabolism of hormones, and changes in receptor binding and intracellular responses.
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CASE STUDY
AD ULT Gemma is a 23-year-old female who does not consume very much dairy food, as she is watching her weight and thinks that dairy products are high in fat. Although she occasionally eats canned salmon, she does not like eating the bones. Overall, her total daily intake of food is rather low. 1 Discuss how parathyroid hormone effects blood calcium levels. 2 Discuss how calcitonin effects blood calcium levels.
3
Describe what Gemma’s levels of parathyroid hormone and calcitonin in the blood would be like. 4 Explain why homeostasis of the blood calcium level is important. (Hint: what is the most important reason that you need calcium in the blood?) 5 If Gemma were to develop a disease that required the total removal of the thyroid gland, how would this influence her blood calcium levels?
CASE STUDY
AG EING William is a 69-year-old who has recently been feeling nauseated in the mornings. He is not sure if he is eating too much dinner, or not enough. Many days, he does not eat anything until late in the morning, or has lunch as his first meal of the day. Despite these changes, William does still sleep his normal pattern most of the time, with regular nighttime sleeping of approximately 7–8 hours. 1 Explain the general effects of cortisol on the liver. 2 Explain the general effects of cortisol on the immune system.
3
Describe the factors which are involved in the regulation of cortisol secretion. 4 Draw a graph which shows how William’s cortisol levels would fluctuate through the 24-hour cycle. 5 Describe the effects of the high peak of cortisol levels. Discuss why it is important for William to eat breakfast, in relation to his cortisol levels.
REVIEW QUESTIONS 1 Compare and contrast the mechanisms of action for the protein-based and steroid-based hormones. 2 Describe the relationship between the hypothalamus and (a) the anterior pituitary and (b) the posterior pituitary. 3 Discuss the effects of antidiuretic hormone and the factors involved in regulation of its secretion. 4 Explain the range of effects of thyroid hormone throughout the body. 5 Discuss the roles of calcitonin and parathyroid hormone.
6 Discuss the importance of insulin in the regulation of blood glucose levels. 7 Explain the function of cortisol. 8 Describe the factors involved in the regulation of aldosterone secretion. 9 Explain the functions of adrenaline and noradrenaline. 10 Briefly describe how the endocrine system and nervous system work together in response to stress.
Key terms acute thyroiditis, 270 autoimmune thyroiditis, 270 Cushing’s syndrome, 261 diabetes insipidus, 257 diabetes mellitus, 264 gestational diabetes mellitus, 266 glycosuria, 265 goitre, 267 Graves’ disease, 267 hyperaldosteronism, 259 hypercalcaemia, 274 hypercortisolism, 260 hyperparathyroidism, 272 hyperthyroidism, 266 hypocalcaemia, 275 hypoparathyroidism, 274 hypothyroidism, 270 myxoedema, 270 painless thyroiditis, 270 postpartum thyroiditis, 270 primary hyperaldosteronism, 259 primary hyperparathyroidism, 272 secondary hyperaldosteronism, 259 secondary hyperparathyroidism, 272 subacute thyroiditis, 270 syndrome of inappropriate antidiuretic hormone secretion (SIADH), 257 thyrotoxic crisis, 269 thyrotoxicosis, 266 toxic adenoma, 268 type 1 diabetes mellitus, 264
CHAPTER
Alterations of endocrine function across the life span
11
Sarah List Chapter outline Introduction, 256 Mechanisms of hormonal alterations, 256 Alterations of pituitary function, 257 Syndrome of inappropriate antidiuretic hormone secretion, 257 Diabetes insipidus, 257 Alterations of adrenal function, 259 Hyperaldosteronism, 259 Hypercortisolism, 260 Hypoadrenalism, 262
Alterations of pancreatic function, 264 Type 1 diabetes mellitus, 264 Diabetes in pregnancy, 266 Alterations of thyroid function, 266 Hyperthyroidism, 266 Hypothyroidism, 270 Alterations of parathyroid function, 272 Hyperparathyroidism, 272 Hypoparathyroidism, 274
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Part 2 Alterations to regulation and control
Introduction The function of the endocrine system involves complex interrelationships and interactions that maintain homeostasis and provide growth and reproductive capabilities. Dysfunction is usually described in terms of excessive or insufficient function of the endocrine gland with alterations in hormone levels. These alterations are caused by either hypersecretion or hyposecretion of the various hormones, leading to abnormal hormone concentrations in the blood. Most hormones have syndromes or disorders resulting from either too much or too little hormone. However, some of these are quite rare — for example, increased secretions of growth hormone affect about 1500 Australians1 and growth hormone deficiency impacts on a similar number across the child and adult population in Australia.2 In this chapter, we focus on those disorders that have greatest relevance to contemporary Australia and New Zealand. We start by exploring hormone abnormalities that influence
fluid and sodium balance, which is of prime focus within healthcare facilities. Then we briefly look at Cushing’s syndrome, which people taking cortisol medications are at risk of developing. Next we introduce diabetes mellitus, and finally we look at disorders relating to the thyroid gland, which are reasonably common.
Mechanisms of hormonal alterations Significantly elevated or significantly depressed hormone levels may result from various causes (see Fig. 11.1). Feedback systems that recognise the need for a particular hormone may fail to function properly or may respond to inappropriate signals. Dysfunction of an endocrine gland may involve its failure to produce adequate amounts of hormone, or a gland may produce and release too much hormone. Once hormones are released into the circulation,
CONCEPT MAP
Is appropriate amount of biologically active hormone being delivered to target cell? No
Yes
Is appropriate need recognised? Yes
No
Is secretory cell producing biologically active hormone? No Pathogenic mechanism No
Yes
Yes No
Is delivery system functioning? Yes Is hormone metabolism appropriate? Yes Is hormone being ectopically produced? No Target cell is receiving appropriate amount of hormone
Is another substance mimicking action of hormone? No Is hormone-receptor binding abnormal? No Is initiation of intracellular events (e.g. generation of second messenger) lacking? No Is cell response to events lacking? No Target cell is responding appropriately to hormone
FIGURE 11.1
Hormone delivery to the cells. Phases at which pathogenic mechanisms may develop in delivering appropriate amounts of hormone to the cells.
Yes
Yes Pathogenic mechanism Yes
Yes
CHAPTER 11 Alterations of endocrine function across the life span
they may be degraded at an altered rate or inactivated by antibodies before reaching the target cell. Hormones produced by non-endocrine tissues may cause abnormally elevated hormone levels; an example of this is a type of lung tumour that can secrete antidiuretic hormone. This mechanism operates without the benefit of the normal feedback system for hormone control and is an example of ectopic hormone production whereby it is produced from a part of the body in which it is not normally made. An additional mechanism of endocrine alteration may result from abnormal receptor function or from altered intracellular response to the hormone at the target cell.
Alterations of pituitary function Syndrome of inappropriate antidiuretic hormone secretion
Diseases of the posterior pituitary are rare and are usually related to abnormal antidiuretic hormone secretion. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterised by high levels of antidiuretic hormone without the normal physiological stimuli for its release.3 The most common cause is ectopic production, which is associated with cancer, wherein tumour cells secrete antidiuretic hormone. Tumours associated with SIADH include small cell carcinoma of the lung (the most common cause).4 Postoperative patients can have fluid volume shifts that result in increased antidiuretic hormone secretion for as long as 5–7 days after surgery. SIADH is seen also in individuals with infectious pulmonary diseases, where antidiuretic hormone is produced by infected lung tissue or posterior pituitary secretion is increased in response to a hypoxia-induced decrease in pulmonary perfusion. PATHOPHYSIOLOGY
The cardinal features of SIADH are symptoms of water intoxication resulting from enhanced renal water retention or increases in total body water, which leads to hyponatraemia (low serum sodium), and urine that is inappropriately concentrated with respect to the serum osmolality. Hyponatraemia is induced due to a relative increase in water without similar increases in sodium concentration. In this syndrome, antidiuretic hormone is released continually. Water retention results from the normal action of antidiuretic hormone on the renal tubules and collecting ducts, increasing their permeability to water and increasing water reabsorption by the kidneys (see Chapter 28). Due to the retention of water, the extracellular fluid volume expands and a dilutional hyponatraemia develops; this means that sodium is diluted in more fluid. In Chapter 6, we examined the role of normal concentrations of sodium and potassium in the normal signalling of neurons. Hyponatraemia can lead to alterations of neural signals, which can have widespread effects
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throughout the body. It is important to remember that blood concentrations of various substances such as sodium can have powerful effects on body systems. CLINICAL MANIFESTATIONS
A diagnosis of SIADH requires the following signs: (1) low total concentration of solute in the serum (low serum osmolality) and hyponatraemia; (2) urine hyperosmolality (that is, urine osmolality is greater than expected for the serum osmolality); (3) urine sodium excretion that matches sodium intake; (4) normal adrenal and thyroid function; and (5) absence of conditions that can alter fluid volume status (e.g. congestive heart failure, hypovolaemia from any cause, or renal insufficiency). The symptoms of this syndrome result from hyponatraemia and are determined by its severity and rate of onset. Fig. 11.2 contrasts the range of signs and symptoms and treatment strategies of an acute onset hyponatraemia compared to that of chronic hyponatraemia. Since hospitalised elderly patients are at particular risk, the incidence may increase as a result of our ageing population. EVALUATION AND TREATMENT
Serum electrolyte levels, serum osmolality, urine volume, urine electrolyte levels and urine osmolality are adequate measures of the presence of SIADH. A chest x-ray is necessary to assist with diagnosis to rule out respiratory conditions. The treatment principles of this syndrome are shown in Fig. 11.2. Resolution usually occurs within 3 days, with a 2–3 kg weight loss and correction of hyponatraemia and sodium loss. Excessive rate of correction of hyponatraemia risks the development of the catastrophic neurologic condition known as osmotic demyelination which can be fatal. Although there are some pharmacological treatments, these are not first-line therapy. Vasopressin receptor antagonists (e.g. tolvaptan) are newer agents that prevent the reabsorption of free water back into the circulation.3
Diabetes insipidus
Diabetes insipidus is related to an insufficiency of antidiuretic hormone, leading to polyuria and polydipsia. It is actually quite rare, affecting approximately 6 in 100 000 people. Note that this is a different condition to the more common diabetes mellitus (usually referred to simply as diabetes), which is increasing in incidence in Australia and New Zealand (refer to the later section on alterations of pancreatic function). The term diabetes means ‘overflow’, or an increased urine volume. The two forms of diabetes insipidus are as follows (see Fig. 11.3): 1 Neurogenic form. Caused by the absence of antidiuretic hormone. This occurs with damage or inflammation to the hypothalamus, pituitary stalk or posterior pituitary, such as brain tumours, aneurysm or following pituitary surgery. This interferes with antidiuretic hormone production, transport or release.
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Signs and symptoms Rapid onset Thirst Impaired taste Anorexia Dyspnoea on exertion Fatigue Dulled sensorium (ability to interpret sensory inputs)
Severe gastrointestinal symptoms • vomiting • abdominal cramps
Confusion Lethargy Muscle twitching Seizures Severe sometimes irreversible neurological damage may occur
requires
Rapid correction Serum Na+ mmol/L
145
142
139 Normal reference range
136
133
130
127
124
121
118
115
Treatment principles • 3% hypertonic NaCl • Increase serum Na+ by no more than – 8–10 mmol/L in first 24 hrs – 18 mmol/L in 48 hrs • Accurate assessment and monitoring of weight and fluid balance • Identify cause and manage
112
Slow correction Can be nonspecific Lethargy and very well tolerated Muscle twitching Confusion Seizure can occur
requires
Slow onset
Treatment principles • Fluid restriction 0.5–1 L/day • Accurate assessment and monitoring of weight and fluid balance • Medications not first line therapy
FIGURE 11.2
Clinical features and management of hyponatraemia. The upper panel shows the progression of numerous clinical features at decreasing levels of sodium, and the management of this acute condition. The lower panel shows the clinical features of chronic hyponatraemia, and illustrates that these do not usually become apparent until substantial declines in serum sodium levels.
2
Nephrogenic form. Caused by inadequate response of the renal tubules to antidiuretic hormone. This occurs with diseases that irreversibly damage the renal tubules, such as pyelonephritis; can occur due to drugs, particularly lithium (up to 40%) and also methoxyflurane anaesthesia. These generally are reversible, but can occasionally be permanent.5
Dehydration develops rapidly without ongoing fluid replacement. CLINICAL MANIFESTATIONS
PATHOPHYSIOLOGY
The clinical manifestations of diabetes insipidus include polyuria, nocturia, continuous thirst, polydipsia, low urine specific gravity, low urine osmolality5 and high–normal plasma osmolality. Plasma osmolality is always higher than urine osmolality after a supervised water deprivation test. However, as there can also be an increasing hypernatraemia, it is critical that a water deprivation test only be performed under direct clinical supervision.
Diabetes insipidus usually has an acute onset. Individuals with diabetes insipidus have a partial or total inability to concentrate urine. Insufficient antidiuretic hormone secretion causes polyuria (excretion of large volumes of dilute urine), leading to increased plasma osmolality. In conscious individuals, the thirst mechanism is stimulated and induces polydipsia (increased thirst, and usually with a craving for cold drinks). The urine output varies and may be more than 12 L/day, with a low specific gravity.
The diagnosis of diabetes insipidus is generally established by correlating the clinical presentation with serum and urine osmolality and serum sodium. Plasma antidiuretic hormone levels may be measured following several hours of deprivation; however it is generally only helpful in identifying the nephrogenic form, as it would be present in high levels. The diagnosis of neurogenic diabetes insipidus is
There is also a psychogenic form, caused by chronic ingestion of extremely large quantities of fluid. It resolves with effective management of fluid intake.
EVALUATION AND TREATMENT
CHAPTER 11 Alterations of endocrine function across the life span
Hypothalamus
NEURO-
1 GENIC
DIABETES INSIPIDUS • Tumours Stalk • Trauma • Surgery Posterior pituitary gland
Neuronal axons Anterior pituitary gland
ADH deficiency
2 KIDNEY Loss of water
Alterations of adrenal function Disorders of the adrenal cortex are most commonly related to hyperfunction. Hyperfunction that causes increased levels of aldosterone leads to hyperaldosteronism, and that which causes hypercortisolism leads to Cushing’s syndrome.
Hyperaldosteronism
NEPHROGENIC DIABETES INSIPIDUS • Renal diseases • ADH-unresponsive kidney • Drugs (lithium)
Polyuria
259
Polydipsia Dehydration
FIGURE 11.3
Diabetes insipidus. The origin of diabetes insipidus, consisting of excess water intake and output, can be neurogenic 1 or nephrogenic 2.
made when, following water deprivation, administration of a drug that mimics the antidiuretic hormone, desmopressin, causes an increase in urinary osmolality. In psychogenic polydipsia the serum osmolality and sodium remain normal but urine osmolality will rise during water deprivation. Treatment of neurogenic diabetes insipidus is based on the aetiology and degree of symptoms experienced by the patient; intravenous fluid resuscitation may be required initially to match urine output. Ongoing therapy will depend on the patient’s age, endocrine and cardiovascular status, and lifestyle. An intact thirst mechanism will generally ensure adequate oral hydration; however, a disturbed sleep is very difficult for most to tolerate, particularly for those with an output > 5 litres/daily. Long-term treatment requires the administration of desmopressin, which acts on the collecting tubules of the kidney to increase water retention. It is important to remember that an adult with an intact thirst mechanism will usually be able to drink sufficiently to maintain an adequate fluid intake. The treatment of nephrogenic diabetes insipidus is more difficult, with maintaining adequate fluid intake being the main form of therapy.5
F O CUS O N L E A R N IN G
1 Describe the effects of SIADH on the kidneys. 2 Discuss how fluid balance is altered with diabetes insipidus.
Hyperaldosteronism is characterised by excessive aldosterone secretion by the adrenal glands. In primary hyperaldosteronism there is an excessive secretion of aldosterone from the adrenal cortex. In secondary hyperaldosteronism, excessive aldosterone secretion results from an extra-adrenal stimulus, most often a renin-angiotensin mechanism. Primary hyperaldosteronism (also known as Conn’s syndrome) presents with hypertension that is difficult to control, even with multiple antihypertensive medications. There can be renal potassium wasting, hypokalaemia and neuromuscular manifestations; however, it is most commonly found in the presence of normokalaemia.6 The most common cause of primary hyperaldosteronism is a benign adrenal adenoma. The incidence of primary hyperaldosteronism is estimated to be 2–10% of all hypertensive individuals.6 This condition therefore is of particular interest in those with hypertension, for which there is a high incidence in Australia and New Zealand6 (hypertension is discussed in detail in Chapter 23). Aldosterone secretion is normally stimulated by the renin-angiotensin-aldosterone system (see Chapter 28); secondary hyperaldosteronism results from sustained elevated renin release and activation of angiotensin II. This occurs in various situations, including decreased circulating blood volume (e.g. in dehydration, shock or hypoalbuminaemia) and decreased delivery of blood to the kidneys (e.g. heart failure or hepatic cirrhosis). Here, the activation of the renin-angiotensin system and subsequent aldosterone secretion may be seen as compensatory, although in some instances (e.g. congestive heart failure) the increased circulating volume further worsens the condition. PATHOPHYSIOLOGY
In primary hyperaldosteronism, pathophysiological alterations are caused by excessive aldosterone secretion and the fluid and electrolyte imbalances that ensue. Hyperaldosteronism promotes: (1) increased renal sodium and water reabsorption with corresponding hypervolaemia (high blood volume, see Chapter 29) and hypertension; and (2) renal excretion of potassium. The extracellular fluid volume overload, hypertension and suppression of normal feedback mechanisms of renin secretion are characteristic of primary disorders. Oedema usually does not occur with primary hyperaldosteronism. In secondary hyperaldosteronism, the effect of increased extracellular volume on renin secretion may vary. If renin secretion is abnormal, increased circulating blood volume
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may not decrease renin secretion through feedback mechanisms. Potassium secretion is promoted by aldosterone, so that with excessive aldosterone, hypokalaemia can occur (see Chapter 29). Hypokalaemic alkalosis, changes in myocardial conduction and skeletal muscle alterations may be seen, particularly with severe potassium depletion (refer to Chapter 6 for the role of potassium in neuron signalling and muscle contraction). The renal tubules may become insensitive to antidiuretic hormone, thus promoting excessive loss of water. In this situation, hypernatraemia may also occur because water is not able to follow the sodium that is reabsorbed. CLINICAL MANIFESTATIONS
CONCEPT MAP
Primary aldosteronism (also known as Conn’s syndrome) causes sodium retention, hypertension, and increased potassium excretion (see Fig. 11.4). Historically for a diagnosis of Conn’s syndrome, the two signs hypertension
Renin leads to production of K+ (in plasma)
Tumour
Angiotensin II cause secretion of
Aldosterone sets on Kidney increased
increased
Na+ retention
Water retention
increased K+ excretion
Increased blood volume lead to Hypertension
FIGURE 11.4
Pathogenesis of aldosterone-induced hypertension. Aldosterone causes the kidneys to retain sodium, and as a result, water is also retained. Overall, this increases the blood volume, which in term increases blood pressure. Aldosterone also causes the kidneys to excrete potassium, and low potassium can cause vasoconstriction, further increasing blood pressure. ECF = extracellular fluid; K+ = potassium; Na+ = sodium.
and hypokalaemia were essential; however, recent evidence suggests that > 60% of cases have normokalaemia.6 Where hypokalaemia has occurred particularly at levels < 2.5 mmol/L muscle weakness, cramping and headache may develop. Hypokalaemic metabolic alkalosis may also occur (see Chapter 29).With sustained hypertension, the chronic effects of elevated arterial pressure become evident; for example, left ventricular dilation and hypertrophy and progressive atherosclerosis, contributing to higher rates of morbidity and mortality in this group.6 EVALUATION AND TREATMENT
Like many endocrine disorders Conn’s syndrome requires a stepwise approach to the diagnostic process. Clinical and laboratory measurements should be performed to assist with management: 1 Elevated blood pressure. 2 Serum potassium may be normal or low, but urinary potassium is elevated. 3 Plasma aldosterone-to-renin ratio (ARR) is regarded as the most reliable screening tool. However it should be collected as per the local laboratory protocol and repeated at least once before proceeding to more complex testing. An inappropriately raised ARR indicates a need for further assessment. Several classes of antihypertensives can affect ARR. A temporary change of medication may be required over the several weeks of diagnostic work-up. 4 Elevated plasma aldosterone can be determined using aldosterone suppression testing. For example, in the saline load test, 2 litres of saline is given intravenously over 4 hours; plasma aldosterone and renin activity are measured before and after the saline administration. If plasma aldosterone production does not decrease < 138 pmol/L and renin secretion remains undetectable, this supports a diagnosis of primary hyperaldosteronism.6 5 A CT scan is the most appropriate imaging technique to visualise the adrenal glands.6 6 Adrenal vein sampling may then be used to identify whether there is excessive aldosterone production unilaterally or bilaterally.6 Treatment includes management of hypertension and hypokalaemia, as well as correction of any underlying causes. A unilateral oversecretion that matches the site of the adenoma is likely to be treated with surgery. If both adrenal glands are found to be secreting high levels of aldosterone, that is, bilateral oversecretion, medical therapy with a mineralocorticoid receptor agonist such as spironolactone would be the first-line treatment.6 Bilateral adrenalectomy would only be done as a last resort given the significant increased morbidity and mortality associated with primary adrenal insufficiency (see ‘Hypoadrenalism’ below).
Hypercortisolism
Hypercortisolism means excessive levels of serum cortisol. When chronic, it leads to the constellation of
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Causes of Cushing’s syndrome
Glucocorticoid therapy e.g. prednisone, dexamethasone inhaled and topical steroids
Exogenous (external to the body)
Excess pituitary ACTH
Excess non-pituitary ACTH e.g. lung tumour
Stimulates excess adrenal cortisol
Stimulates excess adrenal cortisol
This is known as Cushing’s disease
Adrenal adenoma produces excess cortisol
Endogenous (within the body)
FIGURE 11.5
Causes of Cushing’s syndrome. Cushing’s syndrome may arise from causes originating external to the body (medications), or from dysfunction within the body.
signs and symptoms known as Cushing’s syndrome. The most common cause is iatrogenic, that is, it is due to the pharmacological administration of glucocorticoids.7 This may also be referred to as an exogenous cause — arising from outside of the body (see Fig. 11.5). Cushing’s syndrome not due to pharmacological use of glucocorticoids may be referred to as an endogenous form, and is an uncommon disorder affecting only 1 in 50 000 people.7,8 It is more common in adults and is two to three times more common in women than in men. Hypercortisolism can occur at any age, but usually occurs between the ages of 30 and 50 years. If the condition is left untreated, 50% of patients will die within 5 years of onset due to overwhelming infection, suicide and cardiovascular complications. In older adults, it usually results from ectopic adrenocorticotrophic hormone secretion, whereas in children it is usually the result of adrenal tumours. Cushing’s disease occurs when the specific cause of hypercortisolism is the result of excess production of adrenocorticotrophic hormone (ACTH) from the pituitary. This leads to excess stimulation of the adrenal cortex to produce cortisol, and it accounts for approximately 70–85% of cases of Cushing’s syndrome.8 PATHOPHYSIOLOGY
Individuals with endogenous Cushing’s syndrome do not have diurnal or circadian secretion patterns of adrenocorticotrophic hormone and cortisol, and do not
increase secretion of these hormones in response to a stressor.9 When the secretion of cortisol exceeds normal cortisol levels, symptoms of hypercortisolism develop. CLINICAL MANIFESTATIONS
Weight gain is the most common feature and results from the accumulation of adipose tissue in the trunk, facial and cervical areas. These characteristic patterns of fat deposition have been described as ‘truncal obesity’, ‘moon face’ and ‘buffalo hump’ (see Figs 11.6 and 11.7). Transient weight gain from sodium and water retention also may be present. Glucose intolerance occurs because of cortisol-induced insulin resistance and overt diabetes mellitus develops in approximately 20% of individuals with hypercortisolism (see Chapter 36). Polyuria is a manifestation of hyperglycaemia and resultant glycosuria. Protein wasting is caused by the catabolic (breaking-down) effects of cortisol on peripheral tissues. Muscle wasting leads to muscle weakness. In bone, loss of the protein matrix leads to osteoporosis, with pathological fractures, vertebral compression fractures, bone and back pain, kyphosis and reduced height. Cortisol interferes with the action of growth hormone in long bones — children who present with short stature may be experiencing growth retardation related to Cushing’s syndrome rather than growth hormone deficiency. Bone disease may contribute to hypercalciuria and resulting renal stones, which are experienced by approximately 20% of individuals with disease. Loss of collagen also leads to
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Thinning of scalp hair Facial flush Moon face Purple striae
Pendulous abdomen
Easy bruising
Acne Increased body and facial hair
A A A
Supraclavicular fat pad Hyperpigmentation Trunk obesity
Thin extremities
B
FIGURE 11.6
Symptoms of Cushing’s syndrome. Main symptoms include moon face, truncal obesity, and thin extremities.
thin, weakened integumentary tissues, through which capillaries are more visible and which are easily stretched by adipose deposits. Together, these changes account for the characteristic purple striae in the trunk area. Loss of collagenous support around small vessels makes them susceptible to rupture, leading to easy bruising, even with minor trauma. Thin, atrophied skin is also easily damaged, leading to skin breaks and ulcerations. When the Cushing’s syndrome is the result of excess adrenocorticotrophic hormone production, hyperpigmentation can occur, involving the mucous membranes, hair and skin, all of which acquire a characteristic brownish or bronze colour. With elevated cortisol levels, vascular sensitivity to catecholamines (adrenaline and noradrenaline) increases significantly, leading to vasoconstriction and hypertension. High circulating cortisol can increase the activation of the mineralocorticoid (aldosterone) receptors. This is because of structural similarities between the glucocorticoid and mineralocorticoid receptors. This promotes sodium retention and hypokalaemia. Elevated blood pressure occurs in most individuals, and suppression of the immune system and increased susceptibility to infections also occurs.
FIGURE 11.7
Cushing’s syndrome. A Patient before onset of Cushing’s syndrome. B Patient 4 months later: ‘moon face’ is clearly demonstrated.
EVALUATION AND TREATMENT
The diagnosis of Cushing’s syndrome is challenging and various laboratory tests must be used, including 24-hour urinary cortisol excretion, salivary cortisol levels and dexamethasone (a cortisol drug) suppression tests. Visualising procedures may include pituitary MRI and abdominal scanning.9 Treatment is specific for the cause of hypercortisolism and includes surgery, medication, and radiotherapy. Therefore, differentiation among pituitary, adrenal and ectopic causes of hypercortisolism is essential for effective treatment.9
Hypoadrenalism
Adrenal crisis, although rare, is a life-threatening condition which, if unrecognised, has high rates of morbidity and mortality.10,11 It is more likely to occur during an acute
CHAPTER 11 Alterations of endocrine function across the life span
RESEARCH IN F CUS The incidentaloma in endocrinology Incidentalomas are lesions identified during imaging for an unrelated condition. They can be found in several sites; however, in endocrinology incidentalomas of the pituitary and the adrenal glands do present a challenge. Appropriate laboratory investigations are required initially to determine whether the lesion is functioning, and ongoing monitoring over months to years may be required. Pituitary incidentalomas can be seen in up to 20% of CTs and 38% of MRIs. They require a complete assessment of pituitary function, may require assessment of visual fields and surgical review and follow-up over a number years to monitor changes in the lesion. A large proportion of these will in fact be nonfunctioning and never need any intervention. Adrenal incidentalomas are seen on 4.4% of CTs (up to 10% in the older population) and autopsy studies have identified adrenal lesions in up to 9% of cases. About 10–15% may be secreting hormones, thus requiring surgical intervention. About 3% may be malignant in nature. A considered approach to assessment, treatment and monitoring is required. The costs associated with these incidental findings are significant. The importance of early detection of hyperfunctioning or malignant lesions needs to be balanced against the increased anxiety, costs of repeat radiological exposure and the high cost of laboratory testing over several months to years. This highlights the importance of appropriate and judicious imaging at all times.
illness or stress in someone already known to have primary or secondary adrenal insufficiency. It may also be the way in which someone presents for the first time with these conditions. It is easily treated once recognised, with intravenous hydrocortisone and intravenous fluid rehydration. Emergency medical kits, medical alert bracelets and education on sick day management are important clinical strategies in prevention and early treatment of adrenal crisis. Note: Although androgens are also produced in the adrenal cortex, lack of this hormone is not life threatening therefore is not discussed in this section. PATHOPHYSIOLOGY
Primary adrenal insufficiency (Addison’s disease) is the hyposecretion of cortisol, aldosterone and androgens. Eighty per cent of cases are caused by autoimmune adrenalitis, with the remainder caused by adrenal infection such as tuberculosis, metastatic disease, adrenal haemorrhage, congenital adrenal hyperplasia or following bilateral adrenalectomy. Low glucocorticoids and mineralocorticoids result in high ACTH production from the pituitary. Because ACTH also stimulates melanocytes, this sustained raised ACTH causes the classic signs of Addison’s disease, that is,
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hyperpigmentation of the skin and mucous membranes at diagnosis. This is particularly accentuated in sun-exposed areas and over knuckles, elbows and knees. Pigmentation fades once treatment is initiated. Secondary adrenal insufficiency is due to the hyposecretion of pituitary ACTH, resulting in hyposecretion of cortisol. Aldosterone production is maintained, and therefore hyponatraemia and hypotension are not commonly seen unless presentation is acute. The most common reason for this condition is exogenous treatment with glucocorticoid therapy which suppresses ACTH production and consequently resulting in understimulation of the adrenal cortex. If regular glucocorticoid therapy is withheld or the dosage is not increased during acute illness secondary adrenal insufficiency can develop. Rarer causes would be from pituitary ACTH deficiency.12 CLINICAL MANIFESTATIONS
Mild to moderate deficiency presents with weakness, fatigue, anorexia and weight loss. Nausea, vomiting and diarrhoea may develop as the condition progresses. Of greatest concern is the development of hypotension that can progress to complete vascular collapse and shock. Postural hypotension can occur in up to 90% of cases.10 EVALUATION AND TREATMENT
Hypoanatraemia and hyperkalaemia occur in primary adrenal insufficiency. Low cortisol levels reduce the normal movement of leucocytes out of the circulation, resulting in eosinophilia and mild lymphocytosis. Hypoglycaemia is common because of reduced gluconeogenesis from liver stores. Raised ACTH with an inappropriately low serum cortisol levels can be diagnostic for the condition. An ACTH stimulation test may be performed to evaluate cortisol levels if diagnosis is unclear. This involves taking a serum cortisol level, administering an injection of ACTH and then testing cortisol levels 30 and 60 minutes later. The cortisol should increase to > 550 nmol/L. The treatment of primary adrenal insufficiency is lifelong glucocorticosteroid and mineralocorticoids, while secondary adrenal insufficiency is treated with glucocorticoid therapy only. Adrenal crisis (also known as Addisonian crisis) is a life-threatening situation which may occur when any patient with hypoadrenalism has inadequate circulating cortisol. This may occur if their normal glucocorticoid medication is withheld, or during illness such as vomiting or diarrhoea, infection, trauma, surgery, or even significant life stress. Early intervention is critical using parenteral hydrocortisone. Evaluation and treatment of the precipitating cause can proceed once the emergency treatment has been commenced.13 Education of patients and their families in sick day management is an essential aspect of the current care of all patients with adrenal insufficiency. Many patients now carry and administer hydrocortisone themselves prior to arrival in the emergency department. Emergency medical kits and medical alert bracelets are important clinical aids
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in prevention of complications of this condition. These help patients highlight to clinicians their need for more urgent review on admission to emergency departments, than has previously been the practice.10,11 For example, to improve emergency treatment the New South Wales Ambulance Service has established authorised care protocols. This protocol is a collaborative instruction from the treating clinician and the ambulance service which directs immediate treatment for patient with adrenal insufficiency to receive an emergency injection of hydrocortisone as soon as possible to help prevent and treat adrenal crisis.13
F OC US O N L E ARN IN G
1 Discuss the effects of hyperaldosteronism on fluid balance. 2 Describe the clinical features of hypercortisolism. 3 Describe the emergency treatment required for the treatment of adrenal crisis.
Alterations of pancreatic function Diabetes mellitus is not a single disease, but a group of disorders with abnormal glucose metabolism in common. The term diabetes mellitus describes a syndrome characterised by chronic hyperglycaemia and other disturbances of carbohydrate, protein and fat metabolism. While diabetes indicates an increased urine output, mellitus is Latin for honey — hence the urine is sweet (contains glucose) and copious. There are three main categories of diabetes mellitus: 1 type 1 (absolute insulin deficiency) 2 type 2 (insulin resistance with an insulin secretory deficit) 3 gestational diabetes. In this chapter, we consider type 1 and gestational diabetes. Type 2 diabetes is one of the main chronic health complications in Australia and New Zealand, with strong links to obesity, and has had a relatively recent surge in incidence — thus, it is discussed fully in Chapter 36. Importantly, general features that are common to type 2 and other forms of diabetes are reserved for Chapter 36. Other specific types of diabetes are rare and are not covered in this text.
Type 1 diabetes mellitus
Type 1 diabetes mellitus accounts for approximately 10% of diabetes mellitus in Australia, with an incidence of 22 per 100 000 person years among 0–14-year olds. This rates in the top 10 globally for type 1 diabetes diagnosis, affecting some 87 100 Australians,14 25 000 being under 30 years.15 Type 1 diabetes mellitus results from autoimmune destruction of beta (β) cells in the islets of Langerhans and
is thought to be the result of a gene–environment interaction, with the strongest genetic risk markers in the human leucocyte antigen (HLA) region of chromosome 6. Genetic factors may increase susceptibility to environmental causes of diabetes.16 There is a 50% concordance rate in twins. Between 10% and 13% of individuals with newly diagnosed type 1 diabetes have a first-degree relative (parent or sibling) with type 1 diabetes. Diagnosis peaks at 12 years of age but can present in infancy. Historically, type 1 diabetes mellitus has been thought to have an abrupt onset. More recently, however, prospective studies show: a distinctive natural history involving genetic susceptibility; a long preclinical period; immunologically mediated destruction of beta cells, eventually leading to insulin deficiency; and hyperglycaemia. PATHOPHYSIOLOGY
Type 1 diabetes results from a severe or absolute lack of insulin caused by loss of beta cells. At presentation some insulin may still be produced, but this will only decrease with time as beta cells are lost. Destruction of islet cells is related to genetic susceptibility, autoimmunity and environmental factors.16,17 It is a slowly progressive autoimmune T-cell mediated disease that destroys beta cells of the pancreas. Autoantibodies (antibodies produced against the body’s own tissues; see Chapter 15) against these pancreatic cells are often detected long before symptoms appear. Environmental factors that may trigger autoimmune injury are summarised in Box 11.1. Non-autoimmune type 1 diabetes can occur secondarily to other diseases such as pancreatitis.
Environmental factors contributing to type 1 diabetes
BOX 11.1
Drugs and chemicals Alloxan Streptozotocin Pentamidine Vacor (a rodenticide) Nutritional intake Bovine milk (controversial; this may relate to giving cow’s milk to infants) High levels of nitrosamines Viruses Mumps and coxsackie — type 1 diabetes does occur rarely as a complication of viral infections, but no evidence of substantial relationship exists. Rubella — 40% of individuals with congenital rubella infection later develop type 1 diabetes. Cytomegalovirus (CMV) — persistent CMV infections appear to be relevant to pathogenesis of some cases of type 1 diabetes.
CHAPTER 11 Alterations of endocrine function across the life span
Before hyperglycaemia occurs, 80–90% of the insulin-secreting beta cells of the islets of Langerhans must be destroyed. This is because the remaining cells can increase their production of insulin to compensate, but with so few beta cells remaining, insulin production is no longer adequate. Beta cell abnormalities are present long before the acute clinical onset of type 1 diabetes. In addition to the decline in insulin secretion, the production of amylin, another beta cell hormone that is co-secreted with insulin, also falls. One of the critical actions of amylin is to suppress glucagon release from the alpha cells. Regardless of cause, a disequilibrium of hormones produced by the islets of Langerhans occurs in diabetes mellitus. Both beta cell function and alpha cell function are abnormal, with a lack of insulin and a relative excess of glucagon (produced by alpha cells). Hyperglycaemia and ketonaemia can result from insulin deficiency alone, but a relative excess of glucagon clearly facilitates the metabolic alterations seen in diabetes — elevated blood glucose levels fail to suppress the production of glucagon.
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TABLE 11.1 Clinical manifestations and mechanisms for type 1 diabetes mellitus MANIFESTATION
RATIONALE
Polydipsia
Because of elevated blood sugar levels, water is osmotically attracted from body cells, resulting in intracellular dehydration and stimulation of thirst in the hypothalamus
Polyuria
Hyperglycaemia acts as an osmotic diuretic; the amount of glucose filtered by the glomeruli of the kidneys exceeds that which can be reabsorbed by the renal tubules; glycosuria results, accompanied by large amounts of water lost in the urine
Polyphagia
Depletion of cellular stores of carbohydrates, fats and proteins results in cellular starvation and a corresponding increase in hunger
Weight loss
Weight loss occurs because of fluid loss in osmotic diuresis and the loss of body tissue as fats and proteins are used for energy
CLINICAL MANIFESTATIONS
Type 1 diabetes mellitus affects the metabolism of fat, protein and carbohydrates. Hyperglycaemia and glycosuria occur (see below). In addition, proteins and fats break down because of the lack of insulin, resulting in weight loss. Initial clinical manifestations of type 1 diabetes are generally acute, with the classical presentation for those with type 1 diabetes mellitus being: • polyphagia (increased hunger) • polyuria (increased urine production) • polydipsia (increased thirst). Polyphagia occurs because glucose (and lipids) do not enter cells in sufficient amounts and therefore cells are deprived of nutrients, which in turn stimulates increased food intake. Polyuria occurs due to the kidneys’ inability to manage the high amount of glucose in the bloodstream. Glucose filters freely at the nephron, but in the non-diabetic person, all glucose is returned to the blood by reabsorption in the kidneys. However, in the diabetic, the hyperglycaemia means that there is a much higher amount of glucose in the blood that is filtered that cannot be fully reabsorbed, as the transport maximum (or maximum capacity to reabsorb glucose back into the blood) is exceeded. Therefore, some of the glucose appears in the urine, which is known as glycosuria (refer to Chapter 28 for the normal renal handling of glucose). The osmotic effect of glucose in the urine draws water into the urine from the bloodstream, increasing the production of urine (polyuria). The water being lost from the body in the urine leads to dehydration, which triggers increased thirst (polydipsia) in an attempt to rehydrate the cells. Dehydration can lead to low blood volume and hypotension. These features are summarised in Table 11.1. Weight loss and wide fluctuations in blood glucose levels occur. Ketoacidosis is caused by increased metabolism of fats and proteins resulting in high levels of circulating ketones.
The pH drops, triggering the buffering systems associated with metabolic acidosis (see Chapter 29). If acidosis progresses the respiratory system compensates with deeper rapid breaths in an attempt to eliminate carbonic acid. This is known as Kussmaul respirations. Acetone (a volatile form of ketones) is then blown off, giving the breath a sweet or ‘fruity’ odour. These ketones are also excreted by the kidneys and so a urinalysis that detects hyperglycaemia and large ketones may be the first test that detects type 1 diabetes in a patient. Occasionally, diabetic coma is the initial symptom of the disease. Further details that are common with type 2 diabetes mellitus are discussed in Chapter 36. EVALUATION AND TREATMENT
The diagnosis of diabetes is not difficult when the symptoms of polydipsia, polyuria, polyphagia, weight loss and hyperglycaemia are present in fasting and postprandial states. Currently, treatment regimens are designed to avoid high and low levels of glucose and insulin.17 Management requires individual planning according to type of disease, age and activity level, but all individuals require some combination of insulin, meal planning and exercise. Glycated haemoglobin A1c (abbreviated to HbA1c) testing is useful in confirming the diagnosis and in monitoring the effectiveness of treatment and preventing complications (refer to Chapter 36). When assessing blood glucose control, the blood glucose levels that are determined by a glucometer (by the patient) or a blood test indicate the glucose at a particular point in time, while the HbA1c testing gives a longer term view of glucose control over recent weeks. Both types of information are used to determine the effectiveness of the blood glucose control.
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Islet cell transplantation is being explored for treatment of type 1 diabetes and early results are promising.18 Pancreatic transplant is generally reserved for those individuals with type 1 diabetes and associated end-stage renal failure.18 The transition from childhood through to adulthood with this chronic condition is now recognised as a time when accessing healthcare is often limited and focus of support at this time is essential in healthcare services.15 The acute and chronic complications, evaluation and treatment of type 1 diabetes mellitus are similar to those seen in type 2 (refer to Chapter 36 for full discussion).
Diabetes in pregnancy
Diabetes in pregnancy is common, affecting 1 in 20 pregnancies. Some women will have preexisting type 1 or type 2 diabetes. Other women will develop diabetes only during the pregnancy. This is called gestational diabetes mellitus and it resolves once the baby and, more importantly, the placenta has delivered. Those with type 1 and type 2 diabetes should have glycaemic control optimised prior to conception to reduce the risk of fetal abnormality and miscarriage. All diabetes in pregnancy requires focused management to reduce the rates of adverse events including gestational hypertension premature births, caesarian section, and stillbirth.19 Gestational diabetes mellitus develops when glucose intolerance appears during pregnancy. Recent Australian and New Zealand guidelines advise for early screening of gestational diabetes early in pregnancy, through a blood test for HbA1c (refer to Chapter 36) by 20 weeks gestation; where appropriate, an oral glucose tolerance test using 75 g of glucose should be undertaken at 24–48 weeks gestation.19,20 Further to this, women at risk should be screened earlier at the first opportunity after conception with a 75 g oral glucose tolerance test. Risk factors include a family history of diabetes (i.e. first degree relative or sister with gestational diabetes mellitus), membership in a high-risk ethnic group, advanced maternal age (> 40 years of age), a history of delivering large babies, a prior history of gestational diabetes or polycystic ovary syndrome, being overweight before pregnancy (a body mass index, or BMI, > 35 kg/m2), women on corticosteroids or antipsychotics. In Australia, 4–5% of pregnant women are affected with gestational diabetes.19 Approximately one-third of these women are over the age of 35, although only 20% of total births are in this age group; this indicates a higher proportion of women with gestational diabetes in this age group compared with younger mothers. Aggressive treatment is required to prevent morbidity and fetal mortality. When dietary changes do not maintain glucose targets, insulin is recommended as first-line treatment and will be used until delivery.19,21 Metformin has been shown to be effective; however, long-term safety is still of concern.21 Gestational diabetes can progress to type 2 diabetes, particularly within the first 5 years, with the fasting glucose levels during pregnancy being the main risk factor associated with this future risk.22
RESEARCH IN F
CUS
As type 1 diabetes is a result of pancreatic beta cell destruction, strategies to repopulate the pancreas with insulin-producing beta cells is a long-held vision for researchers. There are many challenges that need to be overcome for optimal therapeutic outcomes. The first challenge is to develop cells that are not limited by the availability to produce the donor cells. Currently, each islet transplantation requires three cadaveric donors, which is unsustainable. To address this, reprogramming stem cells is an option. The second challenge to overcome is to develop beta cells that do not elicit an immune response. This can be avoided either by encapsulating the donor beta cells so that they are hidden from the immune system but at the same time are still responsive to changes in blood glucose levels, or by reprogramming patient-derived stem cells to grow into beta cells. This still requires the additional reprogramming of the cells so they are protected from the autoimmune response that destroyed the beta cells in the first place. The third challenge is for the beta cells to be self-renewing, a characteristic of all cells of the body, so that repeated beta cell replacement is avoided. However, uncontrolled cell division can lead to cancer so the difficulty is to strike a balance between cell renewal and death. Finally, with all of this in place the replaced beta cells have to act like normal beta cells and respond in a physiological manner to various stimuli such as blood glucose.
FOCU S ON L EA RN IN G
1 Describe the pathophysiology of type 1 diabetes. 2 Discuss the importance of diagnosing gestational diabetes.
Alterations of thyroid function Hyperthyroidism
Hyperthyroidism is one of the more common endocrine disorders. It is a condition where thyroid hormone levels are higher than normal. When these high levels result in a hypermetabolic state, this is known as thyrotoxicosis. Approximately 2 out of every 100 women will experience hyperthyroidism.23 Factors that contribute to higher rates in females include the pregnancy-related thyroid condition postpartum thyroiditis and a higher female:male incidence of Graves’ disease of 8 : 1 (see below). All forms of thyrotoxicosis share common physiological effects on the individual that are caused by the high thyroid hormone level.24 These effects are the result of an increase in adrenergic stimulation and increased metabolic effects. They
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Causes of Hyperthyroidism
Graves’ disease autoimmune
Toxic nodule
Single nodule
Multi nodular
Thyroiditis
Rare causes
• Subacute • Postpartum • Lymphocytic
• TSH secreting pituitary tumour • Thyroid hormone ingestion
FIGURE 11.8
Causes of hyperthyroidism. The most common causes of hyperthyroidism include autoimmune disease, toxic nodules and thyroiditis.
Graves’ disease
Graves’ disease is the most common cause of hyperthyroidism. It is an autoimmune condition. In normal thyroid physiology thyroid-stimulating hormone (TSH) binds to receptors on the thyroid gland cells to stimulate production and release of thyroid hormone. In Graves’ disease an abnormal immune response triggers the production of antibodies against the TSH receptor. The result is that the thyroid cells are inappropriately stimulated to produce and release high concentrations of the two thyroid hormones thyroxine (T4) and triiodothyronine (T3)24,25 (see Fig. 11.9). The combined action of increased serum levels of thyroid hormone and the immune response produces the signs and symptoms of Graves’ disease: • Thyrotoxicosis: the signs and symptoms listed above will commonly be more significant in Graves’ disease. The active hormone, triidothryonine, is commonly at much higher levels relative to thyroxine as a result of increased
Antibodies bind to the thyroid-stimulating receptors on the thyroid gland causing Thyroid gland to release thyroid hormone which means that Blood level of thyroid hormone rises negative feedback means that Thyroid-stimulating hormone production in the anterior pituitary is decreased resulting in Low levels of circulating thyroid-stimulating hormone
however Antibodies to thyroidstimulating receptors at thyroid gland continue resulting in Thyroid hormone levels continue to rise
FIGURE 11.9
Thyroid hormone levels with Graves’ disease. In Graves’ disease, the receptors for thyroid-stimulating hormone are activated by the binding of antibodies. This stimulates the thyroid gland to produce and release thyroid hormone, in a continual process, leading to constantly high levels of thyroid hormone.
CONCEPT MAP
may include varying degrees of tachycardia, palpitations, nervousness, insomnia, heat intolerance, moist skin, tremor, lid retraction in the eye, increased systolic blood pressure, increased cardiac contractility and weight loss. Goitre is the term used to describe an enlarged thyroid gland, and in the case of hyperthyroidism, goitre occurs by the gland increasing in size as it increases its production of thyroid hormone. Determining the cause of the hyperthyroidism is critical, as it will determine the management of the condition. Fig. 11.8 outlines several causes of hyperthyroidism.23 The most common causes are discussed in the sections that follow. They are all forms of primary hyperthyroidism. This means there is a primary thyroid abnormality. In secondary hyperthyroidism the pituitary gland has the abnormality. This is extremely rare and is not discussed further in this text.25
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production and release and peripheral conversion of T4 to T3. This amplifies the proximal muscle weakness and fine tremor. Eye changes may also include upper lid lag on downward gaze and lag of the eyeball on upward gaze due to adrenergic stimulation. • Immunological stimulation causes several physiological changes unique to Graves’ disease: TSH receptor antibodies stimulate thyroid cells, increasing the gland size and vascularity. This is described as a diffuse enlarged gland (goitre). It is smooth, painless and commonly the increased blood flow can be detected as a bruit on auscultation with a stethoscope placed over the gland. TSH receptors are found on tissue within the orbit which results in antibody infiltration and results in progressive effects on eye position, movement and function. This includes enlargement of the ocular muscles, and results in eyeball protrusion, paralysis of extraocular muscles and damage to the retina and optic nerve which can lead to blindness. These changes result in exophthalmos (protrusion of the eyeball), periorbital oedema and extraocular muscle weakness leading to diplopia (double vision). The individual may experience irritation, pain, lacrimation, photophobia, blurred vision, decreased visual acuity, papilloedema, visual field impairment, exposure keratosis and corneal ulceration (see Fig. 11.10). Smoking is known to exacerbate thyroid eye disease.25 TSH receptor antibody infiltration of the skin can be seen but is rare. Dermopathy (pretibial myxoedema), a thickening of the skin over the tibial region, and acropachy, a thickening of the subperiosteal layer of the metacarpals, can result.
Hyperthyroidism resulting from nodular thyroid disease
The thyroid gland normally enlarges in response to the increased demand for thyroid hormone that occurs in puberty, pregnancy, iodine deficiency and immunological,
viral or genetic disorders. When the condition requiring increased thyroid hormone resolves, TSH secretion normally subsides and the thyroid gland returns to its original size. Irreversible changes may occur in some follicular cells, however, so that they then function autonomously. Hyperthyroidism may or may not result from these irreversible changes. Autonomously functioning cells may produce less thyroid hormone than the body requires. The remainder of the gland then functions to supply the remainder of the body’s need and a euthyroid state (normal thyroid hormone level) is achieved and maintained. If the autonomously functioning cells produce sufficient or excessive thyroid hormone for the usual body requirements, the remainder of the gland undergoes involution, becoming normal but inactive tissue. This condition may result in euthyroidism or hyperthyroidism, depending on the amount of thyroid hormone produced. When hyperthyroidism occurs this is called a toxic multinodular goitre. If only one nodule is hyperfunctioning, it is termed toxic adenoma. Symptoms usually develop slowly and consist of rapid heart action; tremors; elevated basal metabolic rate; enlarged, multinodular goitre or a single, large nodule; and weight loss. Lid lag and lid retraction may be seen, but exophthalmos and pretibial myxoedema do not occur.25
Hyperthyroidism resulting from thyroiditis
Normal thyroid tissue consists of thyroid cells grouped into spherical units called thyroid follicles. They produce, store and secrete thyroid hormone. Thyroiditis is the inflammation of this thyroid tissue. It can occur due to viruses, from trauma, it can be drug induced or it can occur during the postpartum period as the immune system becomes more active.25 During viral (subacute) thyroiditis the gland may be tender. Damaged follicles leak preformed hormone into the circulation causing thyrotoxicosis. Depending on the degree of thyroiditis this may be mild to severe. Thyroxine (T4) has a long half-life of about 7–10 days.25 This means that thyrotoxic symptoms may be present for several weeks until the thyroiditis subsides and the thyroid hormone has been metabolised. The pituitary detects high thyroid hormone levels so TSH will be suppressed and the gland itself does not make extra hormone during this time. A thyroid scan performed would show a negative uptake in this case. Once the thyroiditis phase has passed and thyroid hormone levels have returned to normal, monitoring is still required because a phase of hypothyroidism may occur due to damage to the follicular cells. Occasionally this damage may be permanent and the individual may require thyroxine therapy (see ‘Hypothyroidism’ below).25 CLINICAL MANIFESTATIONS
FIGURE 11.10
Graves’ disease. Note the large and protruding eyeballs.
The clinical effects have already been detailed above and are summarised in Fig. 11.11. The degree an individual will present with these manifestations depends on several factors including the thyroid hormone levels, length of time exposed to them, the underlying cause, comorbidities and the
CHAPTER 11 Alterations of endocrine function across the life span
individual’s age. Minimal or atypical symptoms are common in the elderly population. Up to 20% may have atrial fibrillation, and shortness of breath is seen in this group, which may reflect the cardiovascular and respiratory comorbidities of the older patient.26 EVALUATION AND TREATMENT
Thyroid hormone is measured as the hormones that are not protein bound, namely free thyroxine (T4) and free triiodothyronine (T3). These are the bioavailable hormones
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and treatment for thyrotoxicosis will be targeting changes in these levels. In primary hyperthyroidism (which is the most common form of hyperthyroidism) thyroid hormone levels are raised and as a result TSH will decrease (see Table 11.2). The presence of TSH receptor antibodies is diagnostic for Grave’s disease.26 A thyroid scan may be required to confirm the diagnosis where the clinical picture is not clear. The scan would show diffuse increased uptake of radiolabelled technetium 99 (a tracer isotope) which is used to image the thyroid gland.24,27 Treatment needs to consider two issues: achieve symptom control and reduce thyroid hormone levels where possible. Symptom relief commonly requires the prescribing of a beta-blocking agent such as propranolol. To reduce thyroid hormone, antithyroid medication is commonly the first-line therapy used in Australia.24,25 Carbimazole and propylthiouracil (PTU) interfere with thyroid hormone production and secretion from the thyroid cells. Both medications can cause liver disturbances and monitoring of liver function is essential. Rarely, they can cause agranulocytosis, and so patients should be advised to immediately report sore throats, mouth ulcers or other signs of infection. Antithyroid medications are used particularly for Graves’ disease. Where this therapy fails or is not appropriate radioactive iodine therapy or surgery may be required. Thyroidectomy when performed by experienced thyroid surgeons carries a small risk of permanent hypoparathyroidism of < 2% and recurrent laryngeal nerve damage of < 1%.24,25 Current treatment for Graves’ disease does not reverse the ocular changes. Glucocorticosteroids and surgical intervention may be required in severe cases.24,25
Thyrotoxic crisis
FIGURE 11.11
Hyperthyroidism due to Graves’ disease. Main clinical symptoms of Graves’ disease include goitre, tachycardia and heat intolerance.
Thyrotoxic crisis (thyroid storm) is a rare but dangerous worsening of the thyrotoxic state, in which death occurs within 48 hours without treatment. The condition may develop spontaneously, but it usually occurs in individuals who have undiagnosed or partially treated Graves’ disease. While thyrotoxic they have been subjected to excessive stress, such as infection, or proceeded to thyroid surgery. Handling the thyroid gland during the surgery compounds the problem and the release of excess thyroid hormones creates the ‘storm’.25,28 The systemic symptoms of thyrotoxic crisis include hyperthermia, tachycardia, high-output heart failure, agitation or delirium, and nausea, vomiting or diarrhoea contributing to fluid volume depletion. The symptoms may
TABLE 11.2 Changes to thyroid and pituitary hormones in primary hyperthyroidism TSH
FREE T4
FREE T3
(0.500–4.2 IU/L)
(10–20 pmol/L)
(3.5–6.0 pmol/L)
NORMAL
2.6
16
4.2
PRIMARY HYPERTHYROIDISM
< 0.01
49
18
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Loss of thyroid tissue means there are Low levels of circulating thyroid hormone which stimulate
Hypothyroidism
Deficient production of thyroid hormone by the thyroid gland results in hypothyroidism. Primary causes include: (1) congenital defects; (2) defective hormone production resulting from autoimmune thyroiditis, iodine deficiency or antithyroid drugs; or (3) iatrogenic (inadvertent) loss of thyroid tissue after surgical or radioactive treatment for hyperthyroidism. Causes of secondary hypothyroidism are less common and are related to either pituitary or hypothalamic failure. Hypothyroidism is the most common disorder of thyroid function. It occurs more commonly in women than men and affects 6–10% of women. A number of factors contribute to this incidence and 10% of women in the fifth and sixth decade will have thyroid autoantibodies which predispose to chronic lymphocytic thyroiditis. In the case of hypothyroidism, goitre occurs as the gland attempts to produce thyroid hormone, but lacks the capacity to complete hormone production and secretion. As a result, the gland becomes enlarged as it works harder, yet remains unable to secrete thyroid hormone.
Primary hypothyroidism
Primary hypothyroidism results from several disorders: acute thyroiditis, subacute thyroiditis, autoimmune thyroiditis, painless thyroiditis and postpartum thyroiditis. Acute thyroiditis is caused by a bacterial infection of the thyroid gland and is rare. Subacute thyroiditis is a nonbacterial inflammation of the thyroid often preceded by a viral infection. Both conditions are accompanied by fever, tenderness and enlargement of the thyroid gland. Symptoms may last for 2–4 months and corticosteroids usually resolve symptoms. Autoimmune thyroiditis (Hashimoto’s disease) is the most common cause of hypothyroid disease in Australia.29,30 It results in destruction of thyroid tissue by circulating thyroid antibodies and infiltration of lymphocytes. Autoimmune thyroiditis also may be caused by an inherited immune defect. Goitre formation is common. Painless thyroiditis has a course similar to subacute thyroiditis but is pathologically identical to Hashimoto’s disease. Postpartum thyroiditis generally occurs up to 6 months after delivery with a course similar to Hashimoto’s disease. Spontaneous recovery occurs in 95% of these hypothyroid conditions.29,30 PATHOPHYSIOLOGY
In primary hypothyroidism, loss of thyroid tissue leads to decreased production of thyroid hormone and increased secretion of TSH which results in remaining thyroid tissue increasing in size and a goitre developing (see Fig. 11.12).
Anterior pituitary to release more thyroid-stimulating hormone and High levels of thyroidstimulating hormone to target the thyroid gland but Thyroid gland unable to produce more thyroid hormone
FIGURE 11.12
Secretion of thyroid hormone in hypothyroidism. In hypothyroidism, lack of thyroid hormone usually occurs due to inability to produce sufficient thyroid hormone. The level of thyroid-stimulating hormone is usually high, but due to an inability to produce thyroid hormone for reasons such as thyroid gland dysfunction, the level of thyroid hormone does not increase sufficiently. As a result, the thyroid gland may enlarge, which is known as goitre.
Secondary hypothyroidism is very rare and is usually caused by the pituitary’s failure to produce adequate amounts of TSH. Pituitary tumours, or the results of their treatment, are the most common causes of secondary hypothyroidism. CLINICAL MANIFESTATIONS
Hypothyroidism generally affects all body systems and occurs insidiously over months or years. The decrease in thyroid hormone lowers energy metabolism, heat production and delays neuromuscular processes within the body. The individual develops a low basal metabolic rate, cold intolerance, lethargy, tiredness, constipation, thinning brittle hair and slightly lowered basal body temperature. The decrease in thyroid hormone leads to excessive TSH production and goitre (see Fig. 11.13). The characteristic sign of severe or long-standing hypothyroidism is myxoedema, which results from the altered composition of the dermis and other tissues. The connective fibres are separated by large amounts of protein and other substances that bind water, producing non-pitting, boggy oedema, especially around the eyes (see Fig. 11.14), hands and feet and in the supraclavicular fossae. The tongue
CONCEPT MAP
be attributed to increased sympathetic nervous system stimulation. The treatment is designed to: (1) reduce circulating thyroid hormone levels by inducing a block of thyroid hormone production (using the antithyroid medication propylthiouracil) thereby reducing their effects to eliminate the precipitating disorder; and (2) provide symptomatic and supportive care.28
CHAPTER 11 Alterations of endocrine function across the life span
and laryngeal and pharyngeal mucous membranes thicken, producing thick, slurred speech and hoarseness. EVALUATION AND TREATMENT
In addition to the clinical symptoms of hypothyroidism, a decrease in serum-free T4 is nearly always present. TSH concentration increases because of loss of negative feedback from thyroid hormone.24 (See Table 11.3.) Hormone replacement therapy is the treatment of choice. The restoration of normal thyroid hormone levels should
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be timed appropriately; a regimen of hormonal therapy depends on the individual’s age, the duration and severity of the hypothyroidism, and the presence of other disorders, particularly cardiovascular disorders. Therapy may be increased gradually over months to avoid precipitating acute cardiac events in the elderly. Thyroxine needs to be taken separately from food, vitamins and mineral supplements to ensure adequate absorption.24,25
Thyroid disease and pregnancy
The thyroid undergoes significant physiological changes to meet the demand of metabolism in pregnancy. This includes increased thyroid hormone production and changes in thyroid hormone transport systems which changes the normal reference ranges for thyroid function tests. Iodine is essential for normal thyroid hormone production; however, because of increased renal clearance of iodine in pregnancy, iodine requirements increase. Maintaining adequate iodine intake during the preconception period, pregnancy and breastfeeding is essential to prevent potential detrimental effects on the fetus and infant.31,32 An intake of at least 250 micrograms daily in pregnancy and 270 micrograms per day while breastfeeding is recommended.
FIGURE 11.13
Hypothyroidism. Main clinical symptoms of hypothyroidism include fatigue, low cognitive function, bradycardia, and cold intolerance.
FIGURE 11.14
Myxoedema. Note oedema around the eyes and facial puffiness.
TABLE 11.3 Changes to thyroid and pituitary hormones in primary hypothyroidism TSH
FREE T4
FREE T3
(0.500–4.2 IU/L)
(10–20 pmol/L)
(3.5–6.0 pmol/L)
NORMAL
2.6
16
4.2
PRIMARY HYPOTHYROIDISM
25
8.2
3.3
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Since 2009 in both Australia and New Zealand, it has been a requirement that all bread (except organic) is fortified with iodised salt.33,34 This has helped to address an overall iodine deficiency identified in communities of Australia and New Zealand. Since 2010 pregnancy supplements have included iodine.32,35
FOCU S ON L EA RN IN G
1 Explain how increased thyroid hormone relates to the clinical manifestations of hyperthyroidism. 2 Discuss the visual changes associated with Graves’ disease. 3 List common symptoms associated with hypothyroidism.
HYPERTHYROIDISM
The levels of the beta human chorionic gonadotrophin hormone (βHCG) peaks towards the end of the first trimester. It has a similar chemical structure to the TSH and can stimulate thyroid hormone production. This may cause a mild hyperthyroidism, resulting in a low normal or mildly suppressed TSH in the first trimester. This effect generally resolves in the second trimester when βHCG levels reduce as the placenta takes over pregnancy hormone production. The relative higher levels of βHCG seen in this group of women is felt to be associated with a transient hyperthyroidism and suppressed TSH which may not resolve until the middle trimester.36 The other most common form of hyperthyroidism in pregnancy is Graves’ disease. Undiagnosed Graves’ disease in pregnancy may carry significant maternal and fetal complications.36 All patients should receive pre-pregnancy planning and expert antenatal care to monitor thyroid function and titrate medication. Common to other autoimmune conditions, Graves’ disease improves during pregnancy as the immune system is suppressed. TSH receptor antibodies status needs to be assessed as the antibody can cross the placenta and potentially cause hyperthyroidism in the neonate.36 It is important to monitor patients postpartum to detect recurrence when the immune system returns to normal level of function. HYPOTHYROIDISM
In iodine replete communities the most common cause of hypothyroidism is autoimmune thyroiditis. Overt hypothyroidism in pregnancy is associated with serious adverse outcomes to the fetus including miscarriage, early delivery and poor neurocognitive development of the infant. Early detection and treatment with thyroxine should be commenced, aiming to normalise thyroid function as rapidly as possible. Over the last decade it has been established that the reference range for TSH is lower than in the non-pregnant population. Treatment of subclinical hypothyroidism in pregnancy is controversial.37 All women already on thyroxine prior to pregnancy will commonly require an increase in dose of between 30% and 50% once they are pregnant. Monitoring of TSH levels should be carried out 4–6 weekly until it is in the target range. In Australia it is recommended that all women with thyroid autoantibodies with a TSH > 2.5 mIU/L should be commenced on thyroxine. Fifty per cent of all women with thyroid autoantibodies are at risk of developing postpartum thyroiditis which may impact on their general wellbeing during the time when caring for a new infant.
Alterations of parathyroid function Hyperparathyroidism
Hyperparathyroidism is characterised by greater than normal secretions of parathyroid hormone. Hyperparathyroidism is classified as primary, secondary and tertiary. PATHOPHYSIOLOGY
Estimates suggest that primary hyperparathyroidism occurs in 0.2–0.3% of the adult population, with twice as many cases in women. It is generally found in older adults.38 Because postmenopausal women are at risk for developing osteoporosis, the effects of increased levels of parathyroid hormone (which breaks down bone to release calcium to the blood) on bone disease can be significant. In primary hyperparathyroidism, parathyroid hormone secretion is increased and is not under the usual feedback control mechanisms. Most cases of primary hyperparathyroidism (approximately 80%) result from a single parathyroid adenoma with an increased secretion of parathyroid hormone. Other cases are caused by genetic mutations which are not discussed here.38, 39 Secondary hyperparathyroidism is a compensatory response of the parathyroid glands to chronic hypocalcaemia. Activated vitamin D (which is 1,25 dihydroxy vitamin D, also known as calcitriol), is required to absorb dietary calcium. Fig. 11.15 shows the pathway of vitamin D activation and highlights the stages where deficiencies may occur. In Australia many elderly people will have low ultraviolet light exposure causing vitamin D deficiency, which may lead to a secondary hyperparathyroidism.40,41 If not treated, this may contribute to the development of osteoporosis. Chronic renal disease causes a significant proportion of cases of secondary hyperparathyroidism.42–44 The normal process of activation of vitamin D is shown on the left of Fig. 11.15. Alterations to this pathway may arise from dietary and UV deficiencies, liver dysfunction, or renal causes. Treatments are shown on the right. Tertiary hyperparathyroidism occurs when hyperplasia (increase in the number of cells) of the parathyroid glands and loss of sensitivity to circulating calcium levels cause autonomous secretion of parathyroid hormone, even with normal calcium levels. It occurs in individuals with chronic renal failure even after renal transplant. Signs and symptoms are similar to those of primary hyperparathyroidism.38,45
CHAPTER 11 Alterations of endocrine function across the life span
Pre vitamin D2 and D is hydroxylated in liver to form Inactive 25 hydroxyvitamin D 25(OH) D which is hydroxylated in the kidney into Active 1,25 dihydroxy vitamin D 1,25(OH)2 D which promotes Ca+ absorption from the gut
Problems in the vitamin D activation pathway Low dietary Vitamin D2 and D3 or Low ultraviolet exposure or Liver failure
or Renal impairment
↓ Pre vitamin D2 and D3
Laboratory test results
• • • •
↓ 25(OH) vitamin D ↓ or normal Ca+ ↑ PTH Normal renal function
Treatment
• Cholecalciferol (vitamin D3) • Calcium supplements
↓ hydroxylation in liver which ↓ Formation of inactive 25 hydroxy vitamin D 25(OH) D decreased hydroxylation in kidney which
In renal disease
↓ Formation of active 1,25 hydroxy vitamin D 1,25(OH)2 D
• ↓ or normal 25(OH) vitamin D • ↑ PTH • ↑ Phosphate
In renal disease
CONCEPT MAP
Normal vitamin D activation pathway
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• Calcitriol 1,25(OH)2 vitamin D • Phosphate binding diet
resulting in ↓ Ca+ absorption from the gut resulting in hypocalcaemia which ↑ parathyroid hormone secretion
which ↑ Ca+ resorption from bone
FIGURE 11.15
Vitamin D activation and its role in secondary hyperparathyroidism. The multiple steps in the activation of vitamin D include sun exposure, and roles by the liver and kidney. Activated vitamin D promotes calcium absorption from the gut. Disorders relating to insufficient sun exposure, and liver or kidney dysfunction, may prevent activation of vitamin D, and hence lead to calcium deficiency. As a result of the calcium deficiency, there is increased secretion of parathyroid hormone.
CLINICAL MANIFESTATIONS
Parathyroid hormone hypersecretion causes hypercalcaemia and may be asymptomatic or present with excessive osteoclastic and osteocytic activity, resulting in bone resorption.43,44 (Bone resorption is discussed in Chapter 20.) This leads to the development of osteoporosis and increased risk of fracture. Kyphosis of the dorsal spine and compression fractures of the vertebral bodies may be present. The increased renal filtration load of calcium leads to hypercalciuria. Hypercalcaemia also affects proximal renal tubular function, causing metabolic acidosis and production of an abnormally alkaline urine. Parathyroid hormone hypersecretion enhances renal phosphate excretion and results in hypophosphataemia and hyperphosphaturia. The combination of hypercalciuria, alkaline urine and hyperphosphaturia predisposes the individual to the formation of calcium stones, particularly in the renal pelvis
or renal collecting ducts. These may be associated with infections. Both kidney stones and renal infection can lead to impaired renal function. Hypercalcaemia also impairs the concentrating ability of the renal tubule by decreasing its response to antidiuretic hormone. This causes polyuria leading to increased thirst. Chronic hypercalcaemia of hyperparathyroidism is associated with mild insulin resistance, necessitating increased insulin secretion to maintain normal glucose levels. Hypercalcaemia also affects the muscular, nervous and gastrointestinal systems, causing fatigue, headache, depression, anorexia, nausea and vomiting. It can also cause changes in cardiac muscle function leading to bradycardia and a shortened QT interval (see Fig. 11.16).38,45 EVALUATION AND TREATMENT
Primary hyperparathyroidism is generally diagnosed by excluding all other possible causes of hypercalcaemia.
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NEUROLOGICAL SYMPTOMS
LABORATORY RESULTS Ca2+ PTH
• Memory loss • Confusion Parathyroid adenoma or hyperplasia
Electrocardiogram (ECG) changes
MUSCULOSKELETAL CHANGES • Osteoporosis • Muscle weakness GASTROINTESTINAL CHANGES
RENAL CHANGES
• Peptic ulcer • Constipation • Pancreatitis
• Calciuria • Polyuria • Renal stones
FIGURE 11.16
Clinical changes associated with hyperparathyroidism. Main symptoms of hyperparathyroidism include confusion, ECG changes, and osteoporosis.
A definitive diagnosis must be supported by at least a 6-month history of symptoms associated with hypercalcaemia, including kidney stones, hypophosphataemia, hyperchloraemia and increased urinary calcium levels. With continued improvements in the ability to measure parathyroid hormone, the evaluation of hyperparathyroidism has become simplified. Simultaneous measurements of serum parathyroid hormone and calcium will document elevations of both, and diagnosis is confirmed by measuring 24-hour urinary calcium excretion. A bone mineral density scan should be performed to assess and monitor for osteoporosis.38,43,44 Definitive treatment involves surgical removal of the solitary adenoma or, in the case of hyperplasia, complete removal of three and partial removal of the fourth hyperplastic parathyroid glands. Observation of asymptomatic individuals with mild hyperparathyroidism is also an option. These individuals are advised to avoid dehydration and limit dietary calcium intake.38 Secondary hyperparathyroidism from vitamin D deficiency will benefit from some ultraviolet exposure and oral vitamin D3 supplementation. This is recommended in the elderly to reduce risk of osteoporotic fracture.38 In the last decade a great deal of research has focused on the role of low vitamin D and its association with muscle strength and conditions like diabetes, cardiovascular disease and some cancers.39,42 For those with chronic renal failure Kidney Health Australia recommends monitoring of parathyroid hormone
6–12 monthly when the estimated glomerular filtration rate is < 45 mL/min/1.73 m2. Treatment includes calcitriol and restricted dietary phosphate intake.38,45 Hypercalcaemia is acutely treated with hydration and may require bisphosphonate therapy to suppress osteoclast activity.42 In some cases of hyperparathyroidism where surgical treatment is contraindicated and hypercalcaemia is chronic there is a newer agent available called cinacalcet. This is a calcimimetic which increases the sensitivity of the parathyroid gland’s calcium-sensing receptors to extracellular calcium. This decreases secretion of parathyroid hormone leading to a decrease in serum calcium. It is currently available in Australia only for chronic renal failure patients on dialysis who have secondary hyperparathyroidism; however, it has been shown to effectively treat hypercalcaemia of primary hyperparathyroidism where surgery is contraindicated.38,44
Hypoparathyroidism
Hypoparathyroidism is most commonly caused by damage to the parathyroid glands during thyroid surgery. This occurs because of the anatomical proximity of the parathyroid glands to the thyroid. Transient hypoparathyroidism may also occur when a single hyperfunctioning parathyroid adenoma is removed and the remaining parathyroid glands take time to reestablish secretion.46 Rarer autoimmune and genetic causes of hypoparathyroidism are not discussed. PATHOPHYSIOLOGY
A lack of circulating parathyroid hormone causes depressed serum calcium levels and increased serum phosphate levels. In the absence of parathyroid hormone, resorption of calcium from bone and regulation of calcium reabsorption from the renal tubules are impaired. Phosphate reabsorption by the renal tubules is therefore increased, causing hyperphosphataemia. Magnesium is essential for parathyroid hormone production and secretion, consequently low magnesium levels can lead to hypoparathyroidism. Once serum magnesium levels return to normal, parathyroid hormone secretion does likewise. Hypomagnesaemia may be related to chronic alcoholism, malnutrition, malabsorption, increased renal clearance of magnesium caused by use of aminoglycoside antibiotics or certain chemotherapeutic agents, or prolonged magnesium-deficient parenteral nutritional therapy. CLINICAL MANIFESTATIONS
Symptoms associated with hypoparathyroidism are primarily those of hypocalcaemia. Hypocalcaemia causes a lowered threshold for nerve and muscle excitation so that a nerve impulse may be initiated by a slight stimulus anywhere along the length of a nerve or muscle fibre (see Chapter 6). This creates spontaneous tonic muscular contractions known as tetany. Early signs of acute tetany will be tingling around the mouth and lips and paraesthesia of the fingers, which may progress to painful carpopedal spasms. Left
CHAPTER 11 Alterations of endocrine function across the life span
untreated it may progress to convulsions, laryngeal spasms and, in severe cases, death by asphyxiation Other symptoms of chronic hypocalcaemia include dry skin, loss of body and scalp hair, hypoplasia of developing teeth, horizontal ridges on the nails, cataracts, basal nuclei calcifications (may be associated with a parkinsonian syndrome) and bone deformities. Phosphate retention caused by increased renal reabsorption of phosphate is also associated with hypoparathyroidism. Hyperphosphataemia results from parathyroid hormone deficiency and, in turn, hyperphosphataemia further lowers calcium by inhibiting the activation of vitamin D, thereby lowering gastrointestinal absorption of calcium.46 EVALUATION AND TREATMENT
A low serum calcium and high phosphorus level in the absence of renal failure, intestinal disorders or nutritional deficiencies is diagnostic of hypoparathyroidism. Ideally the four parathyroid glands are identified during thyroid surgery and left in their natural positions. If removal cannot be avoided, they can be transplanted back into the body through a procedure called auto-transplantation. Parathyroid tissue is identified, finely cut up and inserted
275
back into muscle; for example, sternocleidomastoid muscle. Short-term hypocalcaemia may still result for several weeks until the parathyroid tissue regains normal function.46 Postsurgical monitoring of serum calcium and parathyroid hormone levels is essential in all patients following thyroid, parathyroid or neck dissection.46 Hypocalcaemia must be treated to prevent acute symptoms. This involves parenteral administration of calcium, which corrects serum calcium within minutes. Treatment of chronic hypocalcaemia is more difficult, requiring regular pharmacological doses of the active form of vitamin D (calcitriol) and oral calcium. Hypoplastic dentition, cataracts, bone deformities and basal nuclei calcifications do not respond to the correction of hypocalcaemia, but the other symptoms of hypocalcaemia are reversible.46,47 FOCU S ON L EA RN IN G
1 How does excessive parathyroid hormone affect bones? 2 What are the results of a lack of circulating parathyroid hormone?
chapter SUMMARY Mechanisms of hormonal alterations • Abnormalities in endocrine function may be caused by elevated or depressed hormone levels. This may result from: (a) faulty feedback systems, whereby all of the components of a negative feedback loop are not working appropriately; (b) dysfunction of the gland, in that it produces too much or too little of the hormone, despite normal levels of stimulus; (c) altered metabolism of hormones, such that they are metabolised faster or slower than normal; and (d) production of hormones from non-endocrine tissues such as cancerous growths.
Alterations of pituitary function • Disorders of the posterior pituitary include syndrome of inappropriate antidiuretic hormone secretion (SIADH) and diabetes insipidus. SIADH is characterised by abnormally high antidiuretic hormone secretion; while in diabetes insipidus, antidiuretic hormone secretion is abnormally low. • In SIADH, high antidiuretic hormone levels interfere with renal water excretion. As a result, large quantities of retained water dilute plasma sodium, leading to
hyponatraemia and hypo-osmolality. This condition usually arises due to brain injury or with certain forms of cancer, apparently because of secretion of antidiuretic hormone by tumour cells. • Diabetes insipidus is mainly neurogenic (caused by insufficient amounts of antidiuretic hormone) or nephrogenic (caused by an inadequate response by the kidneys to hormone). Its principal clinical features are polyuria and polydipsia.
Alterations of adrenal function • Disorders of the adrenal cortex are most commonly related to excessive secretion of hormones. • Excessive aldosterone secretion causes hyperaldosteronism, which may be primary or secondary. Primary hyperaldosteronism is caused by an abnormality of the adrenal cortex. Secondary hyperaldosteronism involves an extra-adrenal stimulus, often angiotensin. • Hyperaldosteronism promotes increased sodium reabsorption by the kidneys, so that sodium remains in the blood. This corresponds with hypervolaemia (as Continued
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• • • •
• •
Part 2 Alterations to regulation and control
water is retained with the sodium), increased extracellular volume (which is variable) and may cause hypokalaemia (as potassium is excreted by the kidneys when sodium is reabsorbed). Hypercortisolism leads to the development of the constellation signs and symptoms known as Cushing’s syndrome. Hypercortisolism is usually caused by Cushing’s disease but can also be caused by adrenocortical tumours. Complications include obesity, diabetes mellitus, protein wasting, immune suppression and mental status changes. Hypoadrenalism though rare is a potentially lifethreatening condition. Glucocorticoid replacement for life is required and in some mineralocorticoids are needed. When unwell increased doses are required. Patients and their closest family members need to be well educated in understanding how to manage sick days, how to recognise adrenal crisis and how to initiate early treatment with intramuscular hydrocortisone.
Alterations of pancreatic function • Diabetes mellitus is a group of disorders characterised by glucose intolerance, chronic hyperglycaemia (raised blood glucose levels) and disturbances of carbohydrate, protein and fat metabolism. • Type 1 diabetes mellitus is characterised by a gradual process of autoimmune destruction of pancreatic beta cells in genetically susceptible individuals. This leads to a lack of insulin. • In type 1 diabetes mellitus, hyperglycaemia results in glucose being excreted in the urine. The glucose passing through the kidney tubules attracts water and therefore larger amounts of water are lost in the urine. As a result, polyuria and polydipsia are common symptoms. • Women with type 1 and type 2 diabetes have a significant risk of fetal abnormality and miscarriage when there is poor glycaemic control at conception and during the first trimester. • Gestational diabetes is glucose intolerance during pregnancy. It can result in serious life-threatening consequences for the fetus and therefore screening during pregnancy is recommended to allow early treatment.
Alterations of thyroid function • In general, hyperthyroidism has a range of manifestations related to the endocrine, cardiovascular and gastrointestinal systems. It also affects the eyes. These manifestations are caused by increased circulating levels of thyroid hormone and by stimulation of the sympathetic division of the autonomic nervous system. • Goitre, which is an enlarged thyroid gland, can occur with either hyperthyroidism or hypothyroidism, although the cause of the enlargement is different in both cases. • Thyrotoxicosis describes the greater than normal physiological responses to the excess thyroid hormone
•
• •
•
• •
•
•
• • • • •
levels. The condition can be caused by a variety of specific diseases, each of which has its own pathophysiology and course of treatment. Graves’ disease, the most common form of hyperthyroidism, is caused by an autoimmune mechanism that overrides normal mechanisms for control of thyroid hormone secretion and is characterised by thyrotoxicosis, ophthalmopathy and circulating thyroid-stimulating immunoglobulins. Toxic multinodular goitre is caused by independently functioning follicular cell adenomas. Thyrotoxic crisis (thyroid storm) is a rare but severe form of hyperthyroidism that is associated with physiological or psychological stress. Without treatment, death occurs quickly. Primary hypothyroidism is caused by deficient production of thyroid hormone by the thyroid gland. Secondary hypothyroidism is caused by hypothalamic or pituitary dysfunction. Symptoms depend on the degree of thyroid hormone deficiency. Common manifestations include decreased energy metabolism, decreased heat production and myxoedema. Acute thyroiditis is inflammation of the thyroid gland, often caused by bacteria, which can result in hypothyroidism. Subacute thyroiditis is a self-limiting nonbacterial inflammation of the thyroid gland. The inflammatory process damages follicular cells, causing leakage of T3 and T4. Hyperthyroidism is then followed by transient hypothyroidism, which is corrected by cellular repair and a return to normal levels in the thyroid. Autoimmune thyroiditis is associated with infiltration or fibrosis of the thyroid, circulating thyroid antibodies and gradual loss of thyroid function. Autoimmune thyroiditis occurs in those individuals with genetic susceptibility to an autoimmune mechanism that causes thyroid damage and eventual hypothyroidism. Myxoedema is a sign of hypothyroidism caused by alterations in connective tissue with water-binding proteins that lead to oedema and thickened mucous membranes. Pregnancy places an increased demand on thyroid function with a corresponding increase in demand on iodine. Iodine supplementation is of benefit in preconception, pregnancy and during breastfeeding. Laboratory reference ranges change for thyroidstimulating hormone and free T4 during pregnancy. Women with current hyperthyroidism in pregnancy should be screened for Graves’ disease and managed appropriately to reduce risk to the fetus and neonate. The presence of thyroid autoantibodies can increase the risk of miscarriage and early delivery. Women have benefited from thyroid hormone treatment.
Alterations of parathyroid function • Hyperparathyroidism, which may be primary, secondary or tertiary, is characterised by greater than normal secretion of parathyroid hormone.
CHAPTER 11 Alterations of endocrine function across the life span
• Primary hyperparathyroidism is caused by an interruption of the normal mechanisms that regulate calcium and parathyroid hormone levels. Manifestations include chronic hypercalcaemia, increased bone resorption and hypercalciuria. • Secondary hyperparathyroidism is a compensatory response to hypocalcaemia and often occurs with chronic renal failure or vitamin D deficiency.
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• Hypoparathyroidism, defined by abnormally low parathyroid hormone levels, is caused by thyroid surgery, autoimmunity or genetic mechanisms. • The lack of circulating parathyroid hormone in hypoparathyroidism causes depressed serum calcium levels, increased serum phosphate levels, decreased bone resorption and eventual hypocalciuria.
CASE STUDY
ADU LT Susan is a 51-year-old information technology professional. She recently started losing weight without trying, which she found to be quite satisfying! At the same time, she also noticed that she felt quite hot when others around her do not complain of the heat. Susan thought she was probably getting into menopause, as she knows that this is characterised by hot flushes. She tires easily, but put this down to working long hours and getting older. None of these symptoms gave Susan any real cause for alarm. However, what made her think that there might be something wrong is the increasing number of heart palpitations she has — she can feel her heart racing quite quickly. She has been feeling more anxious and suspects that this is because her fast heart rate makes her quite worried. So she decides to seek medical attention.
Physical examination reveals tachycardia (a high heart rate of 105 beats per minute), moist hands, fine tremor of her outstretched hands and brisk reflexes. She had systolic hypertension (high blood pressure of 145/80). Her eyes appear somewhat wide open and there is an enlargement in the anterior (front) of her neck. 1 Which endocrine disorder is consistent with Susan’s signs and symptoms? 2 Discuss the enlargement found in Susan’s neck. 3 Explain why it might be possible to have low levels of thyroid-stimulating hormone and high levels of thyroid hormone. 4 Relate Susan’s symptoms to your diagnosis of the disorder. 5 Briefly discuss some treatment options for Susan.
CASE STUDY
AGEING Helena is an 82-year-old woman who has been self-caring and living in a granny flat in her daughter Gina’s home. She has no significant medical history and is on a cholesterollowering medication only. Over several weeks her daughter notices Helena has lost her appetite, complains of nausea and constipation but is thirsty and regularly visits the bathroom to ‘pass water’. This normally happy and sociable woman appears to be mildly confused, is unusually sad and is unsteady on her feet. Late one night Helena is found on the bathroom floor, confused and holding her right hand which is swollen at the wrist. An ambulance is called because Helena is too confused and weak to get up. In the emergency department Helena’s observations include blood pressure of 168/96 pulse 64. Her electrocardiogram shows sinus rhythm but the QT interval is shortened.
Clinically she is mildly dehydrated but regularly wants to pass urine. Her urine is noted to be clear and dilute. She has proximal weakness and complains of bone pain. Her right wrist is swollen and she is unable to lift her hand. She is mildly confused despite answering some questions well. 1 What condition do you think Helena is acutely suffering from? 2 Her calcium is 2.95 (2.15–2.55 mmol/L). Which endocrine abnormality is the most common cause of this condition? 3 Explain how this endocrine disorder increases the risk of osteoporosis. 4 Explain how Helena’s signs and symptoms relate to the endocrine disorder. 5 What are the possible treatments for this endocrine disorder?
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REVIEW QUESTIONS 1 Describe how the syndrome of inappropriate antidiuretic hormone secretion (SIADH) relates to hyponatraemia. 2 Why do people with diabetes insipidus have large volumes of urine? 3 What are the effects of hyperaldosteronism on the body? 4 What do disorders of antidiuretic hormone and aldosterone share in common? 5 Describe how hyperaldosteronism and hypertension are linked.
6 Explain the clinical manifestations of hypercortisolism, including the effects on immunity. 7 Discuss the cause of type 1 diabetes and relate this to dependency on insulin treatments. 8 List the manifestations of Graves’ disease. 9 Discuss the effects of hypothyroidism. 10 Explain the consequences of hyperparathyroidism.
Key terms adaptive immunity, 282 agglutination, 292 allergens, 288 antigens, 288 antitoxins, 293 cell-mediated immunity, 291 cytokines, 285 cytotoxic T cells, 290 epitope, 288 haptens, 288 helper T cells, 290 human leucocyte antigens (HLAs), 295 humoral immunity, 291 IgA, 291 IgD, 292 IgE, 292 IgG, 291 IgM, 291 immunoglobulin (Ig), 291 innate immunity, 282 lymphocyte, 284 macrophages, 284 major histocompatibility complex (MHC), 288 memory cells, 289 memory T cells, 290 monocytes, 284 mononuclear phagocyte system, 284 neutralisation, 292 neutrophils, 284 pathogens, 284 plasma cells, 289 precipitation, 292 primary immune response, 299 regulatory T cells, 290 secondary immune response, 299 self-antigen, 288
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Lynne Hendrick Chapter outline Introduction, 282 Human defence mechanisms, 282 Innate immunity, 282 Adaptive immunity, 287 Cells of the immune system, 289
Humoral and cell-mediated immunity, 291 Humoral immune response, 291 Cell-mediated immune response, 294 Induction of the immune response, 298 Ageing and the immune system, 301
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Introduction Of all the body systems, the immune system is one of the most complex. Unlike a discrete organ system, such as the pulmonary system, the immune system is not confined to one organ but is spread throughout the entire body. It is composed of several levels, and numerous cell types and molecules work together to provide immune responses. The immune system and its associated responses have many functions, but the most important one is to protect the body from foreign substances. In fact, the word ‘immunity’ is derived from the Latin word immunitas, literally meaning ‘exemption’, referring to a body that is free from disease. For a foreign substance such as a microorganism to enter the body it must pass through highly effective physical barriers, such as the skin, and chemical barriers, such as enzymes in gastric fluid that minimise the spread and impact of these agents. These first-line barriers are supplemented by rapidly activated biochemical and cellular responses — commonly referred to as inflammation — that limit damage and initiate repair. However, the most sophisticated component of the system is its ability to mount an adaptive response that specifically targets each foreign substance and uses various mechanisms to neutralise and destroy it. These responses are very powerful and increase the body’s long-term protective capacity against specific and highly dangerous infectious agents. It is often difficult for students to grasp the structure of the immune system because of the vast assortment of cells and molecules involved in immune responses. Compounding this is the nomenclature — that is, the names designated to various immune components. This nomenclature has changed considerably as more and more components are discovered and the terms are often confusing. In addition, there are many misconceptions about the immune system. For instance, it is not uncommon to hear people comment that a person who has an infection has a ‘weak’ immune system, or that vaccinations are not safe or are linked to various disorders. In reality, the immune system is continually providing protective defences for the body. Moreover, during periods of heightened immune activity, such as when invading microorganisms are causing infection, the immune system is activated further to combat them and assist restoring the body back to homeostasis. It is only over the last three decades that our understanding of the immune system has been greatly enhanced. However, many aspects are still not fully understood and, despite the sophistication of the immune system and technological improvements in therapies and treatment, the immune system is constantly under threat from foreign substances that may enter our bodies. Therefore, a fundamental and thorough understanding of each component of the immune system is required before looking at how they integrate to protect the body and provide immunity. Chapters 12–15 explain the structure and function of the immune system, how it responds and how it can be affected by foreign substances. There are separate chapters on inflammation and fever, and infection, because these
occur in large numbers of individuals in healthcare facilities, especially in hospitalised patients. There is also a separate chapter on alterations of immune function across the life span — that is, factors that cause the immune system to overcompensate and those that attack the immune system directly. We start by exploring the immune system, which provides insight into how the body protects itself and fights foreign invaders such as infectious microorganisms.
Human defence mechanisms We need first to define the term foreign substances, because it is used throughout Chapters 12–15 and there are several terms that can be considered under this broad heading. Foreign substances are anything that comes from outside the body and which are not considered part of the body. For instance, the most commonly used example of foreign substances is that of infectious microorganisms such as bacteria, viruses, parasites and fungi. However, the term also refers to anything that enters the body and is recognised by the immune system as foreign, such as a transplanted organ. Therefore, the immune system is highly sophisticated at recognising what is foreign. The human body is continually exposed to a large variety of conditions that can result in damage, such as sunlight, pollutants, agents that can cause physical trauma and infectious agents (bacteria, viruses, fungi and parasites). Damage may also arise from within, such as cancers. The damage may be at the level of a single cell, which can be easily repaired, or at the level of multiple cells, tissues or organs, which can result in severe alterations, leading to disease and potentially death. The immune system can be divided broadly into two sections that operate on different levels but work cooperatively to protect the body from foreign substances: • Innate immunity — also called natural, native or nonspecific immunity — is a natural resistance that is present at birth and protects the individual by providing a natural barrier, activating cells and molecules that limit and destroy the capacity of foreign substances to enter and spread throughout the body. • Adaptive immunity — also called acquired and specific immunity — develops as the individual is exposed to foreign substances. It is a slower performing system than the innate system, yet is more powerful and precise, as it selectively targets foreign substances that it has identified. While adaptive immunity is commonly referred to as the immune response, the two forms of immunity should be considered as an overall system that provides protection, because without innate immunity, adaptive immunity would not be able to protect the body.
Innate immunity
Innate immunity includes all components of the immune system except those that can specifically recognise and
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Eyes Tears Lymph nodes Macrophages NK cells
Respiratory tract Mucus Cilia Alveolar macrophages
Blood Leucocytes Spleen Macrophages Natural killer (NK) cells
Liver Kupffer cells Digestive system Gastric acid Bile Enzymes Mucus Normal flora
Urogenital tract Flushing of urine Acidity of urine Lymph nodes Resident and recirculating macrophages
Connective tissue Macrophages
Macrophages in bone marrow
Skin Barrier First line of defence Mechanical barriers Chemical barriers Second line of defence Inflammatory response Phagocytosis Third line of defence Specific immune responses
External environment Injury Secretion
Bacteria Skin or mucosa
Internal environment
Macrophage T cell Antibody
FIGURE 12.1
Innate immunity throughout the body. This includes the first line of defence, physical barriers (skin, mucous membranes) and the second line of defence, inflammation and phagocytosis. If a foreign substance enters the system, second-line defence mechanisms are activated to limit the spread.
remember foreign substances that have been encountered. These are shown in Fig. 12.1. Innate immune responses are nonspecific — that is, they provide a generalised response to foreign substances. The system does not need to identify what a specific particle is in order to be activated. Following on from this, the innate immune system does not remember a particular foreign substance, because it never identifies it in the first place. Innate immunity consists of two levels of protection: • The skin and mucous membranes form a physical barrier that is often referred to as the first line of defence — in
most instances this physical barrier successfully prevents the foreign substance from actually penetrating further into the body. This first line of defence is remarkably effective and when it is damaged can leave the body vulnerable to invasion (e.g. a skin wound becoming infected). • The second line of defence consists of a range of cells, chemicals and processes that are activated if a foreign substance has broken through the first line of defence. These include the phagocytes and natural killer cells (cellular components) and cytokines (signalling
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proteins), as well as inflammation and fever (see Chapter 13). The following sections look at the components of innate immunity.
Epithelial barriers
Epithelial cells are those that line cavities and the body surface, such as the skin. The physical barriers that cover the external parts of the human body offer considerable protection from damage and invasion by foreign substances. The external body covering of the skin consists of tightly associated epithelial cells and this is continuous with the mucous membranes that line the gastrointestinal, respiratory and genitourinary tracts. When foreign substances attempt to penetrate these physical barriers, they may be removed by mechanical means — that is, sloughed off with dead skin cells as they are routinely replaced, expelled by coughing or sneezing, vomited from the stomach or flushed from the urinary tract by urine. Epithelial cells of the upper respiratory tract also produce mucus and have hair-like cilia that trap and move foreign substances upwards to be expelled by coughing or sneezing (see Chapter 24). Additionally, the low temperature on the body’s surface (which is typically lower than the core temperature) generally inhibits microorganisms, most of which routinely require temperatures near 37°C for efficient growth. Epithelial surfaces also secrete substances intended to trap or destroy pathogens. Mucus, sweat, saliva, tears and cerumen (earwax) are all examples of biochemical secretions that can trap potential invaders and contain substances that will kill microorganisms. In addition, sweat, tears and saliva contain an enzyme (lysozyme) that attacks the cell walls of gram-positive bacteria. Sebaceous glands in the skin also secrete fatty acids and lactic acid that kill bacteria and fungi. These glandular secretions create an acidic (pH 3 to 5) and inhospitable environment for most bacteria. Epithelial cells secrete small molecular weight proteins, generically termed antimicrobial peptides, which are toxic to bacteria, fungi and viruses. A spectrum of non-pathogenic bacteria, collectively known as normal bacterial flora, resides on the body’s surfaces. The normal flora contributes to our innate protection against microorganisms that cause disease — these are pathogens. Colonisation of the lower gut by normal flora begins quickly after birth and the number and concentration of microorganisms increases progressively during the first year of life. Many of these microorganisms help digest fatty acids, large polysaccharides and other dietary substances; produce vitamin K; and assist in the absorption of various ions, such as calcium, iron and magnesium. They also produce chemicals that inhibit colonisation by pathogens. When individuals are exposed to antibiotic treatment this can alter the normal intestinal flora, decreasing its protective activity, and allow an overgrowth of pathogenic microorganisms, such as the yeast Candida albicans or the bacteria Clostridium difficile. This is often the cause of diarrhoea in individuals on antibiotics. The bacterium Lactobacillus is a major constituent of the
normal vaginal flora in healthy women. This microorganism produces chemicals (hydrogen peroxide, lactic acid and other molecules) that help prevent infections of the vagina and urinary tract by other bacteria and yeast. Diminished colonisation with lactobacilli (e.g. as a result of prolonged antibiotic treatment) increases the risk for urinary tract infections or vaginal infections.
Cellular components PHAGOCYTES
The word phagocyte comes from the Greek word phagein meaning to eat and cyte referring to cells. Therefore, these cells consume other cells or foreign substances. Specifically, phagocytes engulf pathogens and debris, such as dead or damaged cells that are no longer required. Phagocytosis refers to the process of consuming cells and is described in detail in Chapter 13. The phagocytes are types of white blood cells, or leucocytes. There are five types of white blood cells and all of these are required for normal immunity. The phagocytes consist of two types of white blood cells: neutrophils and monocytes. These cells originate from bone marrow and are released into the blood, then move into the tissues when required. Neutrophils are the first-line defenders of the immune system and move rapidly to the site of infection in large numbers and initiate phagocytosis. Monocytes circulate in the blood for about 3 days and are considered an immature form of white blood cell. However, when monocytes migrate into the tissues to provide immune-fighting capabilities, they become macrophages. These supplement and eventually replace the neutrophils and can survive for longer periods of time. Collectively, monocytes and macrophages are referred to as the mononuclear phagocyte system and are located in diverse sites throughout the body (see Fig. 12.1). These cells are described in more detail in Chapter 13 as they are intricately tied to inflammation. NATURAL KILLER CELLS
The main function of natural killer cells, often abbreviated to NK cells, is to recognise and eliminate cells infected with viruses and abnormal host cells, specifically cancer cells. They are derived from a type of white blood cell called a lymphocyte (see Chapter 16 for blood cell types). This is important because there are two other lymphocytes and these are the primary cells of adaptive immunity. As the name implies, natural killer cells have the ability to kill cells that are abnormal without the need for specific recognition via adaptive immunity. Natural killer cells have receptors that allow them to recognise differences between infected or tumour cells and normal cells (see Fig. 12.2). If a natural killer cell binds to a target cell through activating receptors, it produces several molecules that can kill the target.
Chemical mediators CYTOKINES
Apart from the cellular components of innate immunity, there are numerous chemical mediators that enable the immune and inflammatory cells to function more efficiently
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functional activity, for example, tumour necrosis factor; however, as more and more functions are discovered for these cytokines their names can become misleading. Other cytokines are named according to their origin, for example, lymphokines arise from lymphocytes, while other cytokines are classified according to the order in which they were discovered, for example, the interleukins which are denoted using IL. At least 60 cytokines have been classified as interleukins.1 The majority of important cytokines are classified as interleukins or interferons (see Table 12.1), although some critical cytokines are not classified as either. Many of these same cytokines are produced by cells of the adaptive immune system in response to specific antigens and are discussed later in this chapter. Cytokines are produced in the Golgi apparatus. They are either expressed as a cell membrane-bound protein or are released into the cytosol. They are integral to promoting growth, differentiation of cells (which means cells developing into certain types) and activating functions that aid in regulation of immunity. Some cytokines can promote both the stimulation and inhibition of the immune system. Research is currently being conducted into the pathogenic role of cytokines in autoimmune diseases such as systemic lupus erythematosus. Current research has also shown that adipocytes may secrete cytokines that can promote the self-renewal and survival of cancer stem cells thus helping to partially explain why obesity is a risk factor for the development of cancer.2 Chemokines are small cytokines that are thought to play a role in the migration of leucocytes to areas of inflammation. Approximately 50 chemokines have been identified to date.3 Abnormal expression of chemokines and their receptors is thought to play a role in the development of autoimmune diseases and cancer.3 INTERFERONS
FIGURE 12.2
Natural killer cell activity. A Natural killer cells have inhibitory and activating receptors that allow them to recognise cells as either normal, A, or infected, B. APCs = antigen-presenting cells; TH cells = helper T cells; NK cells = natural killer cells; Tc cells = cytotoxic T cells; MHC = major histocompatibility complex.
and assist in their coordination. Collectively, these chemical mediators are referred to as cytokines. The word cytokine is derived from the Greek word cyto meaning cell and kinos meaning movement; therefore, cytokines are molecules that affect other cells (termed cell signalling). The human genome project was largely responsible for enabling the discovery of new cytokines with over 100 cytokines being discovered. The classification of cytokines has been problematic. Some cytokines have been named according to their
Interferons are a family of cytokines that protect against viral infections. Different types of cells produce different kinds of interferons: macrophages and other cells are the primary producers of both interferon alpha (IFN-α) and interferon beta (IFN-β), whereas lymphocytes release interferon gamma (IFN-γ). Interferon alpha and interferon beta induce the production of antiviral proteins, thereby conferring protection on uninfected cells (see Fig. 12.3). Interferon gamma enhances the inflammatory response by increasing the activity of macrophages. This cytokine also facilitates the development of the acquired immune response against viral antigens on infected cells. Although we have examined several components of innate immunity, these are discussed in more detail in our discussion of the inflammatory response in Chapter 13. Inflammation forms the second line of defence when foreign substances have penetrated the epithelial barriers; it is also a major component of innate immunity and is therefore crucial to your understanding of the body’s defences. Furthermore, the components of innate immunity cross over to assist and work with components of adaptive immunity and are essential to coordinated defence responses.
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TABLE 12.1 Key cytokines and receptors that influence the immune response CYTOKINE
PRIMARY SOURCE
PRIMARY FUNCTION
IL-1
APCs
Stimulates T cells to proliferation and differentiation; induces acute phase proteins in inflammatory response; endogenous pyrogen
IL-2
TH1 cells, NK cells
Stimulates proliferation and differentiation of T cells and NK cells
IL-4
TH2 cells, mast cells
Induces B-cell proliferation and differentiation; up-regulates MHC class II expression; induces class-switch to IgE
IL-5
TH2 cells, mast cells
Induces eosinophil proliferation and differentiation; induces B-cell proliferation and differentiation
IL-6
TH2 cells, APCs
Induces B-cell proliferation and differentiation; induces acute phase proteins in inflammatory disease
IL-7
Thymic epithelial cells, bone marrow stromal cells
Major cytokine for induction of B- and T-cell proliferation and differentiation in the central lymphoid organs
IL-8
Macrophages
Chemotactic factor for neutrophils and T cells
IL-10
TH cells, B cells
Inhibits cytokine production; activator of B cells
IL-12
B cells, APCs
Induces NK-cell proliferation; increase production of IFN-γ
IL-13
TH2 cells
IL-4-like properties; decreases inflammatory responses
IFN-α, IFN-β
Macrophages, some virally infected cells
Antiviral; increases expression of MHC class I; activates NK cells
IFN-γ
TH1 cells, NK cells, Tc cells
Increases expression of MHC class II; activates macrophages and NK cells
Interleukins (IL)
Interferons (INF)
Tumour necrosis factor (TNF) TNF-α (cachectin)
Macrophages
TNF-β (lymphotoxin) Tc cells
IL-1-like properties; induces cellular proliferation Kills some cells; increases phagocytosis by macrophages and neutrophils
Transforming growth factor (TGF) Lymphocytes, macrophages, fibroblasts
TGF-β
Interferon molecules Virus
Chemotactic for macrophages; increases macrophage IL-1 production; stimulates wound healing Antiviral protein Viral interferon
Cell infected with virus produces interferon
Interferon binds to uninfected cell and induces production of antiviral protein
Antiviral protein blocks viral nucleic acid production
FIGURE 12.3
The action of interferon on infected cells. Cells that are infected with the virus produce interferon, which is released and targets healthy body cells to increase their antiviral production. As a result, this allows the healthy body cell to be protected from the viral infection.
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RESEARCH IN F
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Adaptive immunity
CUS
In recent years with the discovery of more cytokines there has been extensive research in the mechanisms of immune regulation and the development of certain diseases such as allergy, autoimmune diseases, tissue transplantation, chronic infections and cancer. The roles of the different cytokines in both pro-inflammatory processes and anti-inflammatory processes have been widely investigated. Current research is directed at development of treatment measures for a wide range of diseases by targeting specific cytokine molecules or their receptors. The drugs include interleukin specific human recombinant interleukins (e.g. Human Recombinant IL-7), monoclonal antibodies and interferons. The benefits of this research are far-reaching for the treatment of diseases not directly considered to be immunologically based as chronic inflammation is implicated in diseases such as Alzheimer’s disease, cardiovascular disease and type 2 diabetes.
F O CUS O N L E A R N IN G
1 Explain what the term foreign substance means in an immunological context and provide examples. 2 Outline the role of phagocytes in immune function. 3 Describe how natural killer cells discriminate between infected cells and non-infected cells. 4 Describe what a cytokine is and explain the role that cytokines play in immune function.
The third line of defence is adaptive immunity, often called the immune response. It is specific and has memory, so that it can confer permanent or long-term protection against particular foreign substances, such as microorganisms. Many components of innate resistance are necessary for the development of the adaptive immune response. Conversely, products of the adaptive immune response protect the individual by activating components of innate resistance. Thus, both systems are essential for complete protection against foreign substances. The two systems are compared in Table 12.2. The main defining characteristic of adaptive immunity is the ability to specifically recognise various foreign substances and to remember them. This is very important because it accelerates the immune response the next time that a particular foreign substance is encountered. It should be noted that adaptive immunity, while very powerful and targeted, responds more slowly compared to innate immunity (namely, the inflammatory processes). Nonetheless, when activated, adaptive immunity is highly specific at protecting the body. The first aspect that we look at is how the immune system differentiates between normal and foreign cells.
Antigens
The immune system is continually challenged by a spectrum of substances. One of the primary features of adaptive immunity is the ability to recognise ‘self ’ from ‘non-self ’ — that is, to recognise normal body cells and tissues from what is foreign. Each cell in the body can be identified as self. These cells are not normally attacked by the immune system because they are recognised as self and so immune responses
TABLE 12.2 Overview of human defences INNATE IMMUNITY CHARACTERISTICS
BARRIERS
INFLAMMATORY RESPONSE
ADAPTIVE IMMUNITY
Level of defence
First line of defence against infection and tissue injury
Second line of defence; occurs as a response to tissue injury or infection
Third line of defence; becomes active when innate immune system signals the cells of adaptive immunity
Timing of defence
Constant
Immediate response
Delay between exposure to antigen and maximum response
Specificity
Broad
Broad
Very specific
Cells
Epithelial cells forming anatomical barriers (skin and mucous membranes)
Mast cells, granulocytes (neutrophils, eosinophils, basophils), monocytes and macrophages, natural killer cells, platelets, endothelial cells
T lymphocytes, B lymphocytes, macrophages, dendritic cells
Memory
No memory
No memory
Specific immunological memory by T and B lymphocytes
Protein factors
Toxins from epithelial cells, lysozyme, bacterial toxins
Complement, clotting factors, kinins
Antibodies, complement
Cytokines
Few
Many
Many
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are not triggered. The cells in the body contain a marker (self-marker) that consists of molecules (proteins) of the major histocompatibility complex (MHC). There are two classes: MHC class I and MHC class II. MHC class I proteins are found on all cells in the body with a nucleus and can inform the immune system when they are infected or are cancerous. This can be seen in how natural killer cells respond to infected cells (refer to Fig. 12.2). MHC class II proteins are found on cells that aid the immune system to recognise what is foreign. The cells that contain class II proteins are called antigen-presenting cells. When antigen presenting cells (APCs) encounter a pathogen, they travel to the lymph nodes where they present the antigen to naïve T cells.4 This process is described in greater detail later in the chapter. The immune system recognises non-self cells via antigens. Simply put, antigens are the substances that determine whether an immune response will be initiated — they are identifiers for the immune system. Non-self cells can be infectious microorganisms, such as bacteria, viruses, fungi and parasites, or non-infectious agents, such as pollen and foods. Furthermore, drugs and other body tissues and fluids contain antigens that can be identified as foreign. That is why organ transplants are recognised as foreign, and a transplant recipient must be medicated with immunosuppressive drugs that dampen the usual immune response. The antigen can be the whole non-self cell or a protein on the foreign body surface. A useful analogy to understand antigens is that of personal characteristics that we use to identify individuals. For instance, say you are meeting someone you have not met before. They inform you that they have blonde hair. When you go to meet them, you search for someone with blonde hair, but see only black-haired individuals. After some time, you spot a blonde-haired individual and greet them. In this example, self are analogous with black hair, as you ignored them, and blonde hair is similar to an antigen. You identified the individual by their hair colour (antigen) and made contact with them. Similarly, the immune system identifies what is foreign and what is self, and accordingly identifies what action (or not) needs to be taken. To be antigenic, part of a molecule’s chemical structure must be recognised and become bound to an antibody or to specific receptors on a lymphocyte in a lock-and-key manner. The precise area of the molecule that is recognised is called its antigenic determinant, or epitope. The size of an antigenic determinant is relatively small, perhaps just a few amino acids or simple sugars. A large molecule (e.g. protein, polysaccharide, nucleic acid) usually contains multiple and diverse antigenic determinants. Thus, the immune response against the molecule may consist of a mixture of specific antibodies against several of these determinants. Certain criteria influence the degree to which an antigen is immunogenic (its ability to induce an immune response). These include: (1) foreignness to the host; (2) adequate size; (3) adequate chemical complexity; and (4) being present
in sufficient quantity. These criteria are important for the development of vaccines, which must be highly immunogenic to produce protective immune responses against pathogenic microorganisms. An antigen that fulfils all four criteria except foreignness is considered a self-antigen and does not normally elicit an immune response. Thus, most individuals are tolerant to their own antigens. Some pathogens are successful because they develop the capacity to mimic self-antigens and avoid inducing an immune response. In Chapter 15, we discuss specific diseases resulting from a breakdown of tolerance that leads to an individual’s immune system attacking its own antigens (these are autoimmune diseases). Molecular size also contributes to an antigen’s immunogenicity. In general, large molecules such as proteins, polysaccharides and nucleic acids are most immunogenic. Smaller molecules such as amino acids, monosaccharides and fatty acids tend to be unable to induce an immune response. Many molecules in this size range can function as haptens — that is, antigens that are too small to activate the immune system by themselves but become immunogenic after combining with larger molecules that function as carriers for the hapten. For example, the antigens of poison ivy are haptens, but they initiate allergic responses in individuals after binding to larger proteins in the skin. Antigens that induce an allergic response are also called allergens. Even if an antigen fulfils all these criteria, the quality and intensity of the immune response may still be affected by a variety of additional factors. For example, the route and vehicle of antigen entry or administration are critical to the immunogenicity of some antigens. This has important clinical implications. The most common routes for clinical administration of antigens in the form of vaccines are intravenous, intraperitoneal, subcutaneous, intranasal and oral. Each route preferentially stimulates a different set of lymphocyte-containing (lymphoid) tissues and therefore results in the induction of different types of immune responses. For some vaccines, the route may affect the protectiveness of the immune response, so that the individual is protected if immunised by one route, but may be less protected if administered through a different route (e.g. oral versus injected polio vaccines). Immunogenicity of an antigen also may be altered by being delivered along with substances that stimulate the immune response; these substances are known as adjuvants. Finally, the genetic make-up of the individual can play a critical role in the immune system’s ability to respond to many antigens. Some individuals appear to be unable to respond to immunisation with a particular antigen, whereas they respond well to other antigens. For instance, a small percentage of the population may fail to produce a measurable immune response to a common vaccine, despite multiple injections. An individual’s immune response can be affected by the person’s age, nutritional status, genetic background and reproductive status, as well as by exposure to traumatic injury, concurrent disease or the use of immunosuppressive medications.
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FOCUS O N L E A R N IN G
1 Compare innate immunity and adaptive immunity. 2 Discuss how the immune system distinguishes between self and non-self cells.
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Cell type
Principal function(s)
Lymphocytes: B lymphocytes; T lymphocytes; natural killer cells
Specific recognition of antigens B lymphocytes: mediators of humoral immunity T lymphocytes: mediators of cell-mediated immunity Natural killer cells: cells of innate immunity
3 Describe an antigen and provide a list of what constituents an antigen. 4 Discuss factors that influence whether the antigen will be recognised by the immune system. Lymphocyte
Cells of the immune system
The immune response involves several different cells that can be broadly divided into lymphocytes and antigen-presenting cells. The lymphocytes account for approximately 30% of all white blood cells. Lymphocytes are produced from stem cells, called haematopoietic stem cells, which are involved in the production of all blood cells. These are further divided into lymphoid stem cells that are responsible for the development of two types of lymphocytes: B lymphocytes (B cells), which produce antibodies that enter the blood and react with the antigen; and the T lymphocytes (T cells), which attack the antigen directly. Both cells are extremely specific, so that each individual B or T cell recognises only one specific antigen. In contrast, antigen-presenting cells are responsible for ingesting antigens and presenting them to the T-cell lymphocytes to induce an immune response. The cells are summarised in Fig. 12.4.
Dendritic cell
Effector cells: T lymphocytes; macrophages; granulocytes
Neutrophil
Lymphocytes
The immune response occurs in two phases. Immature lymphocytes are produced in the primary (central) lymphoid organs (see Fig. 12.5) and, when matured into B- and T-cell lymphocytes, have the ability to react against almost any antigen that will be encountered throughout life. It is estimated that B and T cells can collectively recognise millions of different antigenic determinants. When the individual is exposed to an antigen this induces a process that provides further development of only a small group of specialised B and T cells against that particular antigen. B LYMPHOCYTES
The classification of lymphocytes as either B or T is an unusual one. The letter B derives from an organ in birds called the bursa of Fabricius which was found to be responsible for the maturation of B lymphocytes. Humans have no discrete bursa, but the bone marrow makes up the human bursal equivalent and serves as the primary lymphoid organ (see Fig. 12.5) for B cell development. Lymphocytes destined to become B cells circulate through the bone marrow, where they are exposed to hormones that, without the presence of antigen, induce proliferation (producing more cells) and differentiation (develop into more specialised cell types) into B cells. Each
Capture of antigens for display to lymphocytes: Dendritic cells: initiation of T cell responses Macrophages: initiation and effector phase of cell-mediated immunity Follicular dendritic cells: display of antigens Blood monocyte to B lymphocytes in humoral immune responses
Antigen-presenting cells: dendritic cells; macrophages; follicular dendritic cells
Elimination of antigens: T lymphocytes: helper T cells and cytotoxic T lymphocytes Macrophages and monocytes: cells of the mononuclear phagocyte system Granulocytes: neutrophils, eosinophils
FIGURE 12.4
Principal cells of the immune system. The major cell types involved in immune responses and their functions are shown. Micrographs in the left panels illustrate the morphology of some of the cells of each type.
B cell, however, responds to only one specific antigen. They exit the bone marrow and take up residence in other lymphoid organs (secondary lymphoid organs) as immunocompetent (mature) B cells, which means that they have the ability to develop an immune response but have not been activated. Once exposed to an antigen, B lymphocytes can differentiate (or specialise) into plasma cells and memory cells (see Fig. 12.6). Plasma cells are fully differentiated B cells and secrete antibodies, which bind to the antigens to produce an immune response. Memory cells are heterogeneous (vary greatly), long-living cells that remain inactive until subsequent exposure to the same antigen.5 Upon subsequent exposure to that particular antigen, memory cells do not require much further differentiation and rapidly become new plasma cells (see Fig. 12.7).
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Major lymphoid organs
Waldeyer’s ring Lymph nodes Tonsils Adenoids Thymus Bone marrow
Lymph nodes Spleen
Mesenteric lymph nodes Peyer’s patches
Lymph nodes
FIGURE 12.5
Lymphoid tissue throughout the body. Immature lymphocytes migrate through central (primary) lymphoid tissues: the bone marrow (central lymphoid tissue for B lymphocytes) and the thymus (central lymphoid tissue for T lymphocytes). Mature lymphocytes later reside in the T and B lymphocyte-rich areas of the peripheral (secondary) lymphoid tissues. FIGURE 12.6
T LYMPHOCYTES
T cell proliferation (increase in number of cells) is dependent on two factors: the amount of antigen available and the strength of the T cell receptor.6 The primary lymphoid organ for T cell development is the thymus (see Fig. 12.5). Lymphoid stem cells journey through the thymus, where, under the guidance of thymus hormones and without the presence of antigen, they are driven to undergo cell division and simultaneously produce receptors against the diversity of antigens the individual will encounter throughout life. They exit the thymus through the blood vessels and lymphatics as mature (immunocompetent) T cells with antigen-specific receptors on the cell surface and take up residence in secondary lymphoid organs (see Fig. 12.5). There are several different subsets of T cells including: memory cells with similar functions to the B memory cells; regulatory T cells (also called suppressor cells), which help
Differentiation of B cells. Stem cells produce naive B cells that migrate to the secondary lymphoid tissues and bind to an antigen to become activated B cells. These mature into plasma cells, which secrete antibodies specific for the antigen, and memory cells, which accelerate the process when re-exposed to that specific antigen.
regulate T cell immunity; cytotoxic T cells (also called killer T cells), which directly attack antigenic cells; and helper T cells, which assist the activation of both B and T cells. Although the majority of cytotoxic and helper T cells formed during infection die, a small number of antigen-experienced memory T cells will remain and will proliferate again when the body encounters the same pathogen.7 All of these cells are discussed later in the chapter when exploring how the immune response is activated and coordinated.
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in either the direct inactivation of the microorganism or the activation of a variety of inflammatory mediators that will destroy the pathogen. Antibodies are primarily B cell responsible for protection against many bacteria and viruses. receptor This arm of the immune response is termed humoral immunity. Humoral pertains to body fluids and in this Antibodies case refers to the production and secretion of antibodies e.g. IgM that circulate in those body fluids. Lymphocyte T cells also undergo differentiation during B cell Plasma cell an immune response and develop into several subpopulations of effector T cells that react directly with antigen on the surface of foreign substances or infectious agents (see Fig. FIGURE 12.7 12.4). These subpopulations of T cells aid the immune Activation of a plasma cell by a memory cell upon secondary response and are termed cell-mediated immunity, because exposure to the antigen. the immune response is carried out by cells. After the initial exposure to an antigen, subsequent exposure is The success of an acquired immune response depends known as secondary exposure. The immune response is usually on the functions of both the humoral and the cellular-mediated quicker during a secondary exposure, as the antigen binding to B cells leads to quicker production of plasma cells than the initial responses, as well as the appropriate interactions between exposure. them. Repetitive antigen
Antigen-presenting cells
The other cells that are required by the immune system are cells that present antigens to lymphocytes such that an immune response can be initiated. Antigens that enter the bloodstream or lymphatics encounter a variety of antigenpresenting cells. These include macrophages, dendritic cells and B cells. These cells are responsible for engulfing the antigen, breaking it up and presenting antigenic fragments (peptides) on their MHC class I molecules to lymphocytes.8 Dendritic cells come from bone marrow and are similar to macrophages. They have extensive projections, similar to dendrites of neurons, and are located throughout the body. In addition, B cells can also be antigen-presenting cells. Therefore, B cells not only produce plasma and memory cells, but when activated by helper T cells, B cells can present antigens to the T cells to induce an immune response. F O CUS O N L E A R N IN G
1 Discuss how lymphocytes arise from a common blood stem cell in the bone marrow. 2 Describe the formation of B cells and list the various types. 3 Describe the formation of T cells and list the various types. 4 Discuss why antigen-presenting cells are vitally important to the immune system.
Humoral and cell-mediated immunity The adaptive immune response has two arms: antibodies and T cells, both of which protect against infection (see Fig. 12.8).9 Antibodies circulate in the blood and bind to antigens on infectious agents. This interaction can result
Humoral immune response
The primary functions of B cell differentiation are to: (1) produce plasma cells that secrete antibodies in response to antigens; and (2) to produce memory cells that accelerate the process when that particular antigen is encountered again. Therefore, to ensure adequate understanding of the humoral immune response, the types and effects of antibodies need to be understood.
Antibodies
Antibodies, also called immunoglobulin (Ig), are protein compounds found in body fluids that are produced by mature B cells (plasma cells) in response to a challenge by an antigen. The term immunoglobulin is used for all molecules that are known to have specificity for antigen, whereas antibody is generally used to denote one particular set of immunoglobulins known to have specificity for a particular antigen. There are five classes of immunoglobulins (IgG, IgA, IgM, IgD and IgE), which are characterised by antigenic, structural and functional differences (see Fig. 12.9). • IgG is the most abundant class, constituting up to 80% of the immunoglobulin in the blood and accounting for most of the protective activity against infections. As a result of selective transport across the placenta, maternal IgG is the major class of antibody found in the blood of the fetus and newborn. • IgA is found in the blood and body fluids such as tears, saliva and digestive fluids. It accounts for about 10–15% of all antibodies. IgA is important in preventing infectious microorganisms from attaching to epithelial barriers. A small number of individuals do not produce IgA, but the reasons for this are unknown. • IgM is found in the blood, is the largest of the immunoglobulins and accounts for 5–10% of antibodies. It is the first antibody produced during the initial, or primary, response to antigen. IgM is
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Selection, proliferation and differentiation of individual T and B cells with receptors for a specific antigen Antigen CELLULAR IMMUNITY Regulatory T cell
Production of T and B cells with all possible receptors for antigen
Thymus
Immunocompetent T cell
Cytotoxic T cell
Lymphoid stem cell
APC
Bone marrow
TH cell
Memory T cell Memory B cell
Immunocompetent B cell
Plasma cell
Bone marrow Central lymphoid organs
Peripheral lymphoid organs
HUMORAL IMMUNITY
Antibody
FIGURE 12.8
An overview of the adaptive immune response. The immune response arises from cellular divisions and differentiation stages resulting in either immunocompetent T cells from the thymus or immunocompetent B cells from the bone marrow. These cells have never encountered foreign antigen. The immunocompetent cells enter the circulation and migrate to the secondary lymphoid organs (e.g. spleen and lymph nodes), where they take up residence in B- and T-cell rich areas. When exposed to a foreign antigen the cells commence differentiating into the different cell lines. The antigen is usually processed by antigen-presenting cell (APC) for presentation to helper T cells (TH cells). The intercellular cooperation among antigen-presenting cells, helper T cells and immunocompetent T and B cells results in a second stage of cellular proliferation and differentiation, which results in an active cellular immunity or humoral immunity, or both. Cellular immunity is mediated by a population of ‘effector’ T cells that can kill targets (cytotoxic T cells) or regulate the immune response (regulatory T cells), as well as a population of memory T cells that can respond more quickly to a second challenge with the same antigen. Humoral immunity is mediated by a population of soluble proteins (antibodies) produced by plasma cells and by a population of memory B cells that can produce more antibody rapidly to a second challenge with the same antigen.
produced early in neonatal life and its production (synthesis) may be increased as a response to infection in utero. • IgD is found in low concentrations in the blood. Its primary function is as an antigen receptor on the surface of early B cells and for maturation of B cells. Its exact mechanisms are unclear. • IgE is normally at very low concentrations in the circulation. It has very specialised functions as a mediator of many common allergic responses (see Chapter 15) and in the defence against parasitic infections. In individuals with allergies, IgE antibody levels in the blood are often high.
Antigen binding
As can be seen, antibodies have different shapes and sizes (refer to Fig. 12.9). They also have specific sections called antigen-binding fragments, which join with antigens when activated. The chemical nature of the particular amino acids in those sites and the shape of the site determine the
specificity towards a particular antigen. The antigen that will bind most strongly must have complementary chemistry and topography with the binding site formed by the antibody. The antigen fits into this binding site with the specificity of a key into a lock and is held there by the chemical interaction (see Fig. 12.10). It should be noted that most antigens have multiple epitopes — that is, antigenic sites. This means that antigens can bind with more than one antibody, which is advantageous to limiting the spread and proliferation (increase in the number) of pathogenic microorganisms.
The function of antibodies
The chief function of antibodies is to protect the individual from infection. The mechanism can be either direct or indirect (see Fig. 12.11). Directly, antibodies can affect infectious agents or their toxic products by neutralisation (inactivating or blocking the binding of antigen to receptors), agglutination (clumping insoluble particles that are in suspension) or precipitation (making a soluble antigen into an insoluble precipitate). Indirectly, antibodies activate
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IgD Secretory IgA
J chain
IgE
IgG
IgM
FIGURE 12.9
The structural differences of antibodies. The five immunoglobulins (Ig) have different shapes.
Antigen
Epitope
Antibody
Antigen
Epitope
Antibody
FIGURE 12.10
Schematic of antigen–antibody binding. The different shapes of the antigen (i.e. the epitope) dictate how and what type of antibody will bind. This is similar to a lock and key.
components of innate resistance, including the complement system and phagocytes (this is discussed in more detail in Chapter 13). DIRECT EFFECTS
To cause infection, many pathogens must attach to specific receptors on the host’s cells. For instance, influenza viruses
(see Chapter 14 for examples) must attach to specific receptors on respiratory epithelial cells; and the bacteria Neisseria gonorrhoeae (which causes gonorrhoea) must attach to specific sites on urogenital epithelial cells. Antibodies may protect the host by covering sites on the microorganism that are needed for attachment, thereby preventing infection. Many viral infections can be prevented by vaccination with inactivated or attenuated (weakened) viruses to induce neutralising antibody production at the site of the virus’ entrance into the body. A good indication of the degree of protection against viral infection is the level of antibodies found in the blood, which is called antibody titre. This is used clinically to determine the effectiveness of the vaccine. Some bacteria secrete toxins that harm humans. For instance, specific bacterial toxins cause the symptoms of tetanus or diphtheria. Most toxins bind to surface molecules on the host’s cells and damage those cells. Protective antibodies can bind to the toxins, prevent their interaction with the host cells and neutralise their biological effects. Detection of the presence of an antibody response against a specific toxin (antibodies referred to as antitoxins) can aid in the diagnosis of diseases. Antibodies that neutralise bacterial toxins can be induced to confer immunity against bacterial pathogens by means of immunisation. To prevent harming the recipient of immunisation, bacterial toxins are chemically inactivated so that they have lost most of their harmful properties but still retain their immunogenicity. Therefore, an immune response is produced, without the individual developing full symptoms of the toxin or the disease.
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Virus neutralisation
Toxin neutralisation
Virus
Bacterium
Virus receptor
Bacterial toxin
Direct
Complement-mediated killing
Phagocytosis Bacterium
MAC Indirect
Bacterium
C1
Classic pathway Macrophage
FIGURE 12.11
The direct and indirect functions of antibodies. Activities of antibodies can be direct (through the action of antibody alone) or indirect (requiring activation of other components of inflammation). Direct means they include neutralisation of viruses or bacterial toxins before they bind to receptors on the surface of the host’s cells. Indirect means they include activation of the classical complement pathway through C1 resulting in formation of the membrane-attack complex (MAC) or by increased phagocytosis of bacteria opsonised with antibody and complement components bound to appropriate surface receptors on the phagocyte.
INDIRECT EFFECTS
Antibodies can also work by binding to antigens that cause activation of the inflammatory response (see Fig. 12.12). These bindings cause an increase in opsonisation, which is a process that leads to enhanced phagocytosis and activation of the complement system, which may lead to destruction of the pathogen. IgE IgE is a special class of antibody that protects the individual from infection with large parasites. However, when IgE is produced against relatively innocuous environmental antigens it is also the primary cause of common allergies (e.g. hay fever, dust allergies, bee stings). The role of IgE in allergies is discussed further in Chapter 15.
B cell antigen receptor
Another form of antibody serves as an antigen receptor on the B cell, the B cell receptor. Its role is to recognise the antigen and communicate that information to the cell’s nucleus. Therefore, the B cell receptor complex consists of antibody bound to the cell surface and molecules within the cell involved in intracellular signalling. B cell receptors on the surface of B cells that have not yet reacted with antigen are membrane-associated IgM and IgD immunoglobulins
that have identical specificities. After having reacted with an antigen, the B cell receptor on the developing plasma cell may change to other classes of antibody. FOCU S ON L EA RN IN G
1 List the different classes of antibodies and describe their functions. 2 Distinguish between the direct and indirect effects of antibody functions.
Cell-mediated immune response
There are several types of mature T cells, each with a different function. Memory cells induce the secondary immune response; others, such as macrophages, secrete cytokines that activate or signal other cells; cytotoxic cells attack antigens directly and destroy cells with foreign antigens; and regulatory cells, primarily helper T cells, control both cell-mediated and humoral immune responses. T cells are particularly important in protection against viruses, tumours and pathogens that are resistant to killing by normal neutrophils and macrophages. They are also
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Mast cell degranulation IgE Antigen Mast cell degranulation
Acute inflammation
Antigen–antibody
Complement activation Antigen
C5a other fragments Neutrophil chemotaxis T cell Acute or chronic inflammation
Lymphokines Activation of monocyte/macrophage FIGURE 12.12
Antigen–antibody activation of the inflammatory response. Immunological factors may activate inflammation through three mechanisms: (1) IgE can bind to the surface of a mast cell and, after binding antigen, induce the cell’s degranulation; (2) antigen and antibody can activate the complement system, releasing anaphylatoxins and chemotactic factors, especially C5a, which result in mast cell degranulation and neutrophil chemotaxis; and (3) antigen may react with T cells, resulting in the production of lymphokines, which may contribute to the development of either acute or chronic inflammation.
absolutely essential for the development of most humoral responses. The process by which T cells recognise and destroy a target is highly complex and requires an understanding of three different concepts: the T cell receptor complex, antigen presentation molecules and CD molecules (defined in next section). Defects in any of these will lead to major defects in cell-mediated immunity and potentially lead to the individual’s death (see Chapter 15).
T cell recognition of a target cell T CELL RECEPTOR COMPLEX
T lymphocytes use an antigen receptor that is similar to the B cell receptor. The T cell receptor complex is composed of an antibody-like protein and a group of accessory proteins that are involved in signalling to the nucleus. Although the components of the T cell receptor resemble an antibody, they are encoded by different genes. All of the T cell receptors on a single T cell are identical in structure and specificity. ANTIGEN PRESENTATION MOLECULES
Unlike B cells, T cells do not react with soluble antigens. Protein antigen must be presented in a specific manner on the surface of the target cell; it must be held by molecules of the major histocompatibility complex. The immune system uses MHC class I and II molecules to recognise normal
cells from infected or tumour cells. MHC proteins are encoded on chromosome 6 and in humans are referred to as human leucocyte antigens (HLAs) as they were first discovered on leucocytes (white blood cells). They are unique to each individual and this explains why transplanted organs are rejected by the recipients, even when they are closely tissue matched. The T cells use the MHCs to distinguish antigens in the body. Specifically, helper T cells use the complexes to aid in the initiation of an immune response against foreign substances, via the antigen presentation molecules. CD MOLECULES
Cells express a large number of molecules on their surfaces, many of which are important in the immune response. Many of the molecules are part of a nomenclature that uses the prefix ‘CD’ (cluster of differentiation) followed by a number (e.g. CD1 or CD2). The list of CD molecules is constantly increasing (it is currently in excess of 250). Both T and B cells express CD molecules that assist in immune function and can be used to define the subsets of T cells (CD4 helper T cells; CD8 cytotoxic T cells). In this chapter we focus on a small number of highly important examples to illustrate the immensely complicated, but highly effective, interactions that take place to produce a protective immune response.
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antigen membrane and releases cytotoxic chemical, which causes lysis).
T lymphocyte function CYTOTOXIC T LYMPHOCYTES
Cytotoxic T lymphocytes are responsible for the cell-mediated destruction of tumour cells or cells infected with viruses. The cytotoxic T cell must directly adhere to the target cell through an antigen presented by MHC class I molecules and appropriate CD molecules (see Fig. 12.13). Cytotoxic T cell-mediated killing is therefore class I restricted. Because of the cellular distribution of MHC class I molecules, cytotoxic T cells can recognise antigens on the surface of almost any type of cell that has been infected by a virus or has become cancerous. Most cytotoxic T cell killing also requires CD8 on the cytotoxic T cell, which binds to MHC class I on the target. After attachment to a target cell, killing occurs by induction of apoptosis (programmed cell death, but in this case the cytotoxic T cell binds to the
OTHER CELLS THAT KILL ABNORMAL CELLS
Apart from cytotoxic T cells, natural killer cells also target antigens in a similar manner to cytotoxic T cells (see Fig. 12.13). T cells can also activate macrophages via the production of cytokines. The cytokines (particularly interferon-gamma) stimulate the macrophage to become a more efficient phagocyte and increase production of proteolytic enzymes and other antimicrobial substances. REGULATORY T LYMPHOCYTES
Regulatory T cells are a group of T cells that control the immune response.6 Some regulatory T cells suppress immune responses. This population is a mixture of cells that affect
Tu L L
L
T cell receptor 1 Killing by Tc
CD8
MHC I Antigen recognition
APOPTOSIS Target cell with MHC class I
Activation Abnormal receptor surface change
Antigen APOPTOSIS
2 Killing by NK cell
IgG
Target cell without MHC class I 3 Cells other than B and T cells bind to antigen via IgG antibodies
FIGURE 12.13
Cytotoxic T cell mechanisms. Several cells have the capacity to kill abnormal (e.g. virally infected, cancerous) target cells. 1 Cytotoxic T (Tc) cells recognise endogenous antigens presented by MHC class I molecules. The Tc cell mobilises multiple killing mechanisms that induce apoptosis of the target cell. 2 Natural killer (NK) cells identify and kill target cells through receptors that recognise abnormal surface changes. Natural killer cells specifically kill targets that do not express surface MHC class I molecules. 3 Several cells, including macrophages, can kill by IgG antibodies binding to foreign antigen on the target cell. The macrophages then initiate killing. The insert is a scanning electron microscopic view of Tc cells (L) attacking a much larger tumour cell (Tu).
CHAPTER 12 The structure and function of the immune system
surface protein, called CD4. Cells destined to become cytotoxic T cells have a different cell surface protein, called CD8. The role of CD4 and CD8 is to help the interaction between T cells and antigen-presenting cells by reacting with antigen-presenting molecules. Thus, the T cell receptor and CD4 or CD8 both attach to the antigen-presenting molecules on the surface of another cell. CD4 can only interact with MHC class II molecules, whereas CD8 reacts only with MHC class I molecules. To mature into a functional helper cell, the TH cell must receive several signals, including the T cell receptor binding to antigen and CD4 binding to MHC class II. If all the appropriate signalling pathways are activated, the cell will differentiate (or develop more specialised) into a functional TH cell. Additional signals are provided by cytokines. At this early stage of TH cell differentiation, interleukin-1 (IL-1) secreted by the antigen-presenting cell provides this signal. The TH cell then produces interleukin-2 (IL-2), which is secreted and acts in an autocrine (self-stimulating) fashion to induce further maturation and proliferation of the TH cell. Without IL-2 production, the TH cell cannot efficiently mature into a functional helper cell. At this point, TH cells undergo differentiation into either TH1 or TH2 cells (see Fig. 12.14). These subsets have different functions: TH1 cells appear to provide more help in developing cell-mediated immunity, whereas TH2 cells provide more help for developing humoral immunity. The
the immune response in multiple ways: some affect the recognition of antigen and others suppress the proliferative steps that follow antigen recognition. The most characteristic is the helper T cell, which is necessary for the development of most humoral and cellular immune responses. The human immunodeficiency virus (HIV) specifically infects and destroys helper T cells, thus leading to the onset of life-threatening infections. HELPER T LYMPHOCYTES
Regardless of whether an antigen primarily induces a cellular or humoral immune response, antigen-presenting cells usually must present antigen to helper T cells (TH cells; see Fig. 12.14). This extremely important role involves three distinct steps: 1 the TH cell directly interacts with the antigen-presenting cell through a variety of antigen-specific and antigenindependent mechanisms 2 the TH cell undergoes a differentiation process during which a variety of cytokine genes are activated 3 depending on the pattern of cytokines expressed, the mature TH cell interacts with either immunocompetent B or T cells to cause their differentiation into either plasma cells or effector T cells. When T cells develop in the thymus, two different populations are produced. T cells that are destined to become TH cells emerge from the thymus with a characteristic cell Antigenpresenting cell MHC class II
297
IL-2
TH1 cell
4
T-cell immunity 1
IL-1
inhibits
IL-12
6
3 IL-4
Interferon IL-4
inhibits B-cell immunity
Immature helper cell (TH) IL-2 2
TH2 cell
IL-4, IL-5, IL-6
5
FIGURE 12.14
The development of helper T cells. An antigen-presenting cell presents antigen to an immature helper T cell (precursor). 1 An antigen signal is produced by the interaction of the T cell receptor with antigen presented by MHC class II molecules. Cytokines, particularly IL-1, produced by the antigen-presenting cell provide a second signal. 2 In response to these signals, the immature helper T cell begins producing the cytokine IL-2, which binds with the same cell to accelerate differentiation and proliferation. 3 IL-12 assists differentiation into the TH1 cell, whereas IL-4 assists differentiation into the TH2 cell. 4 The TH1 cell produces cytokines that assist in the differentiation of cytotoxic T cells (e.g. IL-2), whereas 5 the TH2 cell produces cytokines that activate B cell differentiation (e.g. IL-4, IL-5, IL-6). (6) TH1 and TH2 cells affect each other through the production of inhibitory cytokines: interferon will inhibit the development of TH2 cells, and IL-4 will inhibit the development of TH1 cells. IL = interleukin.
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two TH subsets differ considerably in the spectrum of cytokines produced by each. Additionally, each TH cell may suppress the other so that the immune response may favour either antibody formation with suppression of a cell-mediated response, or the opposite. For example, antigens derived from viral or bacterial pathogens and those derived from cancer cells seem to induce a greater number of TH1 cells relative to TH2 cells, whereas antigens derived from multicellular parasites and allergens are hypothesised to result in the production of more TH2 cells. Many antigens, however, produce excellent humoral and cell-mediated responses simultaneously. F OC US O N L E ARN IN G
1 Compare humoral and cell-mediated immunity. 2 Distinguish between cytotoxic, regulatory and memory T cells. 3 Describe how cytotoxic T cells kill their targets. 4 Discuss the differences between helper T cells and cytokines.
Induction of the immune response The final aspect of the immune system is to examine how an immune response begins. The antigen is central to this process. Immune responses are triggered by antigens and this activates the B and T cells to differentiate into their respective cell subsets. This generally occurs in lymphoid organs called secondary (peripheral) lymphoid organs in which an antigen selectively reacts with B or T cells. The secondary lymphoid organs include the spleen, lymph nodes, adenoids, tonsils, Peyer’s patches (intestines) and appendix (see Fig. 12.5). Under the control of a variety of cytokines (see Table 12.1) and complex cellular interactions, the selected B or T cells further proliferate and differentiate into plasma cells that produce antibody, T cells that can attack cellular targets or B or T memory cells that will respond more quickly to a second exposure to the same antigen (see Fig. 12.15).
CELLULAR IMMUNITY
HUMORAL IMMUNITY Extracellular microbe (e.g. bacteria)
Intracellular microbe (e.g. viruses) Antigen-presenting cell
B cells
B B
Helper T cell T
Secreted antibody
T-cell receptor
Processed and presented antigen Cytokines
Neutralisation
Proliferation and activation of effector cells (macrophages, cytotoxic T cells)
Cytokine receptor
Lysis (complement) Phagocytosis (neutrophil, macrophage)
Lysis of infected cell Destruction of phagocytosed microbes
FIGURE 12.15
Humoral and cell-mediated immunity from presentation of the antigen to destruction of the pathogen. Humoral immunity targets pathogens which are external to body cells, and works using B cells and antibodies to cause cell lysis (destruction) of the pathogen. Cell-mediated immunity targets pathogens which have entered body cells, and works using T cells to cause lysis of infected cells.
CHAPTER 12 The structure and function of the immune system
The immune response to antigen has classically been divided into two phases — the primary and secondary responses — which are most easily demonstrated by measuring concentrations of circulating antibody over time (see Fig. 12.16). After a single initial exposure to most antigens, there is a latent period, or lag phase, during which B and T cell differentiation and proliferation occurs. After approximately 5 to 7 days, IgM antibody is detected in the circulation. The lag phase is the time necessary for the production of the B and T cell lines. This is the primary immune response, characterised typically by initial IgM followed by IgG against the same antigen. The quantity of IgG may be about equal to or less than the amount of IgM. If no further exposure to the antigen occurs, the circulating antibody is catabolised (broken down) and measurable quantities fall. The individual’s immune system, however, has been primed. A second challenge by the same antigen results in the secondary immune response, which is characterised by the more rapid production of a larger amount of antibody than the primary response. The rapidity of the secondary immune response is the result of B and T memory cells that do not require further differentiation (see Fig. 12.8). IgM may be transiently produced in the secondary response, but IgG production is increased considerably, making it
Log of antibody titre
Primary response
IgM
First exposure to antigen
299
the predominant antibody class. If the antigenic challenge is in the form of a vaccine or occurs through natural infection, the level of protective IgG may remain elevated for decades. FOCU S ON L EA RN IN G
1 Describe the difference between the primary and secondary immune responses. 2 Explain why memory cells are crucial to the immune system.
RESEARCH IN F
CUS
Immunogenomics is a relatively new term coined for the study of genetic sequencing and molecular pathways associated with immunological diseases. By identifying genetic variations that may play a role in the development of these diseases research teams worldwide are looking to find new treatments for immunological disease or for immune intervention in other diseases. It is hoped that this research will also lead to finding ways to overcome the problem of immunosenescence.
Secondary response
IgG
Subsequent exposure to same antigen Relative time after exposure
FIGURE 12.16
Primary and secondary immune responses. The initial administration of antigen induces a primary response during which IgM is initially produced, followed by IgG. Another administration of the antigen induces the secondary response in which IgM is transiently produced and larger amounts of IgG are produced over a longer period of time.
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When born, human infants are immunologically immature with deficiencies in antibody production, phagocytic activity and complement activity. However, in the last trimester the fetus can produce a primary immune response (IgM; T cell independent) to antigenic challenge in utero and to infections (e.g. cytomegalovirus and rubella virus), but cannot produce sufficient IgG response, and only limited amounts of IgA can be detected. In most cases, maternal antibodies provide protection within the fetal circulation (see Fig. 12.17). At birth, total IgG levels are near adult levels (see Fig. 12.18). After birth, antibody titres (levels) drop as maternal antibody is broken down, reaching a minimum at 5 to 6 months; transient hypogammaglobulinaemia (low antibody levels) can then occur. Recurrent respiratory tract infections are common during this transient period
of immune insufficiency, as the immune system is not sufficiently activated to combat foreign substances, such as bacteria and viruses. Antibodies in breast milk may protect the nursing newborn against these infectious disease agents. Colostrum found in breast milk produces colostral antibodies, which provide the newborn with passive immunity against gastrointestinal infections. They do not provide systemic immunity because they do not cross the newborn’s gut into the bloodstream after the first 24 hours of life. Maternal antibodies that pass across the placenta into the fetus before birth provide passive systemic immunity.
Adult levels of IgG Maternal circulation
IgG
Maternal IgG
Relative concentration of IgG
Child’s IgG
Placental syncytiotrophoblast
3
To fetal circulation
9
Months Birth gestation
FIGURE 12.17
Transport of IgG across the syncytiotrophoblast. The human placenta is covered with a specialised multinucleate cell, the syncytiotrophoblast. Transport of maternal IgG across the syncytiotrophoblast and into the fetal circulation is an active process. Maternal IgG binds to receptors on the surface of the syncytiotrophoblast and is internalised by the process of endocytosis (engulfing the cells). Receptors on the syncytiotrophoblast are specific for IgG and do not bind to other classes of immunoglobulins. Interaction of IgG protects the antibody from lysosomal digestion during transport of the vacuole across the cell. On the fetal side of the syncytiotrophoblast, IgG is released by exocytosis (release of contents outside of the cell).
6
2
4 6
8 10 12
Months after delivery
FIGURE 12.18
Antibody levels in umbilical cord blood and in neonatal circulation. Early in gestation, maternal IgG begins active transport across the placenta and enters the fetal circulation. At birth, the fetal circulation may contain nearly adult levels of IgG, which is almost exclusively from the maternal source. The fetal immune system has the capacity to produce IgM and small amounts of IgA before birth. After delivery, maternal IgG is rapidly destroyed and neonatal IgG production increases.
PAEDIATRICS
Paediatrics and the immune system
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Ageing and the immune system self-limiting in healthy young people, tend to lead to the development of complications such as pneumonia resulting in significant morbidity and mortality in the elderly. Chronic inflammation is also a common feature seen in the elderly which may contribute to degenerative diseases such as cardiovascular disease. Individuals older than 60 are also at greater risk of cancer due to decreased immunological surveillance. The incidence of autoimmune diseases also increases in the elderly, where decline in immune function leads to the failure of multiple tolerance checkpoints leading to the generation of an inflammatory environment.
chapter SUMMARY Human defence mechanisms • Innate immunity is natural resistance, and adaptive immunity is gained after birth. • Foreign substances are anything that the immune system recognises as not normal cells or tissue and so activates immune responses. • Inflammation is a rapid, nonspecific defence that is effective at limiting the spread of foreign substances and activating parts of adaptive immunity. • Epithelial barriers are physical structures, such as the skin surface and mucosal membranes, which provide protection from the environment. • Phagocytes are cells that engulf and digest foreign substances as well as diseased and dead cells. They include neutrophils, monocytes and macrophages. • For both the innate and the adaptive immune systems to function, chemicals are released to regulate the immune response. Cytokines is the term referring to these mediators and includes a vast array of different substances that are integral to normal immune function. • Adaptive immunity is a state of protection, primarily against infectious agents, which differs from inflammation by being slower to develop, being more specific and having memory that makes it much longer lived. • The adaptive immune response is most often initiated by cells of the innate system. These cells process and present portions of invading pathogens (i.e. antigens) to lymphocytes in peripheral lymphoid tissue.
• The production of B and T lymphocytes with receptors against millions of antigens that may possibly be encountered in an individual’s lifetime occurs in the fetus in the primary lymphoid organs — the thymus for T cells and portions of the bone marrow for B cells. • Immunocompetent T and B cells migrate from the primary lymphoid organs into the circulation and secondary lymphoid organs to await antigen. • Antigens are molecules that react with components of the immune response, such as antibodies and receptors on B and T cells. Most antigens can induce an immune response. • The antigenic-determinant, or epitope, is the precise chemical structure with which an antibody or B/T cell receptor reacts. • Self-antigens are antigens on an individual’s own cells. The individual’s immune system does not normally recognise self-antigens as immunogenic. • Very small antigens may not normally be immunogenic (haptens) unless they are bound to a larger molecular weight molecule (carrier). • Most antigens must first interact with antigen-presenting cells. • Antigen is processed in the antigen-presenting cell and presented on the cell surface by molecules of the major histocompatibility complex (MHC). The particular MHC molecule (class I or class II) that presents antigen determines which cell will respond to that antigen. Continued
AGEING
As we age the body undergoes a process known as immunosenescence whereby the immune system declines in function. The thymus reaches maximum size at sexual maturity and then shrinks to be small by middle age — by 45–50 years of age, the thymus is only 15% of maximum size. Thymic hormone production drops, as does the organ’s ability to mediate T cell differentiation. Therefore, T cell function deteriorates, although the number of T cells stays approximately the same. These alterations affect both the adaptive and innate branches of the immune system and increase the susceptibility of the elderly to infection. Common viral infections, such as respiratory illnesses, that are usually
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• The adaptive immune response is mediated by two different types of lymphocytes: B lymphocytes and T lymphocytes. Each has distinct functions: B cells are responsible for humoral immunity, which is mediated by circulating antibodies; and T cells are responsible for cellmediated immunity, in which they kill targets directly or stimulate the activity of other leucocytes. • Immature B cells differentiate when exposed to an antigen to become either plasma cells (which release antibodies) or memory cells (which accelerate the process on further antigenic exposure). • Immature T cells differentiate when exposed to an antigen to become cytotoxic T cells (which kill infected cells), memory cells (which accelerate the process on further antigenic exposure), helper T cells (which assist the immune response) or regulatory T cells (which often suppress the immune response).
Humoral and cell-mediated immunity • The humoral immune response is provided by molecules (antibodies) produced by B cells. • Antibodies are plasma glycoproteins that can be classified by chemical structure and biological activity as IgG, IgM, IgA, IgE or IgD. • The protective effects of antibodies may be direct or indirect. • Direct effects result from the binding of antibody directly to a harmful antigen or infectious agent. These include inhibition of processes that are necessary for infection, such as the reaction of an infectious agent with a particular cell in the body, or neutralisation of harmful bacterial toxins. • Indirect effects result from activation of inflammation by antibodies. These include opsonisation to increase phagocytosis, killing the infectious agent through activation of complement and widespread activation of inflammation through the production of biologically active complement components. • Antibodies of the systemic immune system function internally, in the bloodstream and tissues. Antibodies, primarily secretory IgA, are abundant in the secretions of mucous membranes. • T cells are responsible for the cell-mediated immune response. • There are several types of mature T cells: cytotoxic T cells, regulatory T cells including T helper and T suppression, and memory cells. • T cells have antigen-specific receptors (T cell receptors) that must ‘see’ antigen presented on cell surfaces by special antigen-presenting molecules of the MHC. • Cytotoxic T cells bind to and kill cellular targets such as cells infected with viruses or cancer cells.
• Natural killer cells have some characteristics of cytotoxic T cells and are important for killing target cells in which viral infection or malignancy has resulted in the loss of cellular MHC molecules. • The T cell ‘sees’ the presented antigen through the T cell receptor and accessory molecules: CD4 or CD8. CD4 is found on helper T cells and reacts specifically with MHC class II. CD8 is found on cytotoxic T cells and reacts specifically with MHC class I. • A subgroup of helper T cells (TH2 cells) helps B cells respond to antigen and develop into antibody-secreting plasma cells. • A second subgroup of helper T cells (TH1 cells) helps T cells respond to antigen and develop into functional cytotoxic T cells. • Helper T cells require that antigen be presented in a complex with MHC class II molecules. • Cytotoxic T cells require that antigen be presented by MHC class I molecules. • Development of cell-mediated or humoral immune responses usually depends on populations of helper T cells.
Induction of the immune response • Induction of an immune response begins when antigen enters the individual’s body. • The response to antigen can be divided into two phases: the primary and secondary responses. The primary immune response of humoral immunity is usually dominated by IgM, with lesser amounts of IgG. The secondary immune response has a more rapid production of a larger amount of antibody, predominantly IgG.
Paediatrics and the immune system • Mechanisms of self-defence are naturally somewhat deficient in the fetus, the neonate and the elderly individual. • The T cell-independent immune response is adequate in the fetus and neonate, but the T cell dependent-immune response develops slowly during the first 6 months of life. • Maternal IgG antibodies are transported across the placenta into the fetal blood and protect the neonate for the first 6 months, after which they are replaced by the child’s own antibodies.
Ageing and the immune system • T cell function and antibody production are somewhat deficient in the elderly. • Elderly individuals also tend to have increased levels of circulating autoantibodies (antibodies against selfantigens).
CHAPTER 12 The structure and function of the immune system
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CASE STUDY
P AEDIATR IC Dat is 4 months old and has a cough. His parents initially thought Dat was suffering from a mild winter cold but Dat’s breathing has become rapid and wheezy and he is not interested in feeding. His parents decide to seek medical attention and Dat is diagnosed with bronchiolitis. The doctor informs Dat’s parents that bronchiolitis is a viral infection of the respiratory tract that is common in babies under 6 months of age.
1
Why is bronchiolitis common under the age of 6 months? What happens to an infant’s immune function after the age of 6 months? 3 How can babies be protected from infections in the first few months of life? 4 Why is a baby’s immune function greater at birth than at 4 months? 5 Which class of antibodies gives long-lasting protection? 2
CASE STUDY
ADU LT Jamila is a 19-year-old student. She is talking to her friend, Anji, about her expectation that she will develop the flu (influenza) again this winter because she ‘always gets the flu’ and believes she has a weak immune system. However, Anji has attended immunology lectures and says that she thinks Jamila is incorrect in what she is stating — in fact, the immune system is continually responding to an enormous array of different pathogenic microorganisms and is very effective in responding to these through both innate and adaptive immunity.
1 2 3 4 5
Describe in broad terms how innate and adaptive immunity provide continual protection for the body. Explain how the influenza antigen is identified by the immune system. Name the ways in which antibodies may neutralise and destroy the influenza virus. Explain how helper T cells and cytokines aid the process of the immune response. Describe how memory cells work and why Jamila may ‘always get the flu’ despite having a normally functioning immune system.
CASE STUDY
AGEING Valerie is a 78-year-old retired accountant. Her daughter notices that her mother is frequently ill and that her infections seem to have increased in number, severity and longevity. She is concerned about her mother’s health as, even though her mother received a pneumococcal vaccination, her mother still developed pneumonia and required hospitalisation. Valerie’s GP tells Valerie’s daughter not to worry as this is a common occurrence in the elderly and is due to immunosenescence.
1
Explain what is meant by the term immunosenescence. Describe the impact of immunosenescence on the cells and organs of the immune system. 3 Explain why Valerie developed pneumonia despite being vaccinated against pneumococcal pneumonia. 4 Aside from an increase in infections, what other effects may be observed in an elderly person due to decreased immune function? 5 List ways in which the elderly may increase their resistance to disease and improve their health. 2
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REVIEW QUESTIONS 1 Define the term foreign substance. 2 Describe what the term innate immunity means and how it is linked to inflammatory responses. 3 List the phagocytes and describe their actions. 4 Describe adaptive immunity and differentiate between adaptive immunity and innate immunity. 5 Explain what an antigen is and discuss ways in which the immune system recognises antigens. 6 Describe how lymphoid stem cells differentiate into B and T lymphocytes.
7 Explain the cells of the humoral immune response and the functions of antibodies. 8 Explain the cells of the cell-mediated immune response and the functions they perform. 9 Discuss the ways in which the immune system responds to antigens that have already been identified. 10 Differentiate between the immune systems of children and the elderly.
Key terms acute-phase reactants, 320 anaphylatoxins, 316 basophils, 309 chemotactic factors, 314 coagulation (clotting) system, 318 complement system, 316 cytokines, 315 degranulation, 309 dehiscence, 329 endogenous, 323 eosinophils, 311 fever, 320 granulocytes, 309 granuloma, 318 histamine, 313 hyperthermia, 321 hypertrophic scars, 328 hypothermia, 322 interleukins, 316 keloid scars, 328 kinin system, 318 leucocytosis, 320 leukotrienes, 314 macrophages, 310 mast cell, 309 membrane attack complex (MAC), 316 monocytes, 310 neutrophils, 310 nitric oxide, 314 opsonins, 316 phagocytes, 310 phagocytosis, 312 phagosome, 313 platelets, 311 platelet-activating factor, 315 prostaglandins, 315 pyrogen, 323 tumour necrosis factor-alpha (TNF-α), 316
CHAPTER
Inflammation and fever
13
Thea F van de Mortel
Chapter outline Introduction, 306 Acute inflammation, 306 Cellular components of inflammation, 309 Mast cells and basophils, 309 Neutrophils, 310 Monocytes and macrophages, 310 Eosinophils, 311 Platelets, 311 Phagocytosis, 312 Inflammatory mediators, 313 Histamine, 313 Chemotactic factors, 314 Leukotrienes, 314 Nitric oxide, 314 Prostaglandins, 315 Platelet-activating factor, 315 Cytokines, 315 Plasma protein systems, 316 The complement system, 316 The coagulation system, 318
The kinin system, 318 Plasma protein system interactions, 318 Chronic inflammation, 318 Clinical manifestations of inflammation, 319 Fever, 321 Body temperature, 321 Thermoregulation, 321 Body temperature abnormalities, 321 The pathogenesis of fever, 322 The benefits of fever, 323 Clinical patterns of fever, 325 Wound healing, 325 The reconstructive phase, 325 The maturation phase, 327 Dysfunctional wound healing, 327 Ageing and inflammation, thermoregulation and wound healing, 329
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Introduction Inflammation has been recognised for millennia. The earliest known reference to inflammation can be found in ancient Egyptian writings. The Greeks and Romans also documented inflammation. Like other aspects of the immune system, it is only in the last 50 years that our understanding of cellular and chemical properties and how these are coordinated to instigate inflammatory responses has been elucidated. In fact, new aspects are still being discovered and so are contributing to complete the whole pathophysiological picture. Inflammation can arise from many conditions. It is often observed in hospitalised patients — for instance, patients who have undergone surgery have inflammatory responses in the form of tissue repair and wound healing. This is an entirely normal anatomical and physiological response to injury. It is also present and part of almost all diseases. But when inflammation becomes chronic it can cause cellular and tissue damage and can delay wound healing; in this case, inflammation can actually worsen the disease.1 Individuals may be hospitalised due to inflammatory processes, such as those that occur with atherosclerosis in coronary heart disease. Therefore, inflammation can be viewed either as providing restoration for the body — that is, homeostasis — or as a destructive process that significantly contributes to the disease process. Inflammation is one of the primary responses of the innate immune system when a foreign substance passes the first line of defence. In Chapter 12 we explored innate immunity, and in this chapter we cover in detail aspects important to inflammation. It is essential that you have an understanding of the innate and adaptive immune responses to explain how inflammation fits in. Inflammation can be divided into several types: acute, chronic and granulomatous inflammation. The acute inflammatory response is self-limiting — that is, it continues only until the threat to the host is eliminated. This usually takes 8–10 days from onset to healing. This is the most commonly encountered inflammatory response and you will have observed this many times in your own body. For instance, a superficial graze of the skin results in swelling, redness and warmth around the site. However, if the acute inflammatory response proves inadequate, chronic inflammation may develop and persist for weeks or months. If a continued response is necessary, inflammation may progress to a granulomatous response that is designed to contain the infection or damaged site so it no longer poses any harm to the individual. Granulomatous inflammation results in a mass of immune cells, mainly macrophages and other cells that are organised to ward off further foreign threats. For example, this type of inflammation is responsible for the granulomas that form in tuberculosis, the purpose of which is to wall off the infection and prevent its spread through the body. The characteristics of the early (i.e. acute) inflammatory response differ from those of the later (i.e. chronic) response and each phase involves different biochemical mediators and cells that function together. The
acute and chronic types of inflammation may lead to healing without progression to the next phase. The word inflammation is derived from the Latin word inflammare meaning to set on fire. This nicely explains one of the main manifestations of inflammation: heat, which often manifests as fever. Accordingly, we devote the second half of this chapter to thermoregulation and fever, as this is often present in individuals with an inflammatory response and the pathophysiological processes causing fever should be known. We start by exploring the most common type of inflammatory response: acute inflammation.
Acute inflammation Inflammation forms one of the primary defence mechanisms of the immune system in response to tissue injury and infection. Unlike cells of the adaptive immune system that recognise specific antigens, inflammation is triggered by cells that recognise patterns of molecules associated with pathogens or with cellular damage.2,3 Inflammatory responses are rapid, occurring within seconds to minutes — depending on the location of the tissue injury. In response to the injury, inflammatory mediators are released and this initiates several changes. The Roman writer Cornelius Celsus in the first century AD listed the four cardinal signs of inflammation: redness (rubor), swelling (tumor), heat (calor) and pain (dolor).2 The following characteristic changes occur within seconds of the injury, and lead to those signs of inflammation (see Fig. 13.1): • Vasodilation: this increases blood vessel diameter, slowing blood flow and increasing the volume of blood flow to the injured site, allowing increased numbers of inflammatory cells and chemicals to reach the injured area. This leads to the local swelling and pain in the region. • Increased vessel permeability (also known as endothelial cell retraction): retraction of the endothelial cells lining the blood vessels causes gaps to open up between these cells, allowing leakage of plasma out of the vessel (exudation),4 which in turn causes swelling (oedema) at the site of injury. Consequently, the blood in the microcirculation becomes more viscous and flows more slowly. The increased blood volume and increasing concentration of red cells at the site of inflammation cause the local heat and redness observed in inflamed regions. • Diapedesis: white blood cells adhere (stick) to the inner walls of the capillaries and migrate through enlarged junctions between the endothelial cells lining the vessels into the surrounding tissue (see ‘Phagocytosis’ below). As a result of these changes in the blood vessels in response to the initial injury, the characteristic signs of inflammation result: • Redness: due to the increased blood flow resulting from the vasodilation, as well as the increased vascular permeability at the local site, bringing in an increased supply of blood.
CHAPTER 13 Inflammation and fever
Arteriole
Arteriolar constriction
Capillary
Transudate
307
Venule
Emigration of neutrophils
Infiltration by macrophages Emigration of neutrophils
Spillage of erythrocytes
Platelet aggregation
Mediators
Fibrin deposition
Capillary vasodilation
Mast cell degranulation Leucocyte adhesion molecule
Leucocyte
Platelet adhesion Endothelial cell adhesion molecule
Endothelial cell contraction Increased vascular permeability
Chemotaxis for neutrophils
Endothelial cell
FIGURE 13.1
An overview of inflammatory responses. After tissue injury, the processes of capillary vasodilation and increased blood vessel permeability facilitate the emigration of leucocytes from the blood to the tissue. These are attracted to the specific location through the process of chemotaxis.
• Heat: due to the increased blood flow, bringing an increased supply of blood, and blood brings warmth. • Swelling: due to the increased blood from the vasodilation, as well as the increased vessel permeability allowing increased fluid and blood cells to the local region of the cell injury. • Pain: due to the effects of swelling leading to increased fluid in the region, which activates the pain receptors (nociceptors, see Chapter 6). In addition, the inflammatory mediators released by the cell injury also directly activate the pain receptors. These three primary events in the local blood supply, and the resulting four characteristic features of inflammation, are characterised in Fig. 13.2. Each of the characteristic changes associated with inflammation is the direct result of the activation and interaction of a host of chemicals and cellular components found in the blood and tissues. The vascular changes deliver
leucocytes, plasma proteins and other biochemical mediators to the site of injury, where they act in concert (see Fig. 13.3). There are several benefits of inflammation: • It limits and controls tissue damage through the influx of plasma protein systems (e.g. the clotting process) and white blood cells (e.g. eosinophils), which prevent the inflammatory response from spreading to areas of healthy tissue. • It prevents infection by contaminating microorganisms through the influx of fluid to dilute toxins produced by bacteria, the influx and activation of plasma protein systems that help destroy and contain bacteria (e.g. complement system, clotting process), and the influx of phagocytes (e.g. neutrophils, macrophages) that ‘eat’ and destroy infectious agents. • It initiates and promotes the adaptive immune response through the influx of macrophages and lymphocytes and the drainage of microbial antigens
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CONCEPT MAP
Foreign body e.g. bacteria enters Tissues causes Cellular damage results in Mast cells releases Inflammatory mediators e.g. histamine chemotactic factors
cause
Vasodilation
cause Fluid exits blood vessel
increases
Local blood flow
increased transport
increases Red blood cells manifest as Redness
warm central blood manifest as Heat
causes
manifest as Oedema compression of Free nerve endings results in Localised pain
Increased vascular permeability allows
cause
Chemotaxis attracts Phagocytes
Inflammatory cells emigrate to Damage tissue
causes
causes Phagocytosis
Foreign body death
FIGURE 13.2
The inflammatory response. A foreign substance, commonly bacteria, enters the body and causes tissue damage. This stimulates mast cells to release their intracellular granules (inflammatory mediators), which triggers three main actions: vasodilation, increased vascular permeability (cells of the capillary membrane move apart to allow access from the blood to the tissues) and chemotaxis (chemical attraction of inflammatory cells). Collectively, this allows inflammatory cells to move to the site and stimulates the release of other pathways (complement, kinin and clotting) that limit the effect of the foreign substance, allowing time for the immune response.
by lymphatic vessels to the lymph nodes, where they activate lymphocytes. (This process is discussed in Chapter 12 and the lymphatic system is described in Chapter 22.) • It initiates healing through the removal of bacterial products, dead cells and other products of inflammation (e.g. by way of channels through the epithelium or
drainage by lymphatic vessels) and activates mechanisms of repair. We will now explore the cells and chemicals involved in inflammation. We introduced the main components that affect innate immunity in Chapter 12, but here we provide a more complete picture of inflammatory responses to injury and infection.
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Mast cell degranulation
309
Vasodilation results in redness and heat
Vascular permeability results in oedema Cellular injury Pathogenic invasion
Complement Activation of plasma systems Clotting Kinin
Cellular infiltration results in pus formation Thrombosis forms clots
Release of cellular products
Stimulation of nerve endings results in pain
FIGURE 13.3
Acute inflammation. Mast cell degranulation, the activation of three plasma systems and the release of subcellular components from the damaged cells occurs as a consequence of cellular injury. These systems are interdependent, so that induction of one (e.g. mast cell degranulation) can result in the induction of the other two. The result is the development of the characteristic microscopic and clinical hallmarks of inflammation.
FOCUS O N L E A R N IN G
1 Describe how inflammation forms part of the innate immune system. 2 List the 3 major events of inflammation and state the purpose of each. 3 Discuss the benefits of inflammation.
Cellular components of inflammation Several types of cells participate in the inflammatory response. The primary circulating white blood cells are granulocytes, so-called because of the many enzymecontaining granules in their cytoplasm. These are the neutrophils, eosinophils and basophils (with eosinophils and basophils only constituting a small proportion of the circulating blood cells). Other relevant blood components include platelets, monocytes (precursors of macrophages that are found in the tissues) and various forms of lymphocytes. Lymphocyte-like natural killer cells are found in both the circulation and tissues. Additionally, many of the biochemical mediators responsible for the initiation of
inflammation are produced by mast cells from the activation of plasma protein systems, or are released from dying cells.
Mast cells and basophils
The mast cells are probably the most important activator of the inflammatory response (see Fig. 13.4).5 Mast cells are filled with granules, and rather than being in the circulating blood like most leucocytes, these are located in the loose connective tissues in the skin and lining the gastrointestinal and respiratory tracts. Basophils are found circulating in the blood and function similarly to tissue mast cells (see Fig. 13.5).6 In response to a stimulus, biologically active molecules are released from the mast cell granules within seconds and exert their effects immediately. This process is called degranulation, literally meaning that the granules inside the cell are released into the extracellular space. These granules contain molecules such as histamine and chemotactic factors that are important propagators of the inflammatory response (inflammatory mediators). For example, the release of histamine from mast cells causes conditions such as asthma and hay fever, and drugs such as steroids are used in these conditions to stabilise mast cell membranes. In addition to the degranulation of inflammatory mediators, activated mast cells produce other inflammatory
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CONCEPT MAP
Mast cell Degranulation
Production
Histamine Chemotactic factors also known as
Vascular effects – ↑ vascular permeability – ↑ blood flow
Eosinophil chemotactic factor
Neutrophils
Eosinophils
metabolised by attracts
regulate causes
Inflammatory process
Phagocytosis – removal of debris – early activation
Platelet-activating factor
Arachidonic acid
Cyclo-oxygenase synthesis of Prostaglandins
causes Vascular effects Platelet activation
lates
Neutrophil chemotactic factor
stimulates
stimu
attracts
Phospholipase A2
results in
Leukotrienes
results in
results in
Vascular effects – Pain
Vascular effects – ↑ vascular permeability
results in Contribute to temporary haemostatic plug and clot formation
FIGURE 13.4
Mast cells and the degranulation and production of inflammatory mediators upon activation. Mast cells are filled with darkly staining granules that contain a large number of biologically active substances. Among these are histamine, which is a major initiator of vascular changes, and a variety of chemotactic factors. These substances are released immediately after stimulation of mast cells. Other substances are produced in response to mast cell stimulation. These include lipid-based molecules that originate from plasma membrane phospholipids as a result of the action of phospholipase A2, including platelet-activating factor and a variety of prostaglandins and leukotrienes. The biological effects of these inflammatory mediators are shown in the blue boxes.
mediators that are released later than those in the granules. These include leukotrienes, prostaglandins and plateletactivating factor, which are produced from lipids in the plasma membrane. These molecules, which are crucial to the inflammatory response and are responsible for the hallmarks of inflammation, are discussed later in the chapter.
Neutrophils
Neutrophils are produced by the bone marrow and are the most prevalent white blood cells, accounting for 50–60% of all white blood cells. They are sometimes referred to as polymorphonuclear neutrophils7 due to the multilobed nucleus (see Fig. 13.5). Neutrophils are also the most prominent member of the granulocytes. They are also in the group of cells called phagocytes, referring to the process of phagocytosis, which literally means ‘eating’ of foreign
cells and cell debris (see ‘Phagocytosis’ below). Neutrophils are the predominant phagocytes in the early inflammatory site, arriving at the injured tissue 6–12 hours after the initial injury. Several inflammatory mediators (for example, some bacterial proteins, complement fragments and chemotactic factors) specifically and rapidly attract neutrophils from the circulation and activate them. Neutrophils are short lived at the inflammatory site as they become a component of the purulent exudate or pus, which is removed from the body through the epithelium or via the lymphatic system. Neutrophils are responsible for the removal of debris and dead cells, and phagocytosis of bacteria.
Monocytes and macrophages
Monocytes (the immature form of this white blood cell circulating in the blood) and macrophages (the mature
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Blood vessel
Neutrophil
Eosinophil
Basophil
Mast cell
Monocyte
Macrophage
Lymphocyte
Platelets
Plasma cell
FIGURE 13.5
Inflammatory cells and their differentiation when migrating into the tissues. Whilst neutrophils, eosinophils and platelets remain the same when they enter the tissues, the basophils, monocytes and lymphocytes alter their form in the tissues and hence have a different name.
cell located in the tissues) have fewer and larger lysosomes (organelles containing digestive enzymes; see Chapter 3) in their cytoplasm than granulocytes. Monocytes have a nucleus that is often indented or horseshoe-shaped. Monocytes are produced in the bone marrow, enter the circulation and migrate to the inflammatory site, where they develop into macrophages. Monocytes are the precursors of macrophages that are fixed in tissues (tissue macrophages), including Kupffer cells in the liver, alveolar macrophages in the lungs and microglia in the brain. Macrophages are generally larger and more active as phagocytes than their monocytic precursors (see Fig. 13.5). Macrophages enter the site after 24 hours or later, and gradually replace the neutrophils. They migrate to the site after the neutrophils because they move more sluggishly and because many of the chemotactic factors that attract them, such as macrophage chemotactic factor, must first be released by neutrophils. Macrophages are better suited than neutrophils to long-term defence against infectious agents because macrophages can survive and divide in the acidic inflammatory site. The bactericidal activity (ability to kill bacteria) of macrophages can increase markedly with the help of inflammatory cytokines produced by cells of the acquired immune system (subsets of T lymphocytes; see Chapter 12). (Cytokines are a family of proteins that are secreted and activate other inflammatory cells. They are discussed in detail later in this chapter.) Macrophages have cell surface receptors for these cytokines and are further activated to become more effective killers of infectious microorganisms. A less helpful role of the macrophage is to accumulate cholesterol in arterial walls which leads to coronary artery disease.
Eosinophils
Although eosinophils (see Fig. 13.5) are only mildly phagocytic, they have two specific functions: (1) they serve as the body’s primary defence against parasites; and (2) they help regulate vascular mediators released from mast cells.8 The regulation of mast cell-derived inflammatory mediators is a critical function of eosinophils and helps limit inflammation. Mast cells produce eosinophil chemotactic factor-A, which attracts eosinophils to the site of inflammation. Eosinophil lysosomes contain several enzymes that degrade vasoactive molecules, thereby controlling the vascular effects of inflammation. This role is very important, because if inflammation is not limited to the site of injury or infection, it may damage normal tissue.
Platelets
Platelets are cytoplasmic fragments formed from megakaryocytes (large cells in the bone marrow responsible for platelet production) (see Fig. 13.5). They circulate in the bloodstream until vascular injury occurs. After injury, platelets are activated by many products of tissue destruction and inflammation, including collagen, thrombin and platelet-activating factor.9 Activation results in: (1) their interaction with components of the coagulation cascade to stop bleeding; and (2) degranulation, releasing biochemical mediators such as serotonin, which has vascular effects similar to those of histamine. (Platelet function is described in Chapter 16.)
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Pavementing
Basement membrane
Normal endothelium
Opened intercellular junction
Diapedesis
Chemotactic factor gradient
Neutrophils and macrophages Direction of neutrophil migration
A
B
C Bacterium
R
R R M
Wound
M M
Epithelium
Splinter
FIGURE 13.6
Phagocytosis. Phagocytosis is a multistep process that involves diffusion of chemotactic factors from a site of injury. Many additional factors affect the blood vessels and increase adhesion molecules on endothelial cells and phagocytes, resulting in adherence of the neutrophils to the vessel wall (pavementing), retraction of endothelial cells (vascular permeability), and movement of the neutrophils through the opened intercellular junctions (diapedesis) and into the tissue. The cells move along the gradient towards the highest concentration of chemotactic factors (chemotaxis). At the site of injury, phagocytes begin phagocytosis of contaminating bacteria. The actual process of phagocytosis involves several steps (see enlargement). The electron micrographs shows phagocytosis of damaged red blood cells by a macrophage. A Red blood cells (R) attach to the macrophage (M). B The plasma membrane of the macrophage begins to enclose the red blood cells. C The red blood cells are almost totally ingested by the macrophage.
Phagocytosis
Phagocytosis is the process by which a cell ingests and disposes of debris and foreign material, including microorganisms. This process resembles endocytosis (refer to Chapter 3). Cells that perform this process are called phagocytes. The two most important phagocytes are neutrophils and macrophages. Both cells types circulate in the blood and migrate to the site of inflammation before initiating phagocytosis. During inflammation the endothelial cells of the capillaries move apart (known as increased vessel permeability (see ‘Acute inflammation’ above). The surface adhesion molecules assist the phagocytes to undergo diapedesis, or emigration of the cells through the endothelial
junctions that have retracted in response to inflammatory mediators (see Fig. 13.6).10 In order to recruit the immune cells from the circulating blood to the local site of inflammation at the injured tissue, several stages are followed: • Margination or pavementing: this is the process by which the relevant cells move towards the walls of the capillaries and venules (towards the blood vessel lining – the endothelium); a region where the blood flow is slightly slower than in the middle of the vessel lumen. • Adhesion: this is where these leucocytes then bind to the endothelial cells; this process is facilitated by the
cells, particularly the phagocytes, producing surface molecules that increase the adhesion, or stickiness, between leucocytes and the endothelial cells (see Fig. 13.1). • Diapedesis: the adhered cells then undergo a process whereby they exit the blood vessel through the endothelial junctions which have retracted in response to the inflammatory mediators (known as increased vessel permeability. The same surface adhesion molecules from the adhesion stage also assist with diapedesis. As a result of diapedesis, the cells have emigrated through the blood vessel and enter the tissues. • Chemotaxis: once inside the tissue, leucocytes are attracted to the inflammatory site by chemotactic factors, which are chemicals released at the site to attract the leucocytes (see ‘Inflammatory mediators’ below). At the inflammatory site, the process of phagocytosis involves five steps: (1) adherence of the phagocyte to its target; (2) engulfment (ingestion or endocytosis); (3) formation of a phagosome (a vacuole or membrane-bound ‘compartment’ that contains the foreign body); (4) fusion of the phagosome with lysosomal granules within the phagocyte; and (5) destruction of the target (see Fig. 13.6) (lysosomes are described in Chapter 3). Throughout the process, both the target and the digestive enzymes are isolated within membrane-bound vesicles. Isolation protects the phagocyte itself from the harmful effects of the target microorganisms, as well as its own enzymes. Phagocytosis using innate receptors (phagocyte surface receptors that recognise bacteria) is a relatively slow process. Opsonisation (the coating of foreign bodies with opsonin to attract phagocytes) greatly enhances adherence by acting as a glue to increase the adherence between the phagocyte and the target cell. The most efficient opsonins are antibodies and C3b produced by the complement system. Antibodies are made against antigens on the surface of the pathogen and are highly specific to that particular microorganism (see Chapter 12). Alternatively, the complement system is activated during inflammation and deposits C3b on the bacterial surface, which increases phagocytosis (see ‘The complement system’ below). The surface of phagocytes contains a variety of specific receptors that strongly bind to opsonins. Engulfment (endocytosis) is carried out by small pseudopods that extend from the plasma membrane and surround the adherent microorganism (see Fig. 13.6) forming an intracellular phagosome. After the formation of the phagosome, lysosomes converge, fuse with the phagosome and discharge their contents. Destruction of the bacterium (foreign body) takes place inside this compartment called a phagolysosome. The act of phagocytosis switches the glucose metabolism of the phagocyte to a pathway that produces reactive oxygen species such as hydrogen peroxide and superoxide that are highly damaging to the ingested pathogens. Other mechanisms of intracellular killing include an acidic pH in the phagolysosome, and enzymes that bind to and damage
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microbial cell membranes and cell walls.11 Often the process of phagocytosis results in the death of the phagocyte. When a phagocyte dies at an inflammatory site, it frequently lyses (breaks open) and releases its cytoplasmic contents, including the lysosomal enzymes, into the tissue. These can be very destructive and digest the surrounding tissue, causing much of the tissue destruction associated with inflammation. The destructive effects of many enzymes released by dying phagocytes are minimised by natural inhibitors found in the blood, such as α 1-antitrypsin, a plasma protein produced by the liver. Released lysosomal products may also contribute to inflammation by increasing vascular permeability, attracting additional monocytes, and activating the complement and kinin systems (see ‘Plasma protein systems’ below). FOCU S ON L EA RN IN G
1 Name the products that are released by mast cells during inflammation. 2 Describe what constitutes a cell as a phagocyte. 3 Describe the role of neutrophils, monocytes, macrophages, eosinophils and platelets and their location in the body. 4 Discuss the steps in phagocytosis.
Inflammatory mediators Inflammatory mediators are substances that promote inflammation. Literally a flood of these inflammatory substances is released by cells at the site of injury or infection. The mast cell releases several substances when stimulated while others are produced by the cell and act later in the inflammatory period. In addition, some inflammatory mediators circulate in the plasma in an inactive form and are activated during inflammation. Furthermore, for inflammation to occur, many different kinds of cells must cooperate. That cooperation is achieved by the secretion of a variety of signalling proteins — these are cytokines. Therefore, these chemical substances are crucial to inflammation and immunity, and we explore the main mediators to provide an overview of their functions and how they interact during inflammation.
Histamine
Histamine is a small molecule with potent effects on many other cells, particularly those that control the circulation. Histamine is a vasoactive amine, meaning that its action is on blood vessels. Histamine causes temporary, rapid constriction of smooth muscle and dilation of the post-capillary venules, which results in increased blood flow into the microcirculation. Histamine also causes increased vascular permeability resulting from retraction of endothelial cells lining the capillaries (see Figs 13.1 and 13.7) and increased adherence of leucocytes to the
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Arteriole
Normal
Impulse
Closed precapillary sphincter
Nerve cell
Chemotactic factors
Capillaries
Venule Acute inflammation
Dilatation
endothelium. Antihistamines are drugs that block the binding of histamine to its receptors, resulting in decreased inflammation.
Smooth muscle cell
Open precapillary sphincter
Chemotactic factors are released from mast cell granules. Chemotactic factors diffuse from a site of inflammation, forming a gradient and causing the directional movement (chemotaxis) of cells towards the site of injury (see Fig. 13.8). Mast cells contain two specific chemotactic factors: neutrophil chemotactic factor and eosinophil chemotactic factor of anaphylaxis,12 which attract neutrophils and eosinophils. Neutrophils are the predominant cell needed to kill bacteria in the early stages of inflammation, and eosinophils help regulate the inflammatory response.
Leukotrienes
Leukotrienes are sulfur-containing lipids that produce histamine-like effects: smooth muscle contraction and increased vascular permeability. Leukotrienes appear to be important in the later stages of the inflammatory response because they stimulate slower and more prolonged responses than do histamines.
Dilatation Arterial blood
Venous blood
FIGURE 13.7
Vasodilation of the capillary beds during inflammation induced by histamine and nitric oxide. Relaxation of the pre-capillary sphincter in the arterioles results in flooding of the capillary network and dilatation of the capillaries and post-capillary venules.
Nitric oxide
Endothelial cells release nitric oxide (not to be confused with nitrous oxide, or laughing gas), which has at least two effects on inflammation. First, nitric oxide causes vasodilation by inducing relaxation of vascular smooth muscle, a response Bacteria
Chemotactic factor gradient Attracted leucocyte (macrophage) Inflammatory site
Receptor
Movement FIGURE 13.8
Chemotaxis. This occurs when chemotactic factors are released, which attracts inflammatory cells to the site of inflammation. Multiple receptors on the leucocyte’s plasma membrane sense the area of highest concentration of chemotactic factor (dots), and the leucocyte (usually a phagocyte) moves towards this area.
CHAPTER 13 Inflammation and fever
that is local and short lived (see Fig. 13.7). Second, nitric oxide may suppress mast cell release of inflammatory molecules and decrease platelet adhesion and aggregation. Therefore, nitric oxide has both pro- and anti-inflammatory aspects.
Prostaglandins
Prostaglandins cause increased vascular permeability, neutrophil chemotaxis and pain by direct effects on nerves. They are long-chain, unsaturated fatty acids produced when the enzyme cyclo-oxygenase converts arachidonic acid to prostaglandin. Two particular types of prostaglandins, E1 and E2, cause increased vascular permeability and smooth muscle contraction, and E2 is also involved in the production of fever. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, block the production of prostaglandins by inhibiting cyclo-oxygenase (COX), thereby inhibiting inflammation and reducing pain and fever.13
Platelet-activating factor
Platelet-activating factor is produced from a lipid of the phospholipid plasma membrane. Although mast cells are
315
a major source of platelet-activating factor, this molecule can also be produced during inflammation by neutrophils, monocytes, endothelial cells and platelets. The biological activity of platelet-activating factor is virtually identical to that of leukotrienes, namely causing endothelial cell retraction to increase vascular permeability, leucocyte adhesion to endothelial cells and platelet activation.
Cytokines
Cytokines are a large group of proteins that provide a means of communication for the inflammatory and immune cells. Cytokines can be pro-inflammatory or anti-inflammatory, depending on whether they tend to induce or inhibit the inflammatory response. These molecules diffuse over short distances, bind to the appropriate target cells and affect the function of the target cells. Some effects occur over long distances, such as the systemic induction of fever by some cytokines (see ‘Fever’ below). Cytokine effects on other cells are mediated through specific cell-surface receptors. The binding of cytokines to a target cell often induces production of additional cellular products. These are detailed in Table 13.1. Below we list some of the cytokines that strongly influence inflammation.
TABLE 13.1 The actions of the primary inflammatory mediators MEDIATOR
PRINCIPAL SOURCES
ACTION
Histamine
Mast cells, basophils, platelets
Vasodilation, increased vascular permeability, endothelial activation
Serotonin
Platelets
Vasodilation, increased vascular permeability
Prostaglandins
Mast cells, leucocytes
Vasodilation, pain, fever
Leukotrienes
Mast cells, leucocytes
Increased vascular permeability, chemotaxis, leucocyte adhesion and activation
Platelet-activating factor
Leucocytes, mast cells
Vasodilation, increased vascular permeability, leucocyte adhesion, chemotaxis, degranulation
Nitric oxide
Endothelium, macrophages
Vascular smooth muscle relaxation, killing of microbes
Cytokines (TNF-α, IL-1, IL-6)
Macrophages, endothelial cells, mast cells
Local endothelial activation, fever, pain, hypotension, decreased vascular resistance (shock)
Chemokines
Leucocytes, activated macrophages
Chemotaxis, recruitment of leucocytes to sites of inflammation, migration of cells to normal tissues
Complement products (C5a, C3a, C4a)
Plasma (produced in liver)
Leucocyte chemotaxis and activation, vasodilation (mast cell stimulation)
Kinins
Plasma (produced in liver)
Increased vascular permeability, smooth muscle contraction, vasodilation, pain
Proteases activated during coagulation
Plasma (produced in liver)
Endothelial activation, leucocyte recruitment
Cell-derived
Plasma protein–derived
IL-1 = interleukin-1; IL-6 = interleukin-6; TNF-α = tumour necrosis factor-alpha
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Interleukins
The interleukins are produced predominantly by macrophages and lymphocytes in response to their recognition of a pathogen or stimulation by other products of inflammation. Interleukin-1 (IL-1) is a pro-inflammatory cytokine (it encourages the inflammatory process) produced mainly by macrophages.14 It is an endogenous pyrogen, meaning that it is produced from within the body, and reacts with receptors on cells of the hypothalamus to cause fever. It also activates phagocytes and lymphocytes, thereby enhancing both innate and adaptive immunity, and acts as a growth factor for many cells. It induces neutrophil proliferation (increasing the number of circulating neutrophils), and stimulates chemotaxis, increased cellular respiration and increased lysosomal enzyme activity. Interleukin-6 (IL-6) is produced by macrophages, lymphocytes, fibroblasts and other cells. It directly induces liver cells to produce many of the proteins needed in inflammation (acute-phase reactants, discussed later in this chapter). IL-6 also stimulates growth and differentiation of precursors of blood cells in the bone marrow and the growth of fibroblasts. Interleukin-10 (IL-10) is an example of an antiinflammatory cytokine and is primarily produced by lymphocytes to slow both the inflammatory and the acquired immune responses. It achieves this through suppressing the growth of lymphocytes and the production of pro-inflammatory cytokines by macrophages. More than 30 interleukins have been identified. Their effects include: • alteration of adhesion molecule expression on many types of cells • induction of leucocyte chemotaxis • induction of proliferation and maturation of leucocytes in the bone marrow • general enhancement or suppression of inflammation.
Tumour necrosis factor-alpha
Macrophages secrete tumour necrosis factor-alpha (TNF-α) in response to recognition of foreign materials. Other cells, such as mast cells, are additional and crucial sources of this pro-inflammatory cytokine. TNF-α induces a multitude of pro-inflammatory effects, including enhancement of endothelial cell adhesion molecule expression, which results in increased adherence of neutrophils. When secreted in large amounts, TNF-α: • induces fever • increases production of inflammation-related serum proteins by the liver • causes muscle wasting (cachexia) and intravascular thrombosis in cases of severe infection and cancer. Very high levels of TNF-α can be lethal and may be responsible for fatalities from shock caused by gram-negative bacterial infections. (Gram-positive and gram-negative bacteria are discussed in Chapter 14.) Interestingly,
TNF-α also seems to play a role in the development of insulin resistance which can lead to type 2 diabetes mellitus. FOCU S ON L EA RN IN G
1 Describe the function of inflammatory mediators. 2 List and describe the actions of histamine, plateletactivating factor, chemotactic factor and prostaglandin E2. 3 Discuss how cytokines act to influence both innate and adaptive immune responses.
Plasma protein systems Three key plasma protein systems are essential to an effective inflammatory response: the complement system, the coagulation system and the kinin system (see Fig. 13.9). Although each system has a unique role in inflammation, the systems have many similarities. Each system consists of multiple proteins in the blood. To prevent activation in unnecessary situations, each protein is normally in an inactive form. Each system contains a few proteins that can be activated by products of tissue damage or infection. Activation of the first component results in sequential activation of other components of the system, leading to a biological function that helps protect the individual. This sequential activation is referred to as a cascade. Thus, we refer to the complement cascade, the coagulation cascade or the kinin cascade.
The complement system
The complement system is an ancient component of the innate immune system that is thought to have been around in more primitive species for over a billion years.15 It consists of a large number of proteins (sometimes called complement components) that together constitute about 10% of the total circulating serum protein. The complement system is extremely important because activated components can destroy pathogens directly and can activate or collaborate with virtually every other component of the inflammatory response.16 For these reasons, proteins of the complement system are among the body’s most potent defenders against bacterial infection. The most important portion of the complement cascade is activation of C3 and C5, which results in a variety of subunits that are opsonins, chemotactic factors or anaphylatoxins. Opsonins are molecules that coat bacteria and increase their susceptibility to being phagocytosed by neutrophils and macrophages. Anaphylatoxins are molecules that induce rapid degranulation of mast cells, thus increasing inflammation. The most potent complement products are C3b (opsonin), C3a (anaphylatoxin) and C5a (anaphylatoxin, chemotactic factor). Complement components C5b to C9 (membrane attack complex, or MAC) form a complex that creates pores in
CHAPTER 13 Inflammation and fever
Classical pathway
Lectin pathway
Alternative pathway
Coagulation system Cellular injury
Kinin system
Hageman factor XII
Prekallikrein
XIIa
Kininogen
C3
C3b
C3a
Factor X Bradykinin
Opsonin
Anaphylatoxin Thrombin
Phagocytosis
Inflammation
CONCEPT MAP
Complement system
317
Pain Histamine-like effects
Fibrinogen
C5
C5b C5b, 6–9 Membrane attack complex
FPs
Blood clot
Chemotactic factor
C5a
Chemotactic factor Anaphylatoxin
Attraction of phagocytes Death of target cell
Fibrin
Vascular permeability
Inflammation
FIGURE 13.9
Plasma protein systems in inflammation: complement, coagulation and kinin systems. See the text for more detailed information. In this scheme some systems are activated by multiple pathways that come together (at C3 for the complement system and factor X for the coagulation system). Some of the components of the pathways are activated by being split into two active components (C3 and C5 of the complement system and fibrinogen of the coagulation system). The larger of the components usually activates the next component of the pathway (as do C3b and C5b of the complement system). Hageman factor participates in both the coagulation and kinin pathways (i.e. activated factor XII [XIIa] helps activate factor X and prekallikrein). Many of the components of each pathway have potent biological activities (in pink-coloured boxes). Many other components of each pathway are not shown in this drawing but play very important roles in activation of the pathway. FP = fibrinopeptides.
the outer membranes of cells, disrupting the cell membrane and permitting water to enter, causing lysis and death of the cell. This is a particularly effective mechanism for destroying foreign cells that have entered the body. Complement activation can be accomplished in three different ways (see Fig. 13.9): 1 classical pathway: activated by antibodies 2 alternative pathway: activated by gram-negative bacterial and fungal cell wall polysaccharides 3 lectin pathway: activated by certain bacterial carbohydrates. The classical pathway is primarily activated by antibodies.17 When an antibody binds to an antigen it changes the shape of the antibody molecule, opening up a complement binding site on the antibody tail, which activates
the first component of complement (C1). This in turn leads to activation of C3 and C5. Thus, the acquired immune response can use the complement system to kill bacteria and activate inflammation. The alternative pathway is activated by several substances found on the surface of infectious organisms, such as lipopolysaccharide (endotoxin), which is a component of the outer membrane of gram negative bacteria. This pathway uses unique proteins to form a complex that activates C3, which leads to C5 activation and convergence with the classical pathway. Thus, the complement system can be directly activated by certain infectious organisms without antibody being present. The lectin pathway is similar to the classic pathway but is independent of antibody, using instead plasma
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indefinitely. Therefore, the systems are tightly regulated to control and localise inflammation to the appropriate sites. For example, there are enzymes that inactivate or degrade inflammatory mediators such as histamine, complement components and kinins. Similarly, activation of the clotting cascade also activates a fibrinolytic system that limits the size of the clot and facilitates its removal when bleeding has ceased.
proteins such as mannose-binding lectin, which binds to mannose-containing bacterial polysaccharides. Thus, infectious agents that do not activate the alternative pathway may be susceptible to complement through the lectin pathway. In summary, the complement cascade can be activated by at least three different means and its products have four functions: (1) opsonisation; (2) anaphylatoxic activity resulting in mast cell degranulation and inflammation; (3) leucocyte chemotaxis; and (4) cell lysis.
FOCU S ON L EA RN IN G
The coagulation system
1 Describe how plasma protein systems augment the inflammatory response.
The coagulation (clotting) system is a group of plasma proteins that, when activated sequentially, form a fibrinous meshwork at an injured or inflamed site.18 This: (1) forms a clot that stops bleeding; (2) traps infectious organisms and prevents their spread to adjacent tissues; (3) keeps microorganisms and foreign substances at the site of greatest inflammatory cell activity; and (4) provides a framework for future repair and healing. The main substance in this fibrinous mesh is fibrin, an insoluble protein produced by the coagulation cascade. Like the complement cascade, the coagulation cascade can be activated through different pathways that converge and result in the formation of a clot (see Fig. 13.9). The coagulation cascade converges at factor X. From that point on, a common pathway results in fibrin formation. The coagulation cascade is discussed further in Chapter 16. Many substances that are released during tissue destruction and infection, such as bacterial products (e.g. endotoxin), collagen and cellular proteases, can activate the coagulation system. Activation of some clotting factors produces fragments that enhance the inflammatory response.
The kinin system
The third plasma protein system, the kinin system, interacts closely with the coagulation system (see Fig. 13.9). Both the coagulation and kinin systems are activated through activated factor XII (factor XIIa). Another name for factor XIIa is prekallikrein activator because it enzymatically activates the first component of the kinin system, prekallikrein. The final product of the kinin system is a low-molecular-weight molecule, bradykinin. At low doses, bradykinin causes dilation of blood vessels, acts with prostaglandins to induce pain, causes smooth muscle cell contraction and increases vascular permeability (see Fig. 13.3). Bradykinin induces smooth muscle contraction more slowly than histamine and may be more important during the later stages of inflammation.
Plasma protein system interactions
The three plasma protein systems are highly interactive so that activation of one results in secondary activation of the other two. It is beneficial to the individual to activate all three systems, but it would be detrimental if the systems continued producing potent pro-inflammatory molecules
2 Describe how the complement, coagulation and kinin systems are activated.
Chronic inflammation Superficially, the difference between acute and chronic inflammation is duration; chronic inflammation lasts 2 weeks or longer, regardless of cause. Chronic inflammation is sometimes preceded by an unsuccessful acute inflammatory response (see Fig. 13.10). For example, if bacterial contamination or foreign objects (e.g. dirt, wood splinters, glass) persists in a wound, an acute response may be prolonged beyond 2 weeks. Pus formation, purulent discharge and incomplete wound healing may characterise this type of chronic inflammation. Chronic inflammation can occur also as a distinct process without previous acute inflammation. Some microorganisms, chemicals or physical irritants (e.g. inhaled dusts, wood splinters and suture material) can cause a prolonged inflammatory response (see Fig. 13.11). Chronic inflammation is characterised by a dense infiltration of lymphocytes and macrophages. If macrophages are unable to protect the host from tissue damage, the body attempts to wall off and isolate the infected area, thus forming a granuloma. The process of granuloma formation begins when some macrophages differentiate into large epithelial-like cells that cannot phagocytose large bacteria but are capable of taking up debris and other small particles. Other macrophages fuse into multinucleated giant cells, which are active phagocytes that can engulf very large particles — larger than can be engulfed by a single macrophage. These two types of differentiated macrophages form the centre of the granuloma, which is surrounded by a wall of lymphocytes. The granuloma itself is often encapsulated by fibrous deposits of collagen and may become cartilaginous, or possibly calcified, which results in inflexible, somewhat hardened tissue that replaces the normal tissue. FOCU S ON L EA RN IN G
1 Describe the differences between acute inflammation and chronic inflammation. 2 Discuss why chronic inflammation may occur.
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Persistent acute inflammation Lymphocyte and monocyte/macrophage infiltration (pus) Neutrophil degranulation and death Persistence of infection, antigen or foreign body Lymphocyte activation Tissue repair (scar) Fibroblast activation FIGURE 13.10
Chronic inflammation. Inflammation usually becomes chronic because of the persistence of an infection, an antigen or a foreign body in the wound. Chronic inflammation is characterised by the persistence of many of the processes of acute inflammation. In addition, large amounts of neutrophil degranulation and death, the activation of lymphocytes and the concurrent activation of fibroblasts result in the release of mediators that induce the infiltration of more lymphocytes and monocytes/macrophages and the beginning of wound healing and tissue repair.
RESEARCH IN F
CUS
Bacteria and inflammation The incidence of inflammatory diseases such as asthma has increased substantially in developed countries over time. Multiple factors have contributed to this rapid increase including reduced exposure to microbes in very early childhood (the hygiene hypothesis), use of antibiotics (thus reducing the diversity of gut microbes), and a diet low in fibre. Fermentation of fibre by the microbes living in the gut (the microbiota) generates short-chain fatty acids such as acetate, butyrate and proprionate that help to suppress systemic inflammation. A reduced fibre diet and antibiotic use actually change the composition of the gut flora, which in turn predisposes towards inflammation and obesity. Modification of the gut microbiota provides an interesting new way to modify the course of inflammatory diseases.
Clinical manifestations of inflammation As you will now be aware, inflammation produces a distinct clinical picture. Individuals with inflammation often
experience local and systemic signs and symptoms. This is because the inflammatory cells, plasma protein systems and especially the chemical mediators interact to produce the characteristics of inflammation. Local inflammation accompanies all types of cellular and tissue injury, whether infected or sterile, and is responsible for initiating healing. All the local characteristics of acute inflammation (i.e. swelling, pain, heat and redness) result from vascular changes and the subsequent leakage of circulating components into the tissue. Heat and redness are the result of vasodilation and increased blood flow through the injured site. Swelling (oedema) occurs as exudate (fluid and cells) accumulates in the tissues. Swelling is usually accompanied by pain caused by pressure exerted by exudate accumulation, as well as the presence of soluble biochemical mediators such as prostaglandins and bradykinin. Exudate varies in composition, depending on the stage of the inflammatory response. In early or mild inflammation, the exudate is watery (called serous exudate) with very few plasma proteins or leucocytes. An example of serous exudate is the fluid in a blister. In more severe or advanced inflammation, the exudate may be thick and clotted (called fibrinous exudate), such as in the lungs of individuals with pneumonia. If a large number of leucocytes accumulate, as in persistent bacterial infections, the exudate consists of
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ACUTE INFLAMMATION • Vascular changes • Neutrophil recruitment • Limited tissue injury
RESOLUTION • Clearance of injurious stimuli • Clearance of mediators and acute inflammatory cells • Replacement of injured cells • Normal function
INJURY • • • •
Infarction Bacterial infections Toxins Trauma
Pus formation (abscess) Progression
Healing Healing
INJURY • • • •
Viral infections Chronic infections Persistent injury Autoimmune diseases
Healing FIBROSIS • Collagen deposition • Loss of function
CHRONIC INFLAMMATION • Angiogenesis • Mononuclear cell infiltrate • Fibrosis (scar) • Progressive tissue injury
FIGURE 13.11
The differences between acute and chronic inflammation. Acute and chronic inflammation can lead to fibrosis and loss of tissue function.
pus and is called a purulent exudate. Purulent exudate is characteristic of walled-off lesions (cysts or abscesses). There are three primary systemic changes associated with the acute inflammatory response: fever, leucocytosis and an increased level of circulating plasma proteins. Fever is one of the most common clinical manifestations of inflammation. It is an important clinical sign and you should have a thorough understanding of the pathogenesis and patterns of fever, as many individuals in healthcare facilities will experience fever. We discuss fever in detail in the following section. Leucocytosis is an increase in the number of circulating white blood cells. Often the leucocytosis causes production of immature neutrophils that are present in greater than normal proportions; however, because they are immature, they may not function normally. The production of many plasma proteins, mostly products of the liver, is increased during inflammation. These proteins, which can be either pro-inflammatory or anti-inflammatory in nature, are referred to as acute-phase reactants, and
reach maximal circulating levels 10–40 hours after the start of inflammation. IL-1 indirectly induces the production of acute-phase reactants by increasing production of IL-6, which directly stimulates production of acute-phase reactants by liver cells. Common laboratory tests for inflammation measure levels of acute-phase reactants. For example, an increase in blood levels of acute-phase reactants such as C-reactive protein and fibrinogen is considered a good indicator of an acute inflammatory response.
FOCU S ON L EA RN IN G
1 Differentiate between local and systemic clinical manifestations of inflammation. 2 List the types of exudate produced in inflammation. 3 Explain which cytokines stimulate the release of acutephase reactants.
Fever Fever is a fundamental sign of almost all infectious diseases and many non-infectious conditions that arise as a consequence of inflammation. However, to appreciate the mechanisms of fever you need to understand normal thermoregulation to provide a distinction.
Body temperature
In all homeotherms (animals that maintain a stable core temperature independent of environmental temperature), temperature regulation (thermoregulation) is achieved through precise balancing of heat production and heat loss to maintain the core temperature within a range sometimes referred to as the interthreshold zone.19 Maintenance of normal body temperature is critical: too high and body proteins are denatured and stop functioning; too low and metabolism is fatally slowed. The normal range when measured orally is 36.2–37.7°C — and body temperature rarely exceeds 41°C. However, stage of the menstrual cycle, age, level of activity, environmental temperature and time of day influence core temperature. The body temperature peaks around 4–6 pm and is at its lowest during sleep. In addition, the extremities are generally cooler than the trunk while core temperature is generally 0.5°C higher than oral temperature.
Thermoregulation
Peripheral thermoreceptors in the skin and central thermoreceptors in the hypothalamus and other locations provide information about skin and core temperatures. These sensory neurons form feedback loops with effectors that modify the body temperature.20 Whether or not heat production/conservation or heat loss mechanisms are triggered depends on how many thermoreceptors are triggered. For example, touching an ice cube with the tip of a finger would not trigger mechanisms to defend body temperature (although the cerebral cortex would register the cold sensation); however, if large numbers of thermoreceptors are activated, then mechanisms to adjust the body temperature will be triggered. Skin thermoreceptors allow the body to respond to changes in environmental temperature before the core body temperature becomes abnormal.21 The initial response to a skin temperature change is behavioural, as this minimises the associated energy costs. For example, someone feeling cold will put on additional layers of clothing, increase their activity or huddle. These voluntary activities provide insulation, increase heat generation, and decrease the amount of skin surface available for heat loss.21 Conversely, if too hot, the person will seek shade, shed clothes, and stretch out. If a behavioural response is insufficient, then additional autonomic mechanisms (those we do not have conscious control of) are triggered. For example, if core temperature drops or is threatened, chemical thermogenesis (heat production) begins with the production of thyrotrophin-
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releasing hormone (TRH) by the hypothalamus, which in turn stimulates production of thyroid-stimulating hormone (TSH), and subsequently thyroxine. Thyroxine increases the metabolic rate using brown adipose tissue, thus increasing heat production.22 The hypothalamus through stimulation of the sympathetic nervous system initiates the shivering response and triggers peripheral vasoconstriction, which shunts warm blood away from the periphery to the core of the body where heat can be retained (Fig. 13.12). Alternatively, if body temperatures are high, the above mechanisms will be reversed defending core temperature and maintaining homeostasis. Heat loss is achieved through: (1) radiation; (2) conduction; (3) convection; (4) vasodilation; (5) decreased muscle tone; (6) evaporation; (7) increased respiration; (8) voluntary measures; and (9) adaptation to warmer climates. These mechanisms are summarised in Table 13.2.
Body temperature abnormalities
Body temperature can be abnormally high (fever and hyperthermia) or abnormally low (hypothermia). Fever is a controlled response to inflammation and infection that stimulates immune function and decreases pathogen viability.22 In contrast, hyperthermia involves a failure of thermoregulatory mechanisms.
Hyperthermia
Hyperthermia (an uncontrolled increase in core temperature that is not mediated by pyrogens) can produce nerve damage, coagulation of cell proteins and death (see Table 13.3). In core temperatures above 41°C, nerve damage can produce convulsions in the adult, and death is imminent in core temperatures above 43°C. Hyperthermia may be therapeutic, accidental or associated with stroke or head trauma that damages areas of the brain involved in thermoregulation. Therapeutic hyperthermia, is a form of local or general body-induced hyperthermia used to destroy pathological microorganisms or tumour cells by facilitating the host’s natural immune process or tumour blood flow.23 Types of exertional heat illness are summarised below:24 1 Heat oedema: swelling of the extremities caused by peripheral vasodilation. 2 Heat cramps: muscle cramps in the abdomen and extremities that follow exercise. 3 Heat syncope: transient fainting due to blood pooling in the extremities following sudden cessation of exercise. 4 Heat exhaustion: an inability to continue exercising resulting from prolonged high core or environmental temperatures, which cause profound vasodilation and profuse sweating, leading to dehydration, hypotension and decreased cardiac output due to low central blood volume. Symptoms include weakness, dizziness, confusion, nausea and fainting. 5 Exertional heat stroke: a potentially lethal result of overstressed thermoregulation mechanisms. With very
Part 3 Alterations to protection and movement
Activation
Environmental temperature
• • • •
Activation
Peripheral thermoreceptors Sends message to
Adding clothing Seeking warmth Postural changes Voluntary activity
• • • •
Cerebral cortex Triggers
If insufficient stimulates
Anterior hypothalamus
Vasoconstriction Shivering
nt
BAT neurones
causes
ient
Leads to
Disinhibits ic Suff
SNS
Anterior hypothalamus
icie
Stimulates
Vasodilation
Decreased thermogenesis
Sweating
Leads to If insufficient
Chemical thermogenesis
Insufficient
Environmental temperature
Shedding clothing Seeking shade Postural changes Voluntary activity
Behavioural mechanisms
If insufficient stimulates
Suff
CONCEPT MAP
322
Sufficient
HYPERTHERMIA Core body temperature maintained
Sufficient
HYPOTHERMIA Structures Consequences FIGURE 13.12
Thermoregulation. Environmental temperature changes activate skin thermoreceptors, which signal to the cerebral cortex, triggering behavioural mechanisms to normalise body temperature. If these mechanisms are insufficient, the anterior hypothalamus activates additional defence mechanisms. When body temperatures are too cold, the sympathetic nervous system (SNS) is activated, leading to shivering and vasoconstriction. Disinhibition of brown adipose tissue (BAT) neurons results in heat generation via chemical thermogenesis. Conversely, activation of warm sensitive neurons (WSN) triggers sweating and vasodilation, and inhibits BAT thermogenesis. Failure of these thermoregulatory mechanisms results in hypothermia or hyperthermia. (green boxes = structures involved in thermoregulation; pale blue boxes = consequences).
high core temperatures (>40.6°C), the body’s heat loss mechanisms may fail. Complications include cerebral oedema, renal tubular necrosis and eventually death if treatment is not undertaken.
Hypothermia
Hypothermia (a decrease in core temperature below 35°C)25 produces depression of the central nervous and respiratory systems, vasoconstriction, alterations in microcirculation, coagulation and ischaemic tissue damage. Most tissues can tolerate low temperatures in controlled situations, such as surgery. However, in severe hypothermia, ice crystals form on the inside of the cells, causing the cells to
rupture and die. Tissue hypothermia slows cell metabolism, increases blood viscosity, slows microcirculatory blood flow, facilitates blood coagulopathies and stimulates profound vasoconstriction.
The pathogenesis of fever
Fever (also called a febrile response) is defined as a core temperature measured rectally of ≥38°C. Fever is orchestrated through immunological mechanisms in addition to the neurological, endocrine and behavioural mechanisms described previously.20 During fever, cells of the immune system become involved to adjust heat production, conservation and loss to maintain the core temperature at
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TABLE 13.2 Mechanisms of heat production and loss CONDITION
DESCRIPTION
Heat production Chemical reactions of metabolism
Occur during ingestion and metabolism of food and while maintaining the body at rest (basal metabolism); occur in body core (liver)
Skeletal muscle contraction Gradual increase in muscle tone or rapid muscle oscillations (shivering) Chemical thermogenesis (heat production)
Adrenaline is released and produces a rapid, transient increase in heat production by raising basal metabolic rate; quick, brief effect that counters heat lost through conduction and convection; involves brown adipose tissue, which decreases markedly in older adults. Thyroid hormone increases metabolism
Heat conservation Peripheral vasoconstriction
Adrenaline is released producing vasoconstriction of blood vessels supplying the skin; reduces heat losses through the skin by keeping warmed blood in the core
Voluntary mechanisms
Adding layers of clothes, seeking a warmer environment, curling up, increasing activity levels
Heat loss Radiation
Heat loss through electromagnetic waves emanating from surfaces with temperature higher than the surrounding air
Conduction
Heat loss by direct molecule-to-molecule transfer from one surface to another, so that warmer surface loses heat to cooler surface
Convection
Transfer of heat through currents of gases or liquids; exchanges warmer air at body’s surface with cooler air in surrounding space
Vasodilation
Diverts core-warmed blood to surface of body, with heat transferred by conduction to skin surface and from there to the surrounding environment; occurs in response to autonomic stimulation under control of hypothalamus
Decreased muscle tone
Washed-out feeling caused by moderately reduced muscle tone and curtailed voluntary muscle activity
Evaporation
Body water evaporates from surface of skin and linings of mucous membranes; major source of heat reduction connected with increased sweating in warmer surroundings
Increased ventilation
Air is exchanged with environment through normal process; minimal effect
Voluntary mechanisms
’Stretching out’ and ‘slowing down’ in response to high body temperatures, increasing the body surface area available for heat loss; dressing in light-coloured, loose-fitting garments
Adaptation to warmer climates
Gradual process beginning with lassitude, weakness and faintness, proceeding through increased sweating, lowered sodium content, decreased heart rate, increased stroke volume and extracellular fluid volume, and terminating in improved warm weather functioning and decreased symptoms of heat intolerance (work output, endurance and coordination increase, and subjective feelings of discomfort decrease)
a temporarily higher level that functions as a new balance point. This response is mediated by cytokines associated with the inflammatory response. As described earlier in the chapter, inflammation can be triggered by injury to vascular tissue whether infectious organisms are involved or not. Similarly fever, although commonly associated with infection, also occurs in response to aseptic injury through the release of inflammatory cytokines called pyrogens (fever-inducing substances). Endogenous pyrogens (those produced within the body), including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and interferon, are released from phagocytes that respond to tissue injury. These pyrogenic cytokines induce the production of cyclooxeganse-2 and prostaglandins, which act on the hypothalamus to trigger a febrile response, raising the temperature balance point or interthreshold zone to a higher level.26 In response there
is an increase in heat production and conservation to raise the body temperature (see Fig. 13.13). If infectious organisms are involved in the inflammatory response then exogenous pyrogens, such as endotoxins produced by pathogens (see Chapter 14), stimulate the release of the endogenous pyrogens listed above to raise the temperature using the behavioural and autonomic mechanisms described in the section above on normal thermoregulation.
The benefits of fever
Fever is usually beneficial and assists the immune system to respond to pathogenic microorganisms. Raising the body temperature:25,27 • kills or inhibits the growth of many microorganisms • decreases serum levels of iron, zinc and copper — minerals needed for bacterial replication
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• causes lysosomal breakdown and autodestruction of cells, preventing viral replication in infected cells • increases transformation of lymphocytes into B and T cells and increases neutrophil motility, facilitating the immune response • enhances phagocytosis and augments production of antiviral interferon. Conversely, fever can also be harmful to the individual as it may increase the body’s susceptibility to the effects of endotoxins associated with gram-negative bacterial infections (bacterial toxins are described in Chapter 14), and increase the body’s requirements for oxygen, which can be a disadvantage in critical illnesses. Suppression of fever by pharmacological treatment with antipyretic medications, such as aspirin or paracetamol, occurs via inhibition of the cyclo-oxygenase enzyme, which is required for the production of prostaglandin. Therefore, prostaglandin does not influence the hypothalamus and an increase in heat production is blocked. However, antipyretics should be used when a fever produces or is high enough to produce adverse effects upon the cardiopulmonary or nervous systems.27,28
TABLE 13.3 Clinically significant core and skin temperatures CORE TEMPERATURES
>45°C
Possible death without treatment
>40.5°C
Profound clinical hyperthermia (heatstroke)
>39.5°C
Profound hyperthermia
38.5–39.5°C
Moderate hyperthermia (heat exhaustion)
37.2–38.5°C
Mild hyperthermia
36.5–37°C
Normothermia
CONCEPT MAP
SKIN TEMPERATURES
>50°C
Second-degree burn
>45°C
Tissue damage
41–43°C
Burning pain
39–41°C
Pain
33–39°C
Skin warmth through to discomfort (hot)
28–33°C
Thermal comfort
can lead to
Tissue injury
Infection Bacteria Viruses Fungi Protozoans
stimulates Immune cells, eg. monocytes macrophages T cells Heat production Heat loss prevention
that t
rigge
r
to release Endogenous pyrogenic cytokines eg. IL-1, IL-6, TNF, IFN
stimulate release of Exogenous pyrogens eg. Endotoxin
stimulate
causes Muscle tone
synthesis and release stimulates
Hypothalamus
causes
causes
Shivering
Vasoconstriction
Prostaglandin E2 (PGE2)
causes Piloerection
manifest as FEVER
FIGURE 13.13
The pathogenesis of fever. Endogenous pyrogens (cytokines that stimulate fever) are released in response to tissue injury, or following the release of exogenous pyrogens by gram-negative bacteria. The endogenous pyrogenic cytokines stimulate the hypothalamus (pre-optic of anterior hypothalamus) to produce and release prostaglandin E2, which acts on the cells locally in the hypothalamus to trigger increased heat production and heat conservation. This causes an increase in core temperature, which manifests as fever.
Clinical patterns of fever
Four categorised patterns of fever are seen in clinical practice: • during sustained fever, the core temperature remains elevated, often for days, and there is very little variation • intermittent fever occurs when the core temperature returns to normal levels periodically, for example in infections caused by certain strains of malaria • remittent fever occurs when there are minor fluctuations in body temperature but the fever is sustained • relapsing fever is associated with days of normal temperature following fever, with an increase in core temperature, often associated with increasing severity of illness. These fever patterns represent fever mediated through pyrogens from both infectious and non-infectious agents.
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conditions of minimal tissue loss are said to heal by primary intention. Other wounds do not heal as easily. Healing of an open wound (one with extensive tissue loss), such as a pressure injury (called a decubitus ulcer), requires a great deal of tissue replacement so that epithelialisation, scar formation and contraction take longer and healing occurs through secondary intention (see Fig. 13.14). Healing by either primary or secondary intention may occur at different rates for different types of tissue injury. Wound healing occurs in two overlapping phases: the reconstructive phase begins 3–4 days after injury and continues for up to 2 weeks; and the maturation phase begins several weeks after injury and is normally complete within a few years.
The reconstructive phase FO CUS O N L E A R N IN G
1 Explain both behavioural and autonomic temperature regulation. 2 Name and explain the primary heat-production and heatloss avenues. 3 Explain how fever is different from hyperthermia. 4 Describe the cellular physiology of fever related to infection, from invasion of pathogens to increased core temperature.
Wound healing Tissue damage is followed by a period of healing that begins during acute inflammation and may last for up to 2 years (see Fig. 13.14). The most favourable outcome is a return to normal structure and function. The repaired tissues may be close to normal if damage is minor, no complications occur and destroyed tissues are capable of regeneration. However, regeneration may not be possible if extensive damage is present, the tissue is not capable of regeneration, infection results in abscess or granuloma formation, or fibrin persists in the lesion. In those cases, destroyed tissue is replaced with scar tissue. Scar tissue is composed primarily of collagen that fills in the lesion. The tensile strength of scar tissue is not the same as the initial tissue and it cannot carry out the physiological functions of the destroyed tissue. Healing involves processes that (1) fill in, (2) seal and (3) shrink the wound. These characteristics of healing vary in importance and duration among different types of wounds. A clean incision, such as a paper cut or sutured surgical wound, heals primarily through the process of collagen production. Because this type of wound has minimal tissue loss and close proximity of the wound edges, very little sealing (termed epithelialisation) and shrinkage (contraction) are required. Wounds that heal under
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Surgical and penetrating wounds are useful models of both normal and abnormal (dysfunctional) healing. Bleeding is initially sealed off by a blood clot containing a cross-linked mesh of fibrin and trapped platelets. Most surgical wounds are completely sealed within hours after closure. This sealing helps unite the wound edges and creates a physical barrier to bacterial invasion. The fibrin mesh acts as a scaffold for fibroblasts and collagen deposition, which ultimately fills the wound, and is then replaced by normal or scar tissue. Macrophages invade the dissolving clot and clear away debris and dead cells. Macrophages also secrete biochemical mediators that promote healing. Granulation tissue grows into the wound from the surrounding healthy connective tissue, and consists of connective tissue, including fibroblasts. This is a distinguishing feature as granulation tissue leads to fibrosis. Granulation tissue is filled with new capillaries (by the process is called angiogenesis, meaning growing new blood vessels) derived from capillaries in the surrounding tissue, giving the granulation tissue a red, granular appearance. New lymphatic vessels also grow into the granulation tissue by a similar process. Additionally, the extracellular matrix provides not only a scaffold to guide cell placement, but its proteins also direct some cellular functions related to wound healing.2 The healing wound must also be protected. Epithelialisation is the process by which epithelial cells grow into the wound from surrounding healthy tissue. Epithelial cells migrate under the clot or scab to unravel collagen. Migrating epithelial cells contact similar cells from all sides of the wound and seal it, thereby halting migration and proliferation. The epithelial cells remain active, undergoing differentiation to give rise to the various epidermal layers (see Chapter 18). Epithelialisation of a skin wound can be hastened if the wound is kept moist (as opposed to allowing the wound to dry out), preventing the fibrin clot from becoming a scab. Fibroblasts are the most important cells during healing because they secrete collagen and other connective tissue proteins, which are deposited in debrided areas about
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Acute inflammation
Present in inflammatory exudate: • neutrophils • macrophages • bacteria and dead cells • erythrocytes • fibrin
Epithelium Fibrin clot and inflammatory exudate Inflammation New blood vessels
A A
BB
Fibroblasts Wound closure
Scar Re-epithelialisation
Fibroblast migration and collagenproducing epithelial cells recover surface
Epidermis
Collagen formation
C Acute inflammation
EE Fibroblasts Inflammation
Scar Acute inflammation
FFE Fibrin clot and inflammatory exudate Macrophage
Reconstructing phase
DD Reconstructing phase
G G New blood vessels
Granulation tissue
Maturation phase
H H
I H Collagen fibres
Scar tissue
FIGURE 13.14
Wound healing by primary or secondary intention. A to D Healing by primary intention. E to I Healing by secondary intention. See the text for more details.
Epithelialisation
6 days after the fibroblasts have entered the lesion. Collagen is the most abundant protein in the body. It contains high concentrations of the amino acids. As healing progresses, collagen undergoes chemical reactions to form collagen fibres. The complete process takes several months. Wound contraction is necessary for closure to all wounds, especially those that heal by secondary intention. Contraction is noticeable 6–12 days after injury. The granulation tissue contains myofibroblasts — specialised cells that are responsible for wound contraction. Myofibroblasts have features of both smooth muscle cells and fibroblasts. They appear microscopically similar to fibroblasts but differ in that their cytoplasm contains bundles of parallel fibres similar to those found in smooth muscle cells. Wound contraction occurs as extensions from the plasma membrane of myofibroblasts establish connections between neighbouring cells, contract their fibres and exert tension on the neighbouring cells while anchoring themselves to the wound bed.
The maturation phase
Collagen matrix assembly, tissue regeneration and wound contraction continue into the maturation phase — a phase that can persist for years. Scar tissue is remodelled and capillaries disappear, leaving the scar avascular — that is, without a blood supply (the ‘a’ in front of the word vascular means without). Within 2 to 3 weeks after maturation has begun, the scar tissue has gained about two-thirds of its eventual maximum strength. Epidermal wounds that heal by secondary intention and unsutured internal lesions are not completely restored by healing. At best, repaired tissue regains 80% of its original tensile strength. Essentially, this means that the scar tissue is never as strong as the original tissue. Only epithelial, liver and bone marrow cells are capable of the complete mitotic regeneration of normal tissue known as compensatory hyperplasia (described in Chapter 4). In fibrous connective tissue such as joints and ligaments, normal healing results in replacement of the original tissue with new tissue that does not have exactly the same structure or function as that of the original. In some cases this leads to recurrent injury, such as that experienced by athletes. For instance, an athlete sustains a knee injury, undergoes rehabilitation, but re-injures the same knee when competing again. This may occur because the new tissue is not quite as effective as the original tissue, leading to future problems. Some tissues heal without the replacement of cells. For example, damage resulting from myocardial infarction heals with a scar composed of fibrous tissue rather than with cardiac muscle, which can lead to cardiac conduction abnormalities as action potentials cannot propagate through the scar tissue.
Dysfunctional wound healing
Dysfunctional healing may occur during any phase of the process and may involve insufficient repair, excessive repair or infection. The cause of dysfunctional healing can be related to a predisposing disorder, such as diabetes mellitus;
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to an acquired condition, such as hypoxaemia (insufficient oxygen in arterial blood); or to numerous drugs and nutrients. Wound repair delays healing by reactivating inflammatory processes.
RESEARCH IN F
CUS
Wound healing and the NET(s) Neutrophils are the first cellular responder on the scene when tissue damage occurs. One of their defence techniques is to create neutrophil extracellular traps (NETs), by releasing de-condensed chromatin lined with cytotoxic proteins to trap and kill pathogens. An excess of NETs can lead to tissue damage. Research into NET development demonstrated that neutrophils obtained from persons with diabetes were more prone to producing NETs when stimulated than neutrophils from controls without diabetes, and had four times the amount of a key protein, peptidylarginine deiminase 4, that favours NET development. Mechanisms to inhibit the production of NETs or disrupt existing NETs may reduce chronic inflammation and improve wound healing in diabetes.
Dysfunction during the inflammatory response
Healing is prolonged if bleeding is not stopped during acute inflammation. Large clots increase the amount of space that granulation tissue must fill and serve as mechanical barriers to oxygen diffusion. Excess blood cells resulting from haemorrhage must be cleared before repair to avoid prolonging the healing process. Accumulated blood is also an excellent culture medium for bacteria and promotes infection, thereby prolonging inflammation by increasing exudation and pus formation. Excessive fibrin deposition is detrimental to healing. Fibrin released in response to injury must eventually be reabsorbed to prevent organisation into fibrous adhesions. Adhesions formed in the pleural, pericardial or abdominal cavities can bind organs together by fibrous bands and distort or strangulate the affected organ. Decreased blood volume also inhibits inflammation because of vessel constriction rather than the dilation required to deliver inflammatory cells to the site of injury. Anti-inflammatory steroids prevent macrophages from migrating to the site of injury and they also inhibit fibroblast migration into the wound during the reconstructive phase. Optimal nutrition is important during all phases of healing because metabolic needs increase. The substances most needed are glucose, oxygen and protein. Leucocytes need glucose for chemotaxis, phagocytosis and intracellular killing. Therefore, the wounds of individuals with diabetes mellitus who receive insufficient insulin usually heal poorly. People with diabetes mellitus are also at an increased risk for ischaemic wounds because they are likely to have both small-vessel diseases that impair the microcirculation and altered (glycated) haemoglobin (see Chapter 36), which
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has an increased affinity for oxygen and thus does not readily release oxygen in tissues. Oxygen-deprived (ischaemic) tissue is susceptible to infection, which prolongs inflammation. Other abnormalities seen in diabetes include persistence of neutrophils and macrophages, which prolongs inflammation and delays formation of mature granulation tissue, abnormalities of macrophage activation, and abnormal levels of cytokines.29,30 Hypoproteinaemia (a low level of protein in the blood, usually due to nutritional deficiency, liver or renal disease or burns) also prolongs inflammation because it impairs fibroblast proliferation.
Dysfunction during the reconstructive phase IMPAIRED COLLAGEN PRODUCTION
Most of the factors that interfere with the production of collagen in healing tissues are nutritional. Protein and other nutrients such as iron, oxygen, copper and calcium are required for collagen production. Usually such minute amounts of these substances are required as cofactors that deficiencies are not clinically significant. However, progressive remodelling of the extracellular matrix requires proper expression and activation of a group of enzymes called matrix metalloproteinases (MMPs).30 Diabetes interferes with the concentrations and functions of these MMPs. Dysfunctional collagen production also may involve excessive production of collagen, causing surface over-healing leading to abnormal scarring. Hypertrophic scars are large, red scars that are often hard and raised compared to normal scars. They may form when excessive collagen tissue is produced but the defining characteristic is that the tissue remains within the wound edges. Hypertrophic scars tend to regress over time, usually years. Keloid scars, on the other hand, are raised scars that extend beyond the original boundaries of the wound and invade surrounding tissue. They are permanent and are often associated with tenderness and pain. Fig. 13.15 shows hypertrophic and keloid scars.
A
i
ii B
IMPAIRED EPITHELIALISATION
Epithelialisation is suppressed by anti-inflammatory steroids and hypoxaemia. Wound care technique may greatly influence epithelial cell migration. External wounds that are draining or healing by secondary intention often are debrided and protected with dressings. The ideal dressing absorbs some drainage without being incorporated into the clot or granulation tissue. Because epithelial cells must migrate across the wound during healing, dressings that debride healthy epithelial cells along with necrotic tissue prolong epithelialisation. Many solutions that traditionally have been used to clean or irrigate wounds are deleterious to the fragile new cells in the wound bed. Normal saline and potable tap water are the most innocuous solutions that can be used to cleanse or irrigate a wound that is healing primarily by epithelialisation. Solutions such as iodine and hydrogen peroxide are very drying and subsequently inhibit rather than promote epithelial cell migration.
FIGURE 13.15
Different types of scars. A Hypertrophic scars: (i) a 5-month-old scar that is still pink; and (ii) a 1-year-old scar that has reduced in size and lost colour (hypopigmented). B A keloid scar. Keloids on the chest and extremities are raised with a flat surface, and the base is wider than the top.
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Wound disruption
A potential complication of wounds that are sutured closed is dehiscence, in which the wound pulls apart at the suture line. Dehiscence generally occurs 5–12 days after suturing, when collagen production is at its peak. Approximately half of dehiscence occurrences are associated with wound infection, but they also may be the result of sutures breaking because of excessive strain. Obesity increases the risk for dehiscence because adipose tissue is difficult to suture. Wound dehiscence usually is heralded by increased serous drainage from the wound and a feeling that ‘something gave way’. Prompt surgical attention is required.
Impaired contraction
Wound contraction, although necessary for healing, may become pathological when contraction is excessive, resulting in a deformity or contracture. Burns are especially susceptible to contracture development. Internal contraction deformities include duodenal strictures caused by dysfunctional healing
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of an ulcer and oesophageal strictures caused by lye burns. Contracture may occur in cirrhosis of the liver. Scar tissue that becomes contracted constricts vascular flow and contributes to the development of portal hypertension and oesophageal varices. Proper positioning and range-of-motion exercises and surgery are among the physical means used to overcome myofibroblast pull and prevent contractures.
FOCU S ON L EA RN IN G
1 Explain how regeneration of tissue differs from repair of tissue. 2 Describe how healing occurs by primary intention. 3 Discuss the role of fibroblasts in wound healing. 4 Describe various ways wound healing may be dysfunctional.
Paediatrics and inflammation and thermoregulation Newborns have a transiently depressed inflammatory response. The neutrophils are incapable of chemotaxis as they are lacking fluidity in the cell membrane. There is a tendency for infections associated with chemotactic defects — for example, cutaneous abscesses caused by Staphylococci and cutaneous candidiasis. There is also a partial deficiency in complement, especially components of alternative pathways.
Infants produce sufficient body heat, primarily through metabolism of brown fat (called brown fat thermogenesis), but have more difficulty modulating their temperature than adults. This is due to many factors, including their small body size, a greater ratio of body surface to body weight, low sweat production and lower cardiac output.
PAEDIATRICS
Paediatrics
Ageing and inflammation, thermoregulation and wound healing the underlying capillaries, decreases perfusion and increases the risk of hypoxia in the wound. A number of ageing-related factors affect the thermoregulatory capacity of elderly individuals contributing to their ability to respond to large changes in environmental temperature, both high and low. These include: reduced blood flow, reduced cold and warmth sensitivity, with a diminished vasoconstrictor response; structural and functional skin changes such as thinner skin and reduced subcutaneous fat, which change the perception of heat and cold, and mean that the elderly do not sweat as efficiently as younger people; and a decreased shivering response (delayed onset and decreased effectiveness), which overall reduces heatproducing capacity. Moreover, elderly people often have a decreased thirst mechanism coupled with undernutrition, which affects thermoregulation. Elderly people may have blunted fever response, which can lead to diagnostic delays in infectious illnesses.
AGEING
Elderly individuals are at risk for impaired wound healing. This is often associated with chronic illness — for example, diabetes mellitus or cardiovascular disease — which is prevalent in the elderly populations in Australia and New Zealand. Both diabetes mellitus and cardiovascular disease tend to decrease blood flow and oxygen availability to the tissues. In addition, medications such as anti-inflammatory steroids, commonly prescribed in the elderly population, may interfere with healing. Physiological changes in the elderly that can delay wound healing include changes to the extracellular matrix, an increased tendency towards cellular apoptosis (cell suicide) and telomere shortening and dysfunction, which slow cell proliferation. The elderly are also at risk for sustaining wounds because of impaired sensation or mobility and physiological changes in skin. There is a loss of subcutaneous fat associated with ageing, which diminishes the layer of protection, and thickened and less elastic collagen fibres, reducing protection. The atrophied epidermis, including
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chapter SUMMARY Acute inflammation
Inflammatory mediators
• Inflammation is one of the main components of innate immunity. • Inflammation is a rapid and nonspecific protective response to cellular injury from any cause. It can occur only in vascularised tissue. • The hallmarks of acute inflammation are localised vasodilation, increased vascular permeability and diapedesis. • The macroscopic manifestations of inflammation are redness, swelling, heat, pain and loss of function of the inflamed tissues.
• Histamine is the major vasoactive amine released from mast cells. It causes constriction of vascular smooth muscles, dilation of capillaries and retraction of endothelial cells lining the capillaries, which increases vascular permeability. • Chemotactic factors are released from mast cell granules, forming a chemical gradient to attract inflammatory cells towards the site of inflammation. • Leukotrienes produce histamine-like effects, smooth muscle contraction and increased vascular permeability. The biological activity of platelet-activating factor is virtually identical to that of leukotrienes. • Nitric oxide is released from the endothelium and causes vasodilation by inducing relaxation of vascular smooth muscle. It may suppress mast cell release of inflammatory molecules. • Prostaglandins cause increased vascular permeability, neutrophil chemotaxis and pain by direct effects on nerves. • Cytokines are responsible for mediating responses in both the innate and the adaptive immune systems. They are also either pro-inflammatory or anti-inflammatory and include interleukins and interferons. • Tumour necrosis factor-alpha induces a multitude of proinflammatory effects, including enhancement of endothelial cell adhesion molecule expression, which results in increased adherence of neutrophils. It is also a strong mediator of fever.
Cellular components of inflammation • Many different types of cells are involved in the inflammatory process, including neutrophils, monocytes and macrophages, eosinophils and platelets. • The most important activator of the inflammatory response is the mast cell, which initiates inflammation by releasing biochemical mediators (histamine, chemotactic factors) from preformed cytoplasmic granules and producing other mediators (prostaglandins, leukotrienes) in response to a stimulus. • Phagocytic cells (neutrophils and macrophages) engulf and destroy microorganisms by enclosing them in phagocytic vacuoles, within which toxic products and degradative lysosomal enzymes kill and digest the microorganisms. • Polymorphonuclear neutrophils, the predominant phagocytic cells in the early inflammatory response, exit the circulation by diapedesis through the retracted endothelial cell junctions and move to the inflammatory site by chemotaxis. • The macrophage, the predominant phagocytic cell in the late inflammatory response, is highly phagocytic, is responsive to cytokines and promotes wound healing. • Eosinophils release products that control the inflammatory response and are the principal cell that kills parasitic organisms. • Platelets interact with proteins of the clotting system to stop bleeding and release a number of mediators that promote and control inflammation. • Phagocytosis is a multistep cellular process for the elimination of pathogens and foreign debris. The steps include recognition and attachment, engulfment, containment of the foreign debris or pathogen inside a vacuole and finally destruction of pathogens or foreign debris.
Plasma protein systems • Inflammation is mediated by three key plasma protein systems: the complement system, the coagulation system and the kinin system. The components of all three systems are a series of inactive proteins that are activated sequentially. • The complement system can be activated by antigen– antibody reactions (through the classical pathway) or by other products, especially bacterial polysaccharides (through the lectin pathway or the alternative pathway), resulting in the production of biologically active fragments that cause cell lysis. • The most biologically potent products of the complement system are C3b (opsonin), C3a (anaphylatoxin) and C5a (anaphylatoxin, chemotactic factor). • Opsonins, such as antibody and complement component C3b, coat microorganisms and make them
more susceptible to phagocytosis by binding them more tightly to the phagocyte. • The coagulation system stops bleeding, localises microorganisms and provides a meshwork for repair and healing. • Bradykinin is the most important product of the kinin system and causes vascular permeability, smooth muscle contraction and pain.
Chronic inflammation • Chronic inflammation can be a continuation of acute inflammation that lasts 2 weeks or longer. It also occurs as a distinct process without much preceding acute inflammation. • Chronic inflammation is characterised by a dense infiltration of lymphocytes and macrophages. The body may wall off and isolate the infection to protect against tissue damage by formation of a granuloma.
Clinical manifestations of inflammation • Local manifestations of inflammation are the result of the vascular changes associated with the inflammatory process, including vasodilation and increased capillary permeability. The symptoms include redness, heat, swelling and pain. • The functions of the vascular changes are to dilute toxin molecules produced by dying cells or contaminating microorganisms, carry plasma proteins and leucocytes to the injury site, carry debris away from the site, and initiate healing and repair. • The principal systemic effects of inflammation are fever and increases in levels of circulating leucocytes and plasma proteins (acute phase reactants).
Fever • Temperature regulation is achieved through precise balancing of heat-production and heat-loss mechanisms. Body temperature is maintained in a narrow range between approximately 36.2°C and 37.7°C. • Temperature regulation is mediated by the hypothalamus through thermoreceptors in the skin, hypothalamus, spinal cord and abdominal organs. • Heat is produced through chemical reactions of metabolism, skeletal muscle contraction, chemical thermogenesis and conserved through vasoconstriction and voluntary mechanisms. • Heat is lost through radiation, conduction, convection, vasodilation, decreased muscle tone, evaporation of sweat, increased respiration and voluntary mechanisms. • Hyperthermia (an increase in core temperature above normal) can produce nerve damage, coagulation of cell proteins and death.
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• Hypothermia (a decrease in core temperature below normal) slows the rate of chemical reaction (tissue metabolism), increases the viscosity of the blood, slows blood flow through the microcirculation, facilitates blood coagulation and stimulates profound vasoconstriction. • Fever is triggered by the release of pyrogens from bacteria, leucocytes and other cells involved in the immune response. Fever is both a normal immunological mechanism and a symptom of a disease. • Fever involves an increase in the interthreshold zone mediated via prostaglandin E2 production. When the fever breaks, body temperature returns to normal. • Fever aids responses to infection. Higher temperatures kill many microorganisms and decrease serum levels of iron, zinc and copper, which are needed for bacterial replication.
Wound healing • Damaged tissue proceeds to restoration of the original tissue structure and function if little tissue has been lost or the injured tissue is capable of regeneration. This is called healing by primary intention. • Tissues that sustained extensive damage or those incapable of regeneration heal by the process of repair resulting in the formation of a scar. This is called healing by secondary intention. • Wound healing occurs in two separate phases: the reconstructive phase in which the wound begins to heal; and the maturation phase in which the healed wound is remodelled. • Dysfunctional wound healing can occur as a result of abnormalities in either the inflammatory response or the reconstructive phase of resolution and repair.
Paediatrics and inflammation and thermoregulation • Neonates often have transiently depressed inflammatory function, particularly neutrophil chemotaxis and alternative complement pathway activity. • Infants do not conserve heat well because of their greater body surface/mass ratio and decreased subcutaneous fat.
Ageing and inflammation, thermoregulation and wound healing • The elderly are at risk for impaired wound healing, usually because of chronic illnesses. • The elderly have poor responses to environmental temperature extremes as a result of slowed blood circulation, structural and functional changes in the skin, and overall decrease in heat-producing activities.
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CASE STUDY
AD U LT Athena is 54 years old and married with four adult-age children. She works part-time in an after-school care centre during the school semesters. A few days ago she tripped over a toy in the playground and hurt her ankle. Her ankle was swollen, red and tender to touch. It was also painful and so she took several days off work. Athena noticed that when she walked after a few minutes her ankle became painful and more swollen than usual. She also had a fever up to 38.2°C. Her local doctor diagnosed a grade II ankle sprain (moderate tearing of ligaments, internal and external bruising, joint instability and difficulty walking). He prescribed rest, elevation, ice and antipyretics.
1
2 3
4 5
Describe the immediate inflammatory responses that result in vasodilation, increased vascular permeability and chemotaxis. Describe why Athena’s ankle was swollen. List 5 inflammatory mediators either released from the cells or circulating in the plasma. Explain the mechanisms of each of these mediators. Describe why Athena is likely to have fever and how antipyretic medications affect fever. Describe why Athena’s ankle is painful. In your answer discuss how pain can arise from many different mechanisms due to inflammation. You may need to review Chapter 7 on pain to aid your answer.
CASE STUDY
AG EING Jean is a 75-year-old woman with diabetes mellitus who lives alone. Her husband died several years ago, and Jean tends not to cook for herself because ‘it’s too much trouble to go to for one person’. Jean is a long-term smoker and has a history of chronic foot ulcers. About 2 months ago she had surgery to amputate a gangrenous foot. Several weeks following surgery the wound developed a purulent drainage. Now several necrotic areas have developed and the wound has dehisced. Jean has been prescribed an antibiotic and wound debridement.
1
Describe the stages of normal wound healing. List the risk factors Jean has for delayed wound healing. 3 Describe the effects of advanced age on wound healing. 4 Explain why oxygen is very important for normal wound healing. 5 Explain why diabetes mellitus delays wound healing. 2
REVIEW QUESTIONS 1 Describe how the 4 cardinal clinical manifestations (redness, heat, swelling and pain) arise during inflammation. 2 Explain what inflammatory cells are and their respective functions. Provide 3 examples in your answer. 3 Describe what an inflammatory mediator does. In your answer provide 4 examples of mediators and list their functions. 4 The three plasma protein systems of complement, coagulation and kinin are intimately integrated with inflammation. Explain the purpose of each system. 5 Explain the role of phagocytosis in inflammation.
6 Differentiate between acute and chronic inflammation. Identify why chronic inflammation may occur. 7 Explain how body core temperature is maintained in a narrow range despite fluctuating environmental temperatures. 8 Explain how fever arises and why it can be beneficial to the body during infection. 9 Outline the differences between normal and dysfunctional wound healing. 10 Differentiate between a hypertrophic scar and a keloid scar. In your answer provide the possible long-term effects of each scar.
Key terms antibiotics, 346 antifungal, 347 antigenic drift, 345 antigenic shifts, 345 antimicrobials, 347 antiviral agents, 347 bacteria, 338 endotoxins, 340 exotoxins, 339 fungi, 343 gram-negative, 338 gram-positive, 338 healthcare-acquired infections, 352 moulds, 343 multiple antibiotic-resistant bacteria, 353 mycoses, 344 opportunistic microorganisms, 336 pathogens, 336 vaccination, 347 virions, 341 virus, 341 yeasts, 343
CHAPTER
Infection
14
Thea F van de Mortel
Chapter outline Introduction, 334 Infection rates, 334 Definitions, 335 Microorganisms, 335 Normal flora, 335 Pathogens, 336 Classes of microorganisms, 337 Methods of infection, 344 Clinical manifestations of infection, 345
Detection and treatment of microorganisms, 345 Antimicrobials, 346 Vaccines, 347 Infections, 350 Common infections, 350 Infection control and healthcare-acquired infections, 352 Antimicrobial resistance, 353
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Introduction Humans appear to have had some understanding of the factors involved in the transmission of infectious diseases from a very early time. Evidence of purposeful sanitation has been found in ancient civilisations. During the fourteenth century, people infected with the Black Death (a bubonic plague involving an infection of the lymph glands) were isolated because, although the transmission method was unknown, it was realised that infected individuals were contagious. But it was only when Robert Hooke first saw fungi under a rudimentary microscope in 1665 that our understanding of microorganisms and their infectious consequences started to become clearer. The pioneering nurse, Florence Nightingale, obviously understood infection control and the ability to limit the impact of microorganism contamination. During the Crimean War (1853–1856) she instituted fundamental infection-control procedures that dramatically reduced the infection rate of wounded soldiers and therefore the mortality rate.1 Joseph Lister, a surgeon in the 1800s, implemented the use of antiseptics for surgery in operating theatres, greatly reducing surgical infections, which were catastrophic in patients and caused massive mortality rates.2 However, it was not until Alexander Fleming’s discovery of penicillin in 1923 and the subsequent extraction of commercial quantities by the Australian pharmacologist, Howard Florey, in the 1940s that our ability to eradicate microorganisms using antibiotics occurred. This discovery paved the way for modern healthcare methods to treat and prevent infectious diseases in individuals who might otherwise die. Coupled with this discovery, sanitary living conditions, clean water and adequate nutrition in developed countries like Australia and New Zealand have greatly reduced the mortality rate from infectious diseases. This chapter examines what microorganisms are and which ones are harmful to humans. We also explore
treatment and prevention, including antimicrobials and vaccines, as well as the more common infections and those acquired in healthcare settings, particularly hospitals. The final section looks at a growing problem in Australia and New Zealand: antimicrobial resistance to drug therapies.
Infection rates Currently, the mortality rate attributable to infectious diseases in Australia is very low compared to 90 years ago (see Fig. 14.1). In 1907 the death rates (age standardised) for infectious diseases in Australia were 356 and 288 per 100 000 females and males, respectively, whereas by 2013 it had declined considerably to 8.5 per 100 000 for males and females. There were just over 2000 deaths due to infectious diseases in 2010 — septicaemia accounted for most of these (63.5%).3 The vast majority of deaths due to infectious diseases were caused by bacteria (85%). Viruses accounted for 12%, while other groups of pathogens were responsible for only 3%. The majority of deaths in Australia and New Zealand reflect those of other developed countries, where people die predominantly from cardiovascular disease, dementia and cancers. Nonetheless, in 2013–2014 in Australia, 147 309 hospitalisations were for infectious diseases.4 Globally the picture is somewhat different. Pneumonia, diarrhoeal diseases, and human immunodeficiency virus (HIV) infections are the third, fifth and sixth leading causes of mortality.5 If low income countries are examined separately then 5 of the 10 leading causes of mortality are infectious in origin, and the top three leading causes of death are infectious diseases, while in high income countries, only one of the top 10 causes of death is infectious, and it is ranked sixth. While the reasons for this are multifactorial, developing countries do not have the infrastructure and living standards of countries such as Australia and New
FIGURE 14.1
Mortality rate for infectious and parasitic diseases between 1907 and 2015.
Zealand, and with high concentrations of people living in close quarters, infectious contamination occurs more readily. In addition, vaccination coverage is not as extensive in developing countries and unfortunately children acquire diseases that are eradicated in Western countries, which significantly impacts on the mortality rate. Developing countries with dense populations and poor sanitation suffer from plague, cholera, malaria, tuberculosis, leprosy and schistosomiasis. Only smallpox has been eradicated worldwide by vaccination. Although vaccines and antimicrobials have altered the prevalence of some infectious diseases, mutant strains of bacteria and viruses have emerged showing resistance to the protection provided by drug therapy. The emergence of new diseases, such as West Nile virus, severe acute respiratory syndrome (SARS), Lyme disease, Zika virus, Hantavirus and drug-resistant tuberculosis, indicates the current intense challenges being faced in the struggle to prevent and control infectious diseases.
Definitions To gain a fuller understanding of the infectious disease process, you first need to understand several terms, as the interaction between microorganisms and humans is complex. These terms are used throughout the chapter and so understanding them is vital. • Antimicrobial: a chemical agent that acts to inhibit the growth of, or destroy microorganisms. The most common antimicrobial is antibiotics and these are effective against pathogenic bacteria. • Colonisation: refers to the presence, growth and multiplication of an organism without observable clinical symptoms or immune reaction in a patient. • Endemic: the normal background incidence of a disease in a population. • Epidemic: a sudden increase in the incidence of a disease, which many people acquire within a short time frame, and usually within a particular location — for example, an outbreak of gastroenteritis. • Pandemic: a disease that spreads rapidly and widely across multiple countries or continents, or even the world. This is greater in magnitude than an epidemic. For example, the spread of swine flu, influenza A H1N1, across several continents in 2009 from a base in Mexico was a pandemic (an explanation of H1N1 terminology is provided later in this chapter). • Flora: microorganisms that inhabit a body region without causing infection — for example, bacteria within the gastrointestinal system. • Healthcare-acquired infection: an infection acquired by an individual in a healthcare facility. Such infections are often antibiotic-resistant bacteria in hospitals and were previously known as nosocomial infections. • Infection: invasion of a pathogenic microorganism causing symptoms.
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• Microorganisms: these include bacteria, viruses, fungi and parasites. Microbe is another commonly used term that is synonymous with microorganism. Many microorganisms do not harm humans: in fact, they live on our skin, in our bodies and in the environment. However, others cause infections that range from being irritating to the individual to life threatening. • Opportunistic infection: a microorganism causing infection in an individual that would not normally harm a healthy individual. For example, an immune-compromised person receiving chemotherapy acquires infections more readily. • Pathogen: a microorganism that causes disease. • Superinfection: an infection that arises when an individual is administered antimicrobials that reduce the body’s normal flora allowing overgrowth with other microorganisms. • Vaccine: a biological agent that confers immunity to a disease. The vaccine stimulates antibody production but does not cause infection, and so the individual develops immunity against the disease.
Microorganisms Normal flora
The human body provides a very hospitable site for microorganisms to grow and flourish. The microorganisms are provided with nutrients and appropriate conditions of temperature and humidity. In many cases a mutual relationship exists in which humans and microorganisms benefit. For instance, the human gut is colonised by a large variety of microorganisms. At birth, the gastrointestinal tract becomes progressively colonised with microorganisms that provide vital functions throughout the individual’s life. The large intestine contains numerous bacteria, yeasts and parasites.6 In fact, it has been estimated that in excess of 1011 bacteria (that is, 100,000,000,000 or one hundred billion) are contained in each gram of human faeces, so there are more bacteria in one gram of faeces than there are people in the world or cells in your entire body! Table 14.1 summarises the microorganisms that are the normal flora of different body regions. These bacteria are provided with nutrients from ingested food and in exchange they produce: (1) enzymes that facilitate the digestion and utilisation of many molecules in the human diet; (2) antibacterial factors that prevent colonisation by pathogenic microorganisms; and (3) usable metabolites (e.g. vitamin K is needed in clotting and is produced by bacteria in the large intestine). This relationship normally is maintained through the physical integrity of the skin and mucosal epithelium (lining of the gastrointestinal tract) and other mechanisms that guarantee that the immune system, including the inflammatory process, does not attack these microorganisms comprising the normal body flora. If any location in the body that normally contains microorganisms is compromised, microorganisms may leave the site and
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TABLE 14.1 Normal indigenous flora of the human body LOCATION
MICROORGANISMS
Skin
• Predominantly gram-positive cocci and rods • Staphylococcus epidermidis, corynebacteria, mycobacteria and streptococci are primary inhabitants; Staphylococcus aureus in some people; also yeasts (Candida) in some areas of skin • Numerous transient microorganisms may become temporary residents • In moist areas, gram-negative bacteria • Around sebaceous glands, Propionibacteria and brevibacteria • The mite Demodex folliculorum lives in hair follicles and sebaceous glands around the face
Nose
• Predominantly gram-positive cocci and rods, especially Staphylococcus epidermidis • Some people are nasal carriers of pathogenic bacteria, including Staphylococcus aureus, β-haemolytic streptococci and Corynebacterium diphtheria
Mouth
• A complex of bacteria that includes several species of streptococci, Actinomyces, lactobacilli and Haemophilus • Anaerobic bacteria and spirochetes colonise the gingival crevices
Pharynx
• Similar to flora in the mouth plus staphylococci, Neisseria and diphtheroids • Some asymptomatic individuals also harbour the pathogens pneumococcus, Haemophilus influenzae, Neisseria meningitidis and Clostridium diphtheria
Distal intestine
• Enterobacteria, streptococci, lactobacilli, anaerobic bacteria, and Clostridium albicans
Colon
• Bacteroides, lactobacilli, clostridia, Salmonella, Shigella, Klebsiella, Proteus, Pseudomonas, enterococci and other streptococci, bacilli and Escherichia coli
Urethra
• Typical bacteria found on the skin, especially Staphylococcus epidermidis and diphtheroids; also lactobacilli and non-pathogenical streptococci
Vagina
• Birth to 1 month: similar to adult • 1 month to puberty: Staphylococcus epidermidis, diphtheroids, Escherichia coli and streptococci • Puberty to menopause: Lactobacillus acidophilus, diphtheroids, staphylococci, streptococci and a variety of anaerobes • Postmenopause: similar to prepubescence
cause infection. Individuals with deficiencies in their immune system become easily infected with opportunistic microorganisms — those that normally would not cause disease but seize the opportunity provided by the person’s decreased immune or inflammatory responses.
Pathogens
True pathogens have devised means to circumvent the normal controls provided by the host’s main defensive barriers, the inflammatory system and the immune system. Infection by a pathogen is influenced by several factors: • Mechanism of action: direct damage of cells, interference with cellular metabolism and rendering a cell dysfunctional because of the accumulation of pathogenic substances and toxin production. • Infectivity: the ability of the pathogen to invade and multiply in the individual — for example, coagulase (an enzyme) that causes coagulation and allows some microorganisms, such as Staphylococcus, to clot and form
a sticky layer around themselves, protecting themselves against host defences. • Pathogenicity: the ability of an agent to produce disease — success depends on its speed of reproduction, extent of tissue damage and production of toxins. • Virulence: the potency of a pathogen measured in terms of the number of microorganisms or micrograms of toxin required to kill a host — for example, measles is of low virulence; the rabies virus is highly virulent. • Immunogenicity: the ability of pathogens to induce an immune response. • Toxigenicity: a factor important in determining a pathogen’s virulence, such as production of soluble toxins or endotoxin. The portal of entry is the way the pathogen enters the body. Humans have several defence mechanisms that preclude entry of microorganisms into the body and if these are overcome sophisticated defences can be activated immediately. The pathogen can enter the body via direct
CHAPTER 14 Infection
Penetration of skin
Direct contact
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Inhalation Ingestion
Dengue Malaria Typhus
Lymph node Lymphatic Bloodstream
Brain
Skin
Chickenpox
Lungs
Measles Rubella
Kidney
Salivary gland
Haematogenous Mumps pyelonephritis Rabies
Liver
Hepatitis B Yellow fever
FIGURE 14.2
The route of entry and spread of microorganisms that cause infection in the body. Main routes of entry include through the skin (usually skin with compromised integrity such as a wound), through direct contact, or through inhalation or ingestion of microorganisms. Once entered the body, these microorganisms enter cells, and can spread to other sites via the lymphatics or bloodstream.
contact, inhalation, ingestion or penetration of the skin. Direct contact typically occurs when human-to-human contact permits transmission of the pathogen to the host — sexually transmitted infections are an example when close contact occurs between humans. Inhalation is a common form of pathogen transmission despite several anatomical and physiological barriers in the upper respiratory tract. Infections that occur from inhalational entry include pneumonia, the common cold and tuberculosis. Ingestion of pathogenic microorganisms allows direct entry into the body. However, the acidity of the stomach and the normal flora of the gastrointestinal tract must be overcome by the pathogen. Lastly, direct penetration of the skin may occur due to puncturing of the dermal layer — for example, a bite — or due to a breakdown in the integrity of skin. Either way, pathogens can infect wounds or cause skin lesions that can be infective. Spread of infection is facilitated further by the ability of pathogens to attach to cell surfaces, release enzymes that
dissolve protective barriers, escape the action of phagocytes or resist the effect of low pH, such as in the stomach. After penetrating protective barriers, pathogens spread through the lymph and blood for invasion of tissues and organs, where they multiply and cause disease. In humans the route of entrance of many pathogenic microorganisms also becomes the site of shedding of new infectious agents to other individuals, completing a cycle of infection (see Fig. 14.2).
Classes of microorganisms
Infectious disease in humans can be caused by microorganisms that range in size from 20 nanometres (1 nanometre is 0.000001 of a millimetre) — for example, the poliovirus, which causes poliomyelitis — to 10 metres — for example, a tapeworm. There are six main classes of microorganisms: bacteria, viruses, fungi, parasites, protozoa and algae. In reality, algal, parasitic and protozoan infections
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are uncommon (compared to bacterial and viral infections) in Australia and New Zealand and so they are not discussed further in this chapter. However, Giardia intestinalis is a common intestinal protozoan found in contaminated drinking water, which causes diarrhoea and abdominal pain. Table 14.2 provides an overview of the most common classes of pathogens and their characteristics.
Bacteria
There are many different bacteria and the majority are harmless to humans. However, some that are pathogenic can be particularly destructive to humans and can rapidly cause death. In hospitals, bacteria remain the number one cause of infections, acquired both outside and within the hospital. Bacteria are prokaryocytes (lacking a discrete nucleus) and are relatively small. They can be aerobic (they need oxygen), obligate anaerobes (they require an oxygen-free environment) or facultative anaerobes (they can survive without oxygen). In addition, they can be motile (they can move) or non-motile. There are three main bacterial shapes: (1) spherical, called cocci; (2) rod-shaped, called bacilli; and (3) spiral-shaped, termed spirochetes. These can be
TABLE 14.2 Classes of human infectious microorganisms CLASS
SIZE
EXAMPLES OF DISEASE
Viruses
20–30 nm
Measles Hepatitis B
viewed under a microscope and provide a simple identification method (see Fig. 14.3). The other primary classification method for bacteria is the difference in cell wall constituents. A test called the gram stain was devised to differentiate between the two broad categories of bacteria, namely gram-positive and gram-negative. Briefly, the gram stain involves attaching bacteria to a glass slide and applying crystal violet (purple dye), which is then washed off. Iodine is then applied, which colours all bacteria a deep purple. Next, alcohol is applied and this washes off the purple colour from some bacteria, while others retain the purple colour. Finally, a red counter stain is applied which colours gram-negative bacteria (that did not retain the purple dye) red. Under a microscope, the difference in colours is used to identify gram-positive and gram-negative bacteria. Bacteria that are gram-positive have a thick layer of peptidoglycan, which is found in the cell walls of bacteria. The iodine of the gram stain becomes trapped in the peptidoglycan layer, hence the name gram-positive. In contrast, gram-negative bacteria have only a thin peptidoglycan layer, and have an additional outer membrane outside the cell wall. These factors prevent the retention of the crystal violet and iodine but allow absorption of the red counter stain, which provides the red appearance, hence the name gram-negative. The cellular structure of gram-positive and gram-negative bacteria and the gram stain are illustrated in Fig. 14.4, and different gram-positive and gram-negative bacteria are shown in Fig. 14.5. The gram stain provides useful information on which antibiotics to choose. Bacterial survival and growth depends on the effectiveness of the body’s defence mechanisms and on the microbes’
Influenza (flu) Human immunodeficiency virus (HIV) Bacteria
0.8–15 µm
Staphylococcal wound infection Cholera Streptococcal pneumonia
Chlamydia
200–1000 nm Sexually transmitted infection (Chlamydia)
Rickettsiae
300–1200 nm Australian tick typhus
Mycoplasma
125–350 nm
Mycoplasma pneumonia
Mycobacterium
1–10 µm
Tuberculosis
Fungi
2–200 µm
Tinea pedis (athlete’s foot) Thrush (Candida) Histoplasmosis
Protozoa
1–360 µm
Giardiasis Malaria
Parasitic worms 3 mm to 10 m Trichinosis (Helminths) Filariasis Note: Chlamydia, Rickettsiae, Mycoplasma and Mycobacterium are classified as bacteria.
FIGURE 14.3
Morphology of bacteria. The different shapes of bacteria, which provide a means of identification.
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A
339
Division septum Outer membrane Peptidoglycan (Capsule) layer
(Capsule) Cytoplasmic membrane
Peptidoglycan layer
Cytoplasmic membrane
Ribosome Surface proteins
(Flagellum)
B
Ribosome Chromosome
Gram-positive bacterium
Gram-positive Staphylococcus aureus
(Flagellum)
Gram-negative bacterium
Gram-negative Escherichia coli
Step 1 Crystal violet Step 2 Gram iodine Step 3 Decolouriser (alcohol or acetone) Step 4 Safranin red
FIGURE 14.4
Gram-positive and gram-negative bacteria and the gram stain. A Gram-positive bacteria have a thick layer of peptidoglycan (filling the purple space), whereas gram-negative bacteria have a thin peptidoglycan layer (single black line) and an outer membrane. B The iodine of the gram stain is trapped in the thick peptidoglycan layer in gram-positive bacteria. Gram-negative bacteria take up the counterstain, which provides the red appearance.
ability to resist these defences. Many pathogens have devised ways of preventing destruction by the inflammatory and immune systems. For example, some bacteria produce thick capsules of carbohydrate or protein that are antiphagocytic, preventing efficient opsonisation and phagocytosis (see Chapter 13 for more details on phagocytosis). Such coatings include the thick polysaccharide covering of the pneumococcus and the waxy capsule surrounding the tubercle bacillus. Other bacteria survive and proliferate in the body by producing toxins — poisonous substances that are produced during metabolism and growth of the microorganism. The toxins have the ability to cause direct damage to the host
cells or change normal cellular function. Two broad groups of toxins are produced by bacteria: • Exotoxins are proteins released during bacterial growth. They are usually enzymes and have highly specific effects on host cells. They include cytotoxins, neurotoxins, pneumotoxins, enterotoxins and haemolysins. Exotoxins can damage cell membranes, activate second messengers and inhibit protein production. Exotoxins are immunogenic and elicit the production of antibodies known as antitoxins. Fortunately, vaccines are available for many of the exotoxins (i.e. tetanus, diphtheria and pertussis). Some strains of toxin-producing group A
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Gram stain
Shape
O2 requirement
Other characteristics
Identity
Anaerobic Spheres (Cocci)
Clusters
Staphylococcus
Chains, pairs
Streptococcus
Spore forming
Clostridium
Non-spore forming
Propionibacterium
Spore forming
Bacillus
Non-spore forming
Listeria
Aerobic
Grampositive Anaerobic Rods Aerobic
Anaerobic
Bacteroides
Growth on complex media
Rods
Legionella, Haemophilus, Bordetella, Brucella, Campylobacter
Aerobic Gramnegative
Growth on simple media Spheres (Cocci)
Aerobic and anaerobic
Pairs
Vibrio, Escherichia, Klebsiella, Salmonella, Shigella, Pseudomonas Neisseria
FIGURE 14.5
Types of gram-positive and gram-negative bacteria. Gram positive and gram negative bacteria both consist of rods or cocci, as well as have anaerobic and aerobic types. The main grampositive and gram-negative bacteria are listed.
streptococci cause destructive skin infections (e.g. flesheating bacteria syndrome or necrotising fasciitis) and pneumonia, which may kill an individual within 2 days. • Endotoxins are formed from lipopolysaccharides, which are contained in a layer outside of the cell wall of certain gram-negative bacteria (e.g. Bordetella pertussis, Escherichia coli, Haemophilus influenzae, Neisseria meningitidis, Pseudomonas, Salmonella, Shigella). The endotoxins are released during cell lysis or destruction of the bacteria. The presence of an endotoxin in gram-negative bacteria increases virulence. Inflammation is the body’s initial response to the presence of bacteria. Vascular permeability is increased, allowing blood-borne substances (i.e. the complement system) involved in bacterial destruction to access the site of infection. Endotoxins increase capillary permeability further
by activating the complement cascade. Capillary permeability may increase sufficiently to permit the escape of large volumes of plasma, contributing to hypotension and, in severe cases, shock (see Chapter 23). Endotoxins can also activate the coagulation cascade (see Fig. 14.6). Septicaemia refers to the presence of microorganisms in the blood, while bacteraemia is the presence of bacteria in the blood and is caused by a failure of the body’s inflammation and immune defence mechanisms. Historically, septicaemia was most commonly caused by gram-negative bacteria but gram-positive bacteria have taken over as the most common cause. Symptoms of gram-negative septic shock are produced by the release of endotoxins. Once in the blood, endotoxins cause the release of vasoactive peptides and cytokines that affect blood vessels, producing vasodilation, which reduces blood pressure, causes decreased oxygen delivery and produces septic shock (see Chapter 23).
CONCEPT MAP
CHAPTER 14 Infection
↑ Vascular permeability
Human DNA viruses Hypotension
Shock
Papovavirus
Mast cell Endothelial cells
↓ Iron
Monocyte
Mediators Platelets IgE
Parvovirus
C3a C5a
Abnormal clotting
Adenovirus
Human RNA viruses
Bacteriophage MS2 Bacteriophage M13 Tobacco mosaic virus
IFN-
ENDOTOXIN
Fever
Bacteriophage T2
Reovirus Togavirus Coronavirus
Rhabdovirus Paramyxovirus
Chlamydia
Clotting Alternative complement pathway
T cell Acute phase proteins
Picornavirus
Orthomyxovirus
Herpesvirus
Poxvirus TNF IL-1
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Escherichia coli (6 µm long) Neutrophil FIGURE 14.7
Liver
Hypoglycaemia
Comparison of viral and bacterial shapes and sizes. Viruses are considerably smaller than bacteria; the bacteria shown here are Escherichia coli and Chlamydia.
FIGURE 14.6
Endotoxin release activates every immune mechanism and the clotting cascade. This bacterial endotoxin activates almost every immune mechanism, as well as the clotting pathway. IFN-γ = interferonγ; IgE = immunoglobulin E; IL-1 = interleukin-1; TNF = tumour necrosis factor.
While the mechanisms are somewhat different, the symptoms of gram-positive shock are similar.
Viruses
The word virus comes from the Latin meaning poison or toxin. Viruses are much smaller than bacteria and are the smallest pathogenic microorganisms (see Fig. 14.7). Viruses are very simple microorganisms consisting of nucleic acid (genetic material) protected from the environment by a layer of protein, called a capsid (see Fig. 14.8). The genetic information is in either RNA (ribonucleic acid) or DNA (deoxyribonucleic acid). Viral diseases are the most common causes of illness in humans and include a variety of diseases ranging from the common cold to several types of cancers and immunodeficiency (HIV), which leads to acquired immunodeficiency syndrome (AIDS). Viruses are sensitive to many environmental factors and cannot survive for long outside of a host cell. Virions (viral particles) do not possess any of the metabolic organelles found in bacteria or human cells. Therefore, they are not capable of replicating without the assistance of a host cell, which provides the capability for reproduction. Some scientists consider that viruses are not
‘alive’ as they are not cells (no cytoplasm, no organelles, and only one type of nucleic acid). Infection with a virus begins with a virion binding to a specific receptor on the plasma membrane of a host cell. The virus then changes the activity of the host cell such that viral replication occurs. The clinical symptoms will reflect the alteration of the function of the infected cells (see Fig. 14.9) — for example, the influenza virus binds to a receptor on respiratory epithelial cells, causing symptoms of an upper respiratory tract infection. The viral capsid (protein coat) must be removed in the cytoplasm of the infected host cell (uncoating). The viral genetic material may be processed by one of several paths, depending on the particular virus. Generally, all RNA viruses, except influenza and retroviruses, replicate their genetic material in the cytoplasm of the infected cell, and all DNA viruses, except poxviruses, require the DNA to enter the nucleus and use the cell’s DNA enzyme to replicate. Poxviruses provide their own DNA polymerase and replicate their DNA in the cytoplasm of the infected cell. Retroviruses generally convert their RNA genetic information to DNA using an enzyme contained in the virion — reverse transcriptase. After infection, viruses usually make multiple copies of their genetic material and produce the necessary viral proteins for replication. New virions are assembled in the host cell’s cytoplasm and are released from the cell for transmission of the viral infection to other host cells. This cycle is referred to as the productive or lytic cycle because a large number of offspring are produced and the result is often destruction of the host cell.
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Virus Receptor
NAKED CAPSID VIRUS Nucleocapsid
Entry, uncoating
RNA
Viral genome replication, mRNA synthesis ENVELOPED VIRUS
Protein
Lipid bilayer Structural protein Glycoprotein
Reduced host cell DNA, RNA, protein synthesis Viral inclusions
Viral protein synthesis VIRAL PROTEINS Virus assembly
Metabolic derangements Cell lysis or fusion Neoplastic transformation Viral antigens
B
Host T cell–mediated injury FIGURE 14.9
Mechanisms of viral injury to host cells. Viral injury can cause multiple events to be altered within the cell.
i
iii
ii
iv
FIGURE 14.8
The structure of a virus. A Note the enveloped virus, which refers to a lipid membrane surrounding the nucleic acid. Naked viruses do not have this layer. B Electron microscope images of viruses: (i) adenovirus, (ii) Epstein-Barr virus, (iii) rotavirus and (iv) paramyxovirus.
Some viruses are not productive initially, but instead initiate a latency phase during which the host cell is transformed. During this phase, the viral DNA may be integrated into the DNA of the host cell and become a permanent passenger in that cell and its offspring. In response to stimuli — such as stress, hormonal changes or disease — the virus may exit latency and enter a
productive cycle and cause signs and symptoms of infection in the individual. An example of this is the varicella zoster virus, which causes chickenpox. Although the initial infection subsides rapidly, the virus can lie dormant in the individual and then reappear later to produce the painful illness herpes zoster, more commonly known as shingles. Besides taking over the host cell’s metabolic machinery, viral infection can injure cells. In some viral infections, cellular destruction results from large quantities of virus being released from the cell’s plasma membrane. Alteration of the plasma membrane by the expression of new antigens as a result of viral infection can incite an immune response against the individual’s infected cells (e.g. hepatitis B virus). Once inside the human host cell, virions have many harmful effects, including the following: • the cessation of DNA, RNA and protein production (e.g. herpes virus) • disruption of lysosomal membranes, resulting in release of ‘digestive’ lysosomal enzymes that can kill the cell (e.g. herpes virus) • fusion of host cells, producing multinucleated giant cells (e.g. respiratory syncytial virus)
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TABLE 14.3 Disease-causing viruses DNA VIRUSES
Family
Viral members
Adenoviridae
Human adenoviruses
Hepadnaviridae
Hepatitis B virus
Herpesviridae
Herpes simplex 1 and 2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpes viruses 6, 7 and 8
Papillomaviridae Parvoviridae Polyomaviridae Poxviridae
Human papilloma viruses Parvovirus B-19 BK and JC-polyomaviruses Variola, vaccinia, orf, molluscum contagiosum, monkeypox
RNA VIRUSES
Family
Viral members
Arenaviridae
Lymphocytic choriomeningitis virus, Lassa fever virus
Astroviridae
Gastroenteritis-causing astroviruses
Bunyaviridae
Arboviruses including California encephalitis and Lacrosse viruses; non-arboviruses including sin nombre and related hantaviruses
Caliciviridae Coronaviridae Filoviridae Flaviviridae Orthomyxoviridae Paramyxoviridae Picornaviridae Reoviridae
Noroviruses and hepatitis E virus Coronaviruses, including SARS coronavirus Ebola and Marburg haemorrhagic fever viruses Arboviruses including yellow fever, dengue, West Nile, Japanese encephalitis and St Louis encephalitis viruses; non-arboviruses including hepatitis C virus Influenza A, B and C viruses Parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus, metapneumovirus, Nipah virus
Retroviridae
Polio viruses, coxsackie A viruses, coxsackie B viruses, echoviruses, enteroviruses 68–71, enterovirus 72 (hepatitis A virus), rhinoviruses
Rhabdoviridae
Rotavirus, Colorado tick fever virus
Togaviridae
Human immunodeficiency viruses (HIV-1 and HIV-2), human T-lymphotrophic viruses (HTLV-1 and HTLV-2) Rabies virus Eastern, Western and Venezuela equine encephalitis viruses, rubella virus
• alteration of the antigenic properties or ‘identity’ of the infected cell, causing the individual’s immune system to attack the cell as if it were foreign (e.g. hepatitis B virus) • transformation of host cells into cancerous cells, resulting in uninhibited and unregulated growth (e.g. human papilloma virus) • promotion of secondary bacterial infection in tissues damaged by viruses. Examples of human diseases caused by specific viruses are listed in Table 14.3.
Fungi
Fungi are relatively large eukaryotic microorganisms that grow as either single-celled yeasts (spheres) or multicelled moulds (filaments or hyphae) (see Fig. 14.10). Some fungi can exist in either form and are called dimorphic fungi. The
MOULDS Filamentous fungi grow as multinucleate, branching hyphae, forming a mycelium (i.e. ringworm)
YEASTS Yeasts grow as ovoid or spherical; single cells multiply by budding and division (i.e. Histoplasma)
FIGURE 14.10
Types of fungi. Moulds and yeasts can both cause infection in humans.
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cell walls of fungi are rigid and multilayered. The wall is composed of polysaccharides different from the bacterial peptidoglycans. Importantly for clinical practice, the lack of peptidoglycans allows fungi to resist the action of bacterial cell wall inhibitors such as penicillins and cephalosporins. In contrast to bacteria, the cytoplasm of fungi contains organelles: mitochondria, ribosomes, Golgi apparatus, microtubules, microvesicles, endoplasmic reticulum and nuclei. Moulds are aerobic and live in a variety of environments, such as bread, vegetables, soil and water. Yeasts are facultative anaerobes, which produce ATP using aerobic respiration if present; however, they have the capacity to adapt to anaerobic conditions and can survive if needed. They usually reproduce by simple division or budding. Pathological fungi cause disease by adapting to the host environment. Fungi that colonise the skin can digest keratin (the protein in the skin that provides structure). Other fungi can grow with wide temperature variations in lower oxygen environments. Still other fungi have the capacity to suppress host immune defences. Phagocytes and T lymphocytes are important in controlling fungi, while low white blood cell counts promote fungal infection. Diseases caused by fungi are called mycoses. Mycoses can be superficial, deep or opportunistic (remember, these microorganisms would not normally harm a healthy individual). Superficial mycoses occur on or near skin or mucous membranes and usually produce mild and superficial disease. Fungi that invade the skin, hair or nails are known as dermatophytes. The diseases they produce are called tineas (ringworm) — for example, tinea capitis (scalp), tinea pedis (feet) and tinea cruris (groin). Superficial dermatophytes grow in a ring-like, erythematous patch with a raised border. Itching is often intense and cracking of tissue can occur and lead to secondary bacterial infection. Infections of the scalp are accompanied by scaling and hair loss. (Chapter 19 discusses the various skin disorders caused by fungi.) Deep infections involving internal organs can be life threatening and are most common in association with other diseases or as an opportunistic infection in immunosuppressed individuals. Fungi causing deep infection enter the body through inhalation or through open wounds. Filamentous forms can multiply extracellularly, but the spherical yeasts multiply within cells, including leucocytes (white blood cells). Some fungi are a part of the normal body flora and become pathological only when immunity is compromised, allowing exaggerated growth and translocation. For example, Candida albicans is usually found in the mouth, gastrointestinal tract and vagina of healthy individuals. Changes in pH and the use of antibiotics that kill bacteria that normally inhibit Candida growth permit rapid proliferation and overgrowth, which can lead to superficial or deep infection.
Methods of infection
Microorganisms use a diversity of methods to invade the host and promote growth, often resulting in infection (see
Table 14.4). Because primary immune responses may take a week to develop adequately, some pathogens proliferate at rates that surpass the development of a protective response. Viral pathogens bypass many defence mechanisms by developing intracellularly, thus hiding within cells and away from normal inflammatory or immune responses. In many cases, however, because viral agents must spread from cell to cell, the developing immune response eventually cures the infection so the disease is usually self-limiting, in that it resolves without the need for medications. However, many viruses (e.g. measles, herpes) are inaccessible to antibodies after initial infection because they are not in the bloodstream but instead remain inside infected cells, spreading by direct cell-to-cell contact. Some viruses will persist and a state of unapparent infection may result. In persistent infections, cellular injury may be minimal and the virus persists until it is activated to replicate (e.g. the cold sores of herpes virus infection). Immunity may limit recurrent outbreaks and protect the individual from an acute exacerbation only, or may be sufficiently strong to prevent disease.
TABLE 14.4 Mechanisms of tissue damage and associated microorganisms PATHOGENS THAT CAUSE TISSUE DAMAGE
Infectious agent
Disease
Produce exotoxin Streptococcus pyogenes
Tonsillitis, scarlet fever
Staphylococcus aureus
Skin abscess (boils), toxic shock syndrome, food poisoning
Corynebacterium diphtheriae
Diphtheria
Clostridium tetani
Tetanus
Vibrio cholerae
Cholera
Produce endotoxin Escherichia coli
Gram-negative sepsis
Haemophilus influenzae
Meningitis, pneumonia
Salmonella typhi
Typhoid
Shigella
Bacillary dysentery
Pseudomonas aeruginosa
Wound infections
Yersinia pestis
Plague
Cause direct damage with invasion Variola
Smallpox
Varicella zoster
Chickenpox, shingles
Hepatitis B virus
Hepatitis
Poliovirus
Poliomyelitis
Measles virus
Measles, subacute sclerosing panencephalitis
Influenza virus
Influenza
Herpes simplex virus
Herpes labialis (cold sores)
CHAPTER 14 Infection
Some viruses elude the immune response by undergoing antigenic variation — changing their appearance by altering surface antigens. For example, the influenza virus undergoes yearly antigenic drift resulting from mutations in key surface antigens, haemagglutinin (H antigen) and neuraminidase (N antigen), allowing the emergence of new strains of influenza virus. Thus, immunity against the previous year’s viruses is no longer completely protective, creating the need for new vaccines every year. Antigenic shifts are major changes in antigenicity that occur from recombination of genes for H and N among different strains of viruses, and can result in major worldwide pandemics. For example, the spread of swine flu in 2009 was due to H1N1, while the avian (bird) flu of 2004–05 was due to H5N1. Other pathogens, such as some parasitic microorganisms, use a similar approach and change surface antigens by gene switching. Table 14.5 contains examples of microorganisms that fight off the immune system or cause it to attack the host.
Clinical manifestations of infection
This section provides an overview of the general clinical manifestations of infections. The progression from infection to infectious disease follows predictable stages (infection,
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incubation, symptoms, shedding of the microorganism), as demonstrated by the pathogenesis of measles illustrated in Fig. 14.11. Clinical manifestations of infectious diseases vary, depending on the pathogen and the organ system affected. Manifestations can arise directly from the infecting microorganism or its products; however, the majority of clinical symptoms result from the host’s inflammatory and immune responses. Infectious diseases typically begin with nonspecific or general symptoms of fatigue, malaise (general unwell feeling), weakness and loss of concentration. Generalised aching and loss of appetite (anorexia) are common complaints. The hallmark of most infectious diseases is fever and this is covered in detail in Chapter 13.
Detection and treatment of microorganisms
The detection and treatment of pathogenic microorganisms are challenging and often difficult tasks. Our immune and inflammatory systems are far superior to any manufactured drug at both detecting and eradicating pathogens from our bodies. However, our systems are sometimes unable to cope with the proliferation of pathogens. In addition, for both the very young, whose immune systems are immature, and the ageing population, who have more comorbidities,
TABLE 14.5 Pathogen resistance to immune function MECHANISMS
EFFECT ON IMMUNITY
EXAMPLE
Destroys or blocks component of immune system Produce toxins
Kills phagocyte or interferes with chemotaxis Prevents phagocytosis by inhibiting fusion between phagosome and lysosomal granules
Staphylococcus, Streptococcus, Mycobacterium tuberculosis
Produce antioxidants (e.g. catalase, superoxide dismutase)
Prevents killing by oxygen-dependent mechanisms
Mycobacterium spp., Salmonella typhi
Produce protease to digest IgA
Promotes bacterial attachment
Neisseria gonorrhoeae (urinary tract infection), Haemophilus influenzae, Streptococcus pneumoniae (pneumonia)
Produce surface molecules that Prevents activation of complement system mimic Fc receptors and bind Prevents antibody functioning as opsonin antibody
Staphylococcus, herpes simplex virus
Mimic self-antigens Produce surface antigens (e.g. M protein, red blood cell antigens) that are similar to self-antigens
Pathogen resembles the individual’s own tissue; in some individuals, antibodies can be formed against the self-antigen, leading to hypersensitivity disease (e.g. antibody to M protein also reacts with cardiac tissue, causing rheumatic heart disease; antibody to red blood cell antigens can cause anaemia)
Group A streptococcus (M protein), Mycoplasma pneumonia (red cell antigens)
Immune response delayed because of failure to recognise new antigen
Influenza, HIV, some parasites
Change antigenic profile Undergo mutation of antigens or activate genes that change surface molecules
Continued
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TABLE 14.5 Pathogen resistance to immune function—cont’d PATHOGENS ASSOCIATED WITH TISSUE DAMAGE
Infectious agent
Disease
Produce immune complexes Hepatitis B virus
Kidney disease
Malaria
Vascular deposits
Streptococcus pyogenes
Glomerulonephritis
Treponema pallidum
Kidney damage in secondary syphilis
Most acute infections
Transient renal deposits
Produce antibody against cells or tissues (autoantibody) Streptococcus pyogenes
Rheumatic fever
Mycoplasma pneumonia
Haemolytic anaemia
Cause cell-mediated immunity Mycobacterium tuberculosis
Tuberculosis
Mycobacterium leprae
Tuberculoid leprosy
Lymphocytic choriomeningitis virus
Aseptic meningitis
Borrelia burgdorferi
Lyme arthritis
Schistosoma mansoni
Schistosomiasis
Herpes simplex virus
Herpes stromal keratitis
treatment with antimicrobial agents is often necessary and in some cases life saving. There are two requirements to diagnosing pathogenic microorganisms in humans: • a detailed clinical history and physical examination, which often provides clues to the origin of the infection and the likely pathogen • laboratory evidence of the infectious agent. Bacteria are detected from body fluids and specimens using cultures. Growth medium, such as agar, promotes the growth of bacteria such that it can be identified. The gram stain, described previously, is the mainstay of bacterial determination. The bacteria are viewed under a microscope and their shape and gram stain provide evidence of the particular type of bacteria (see Figs 14.3 and 14.4). Sensitivity analysis to determine which antimicrobial agents the bacteria are sensitive to also guides treatment. Viruses are harder to detect due to their size. They are not observable under a light microscope and most diagnoses are based on clinical manifestations only. However, various techniques can be used to identify viruses, including immunofluorescence, serology (antigen and antibody detection, e.g. hepatitis) and cell cultures. Fungi are diagnosed by microscopic observation of specimens to visualise either spheres or filaments. The treatment of pathogenic microorganisms has been one of the greatest advances in healthcare over the last 50 years. The advent of penicillin and other antimicrobial agents has significantly reduced mortality due to infectious diseases. Antimicrobial agents destroy or neutralise the pathogen
once the disease process has started. In addition, prophylactic procedures (namely, vaccines) have been developed to prevent pathogens from initiating disease. The majority of vaccine development has focused on preventing the most severe and common infections. With the initial success of antibiotic therapy, there was no perceived need for vaccination against many common and non-life-threatening infections. However, the increasing problem of antibioticresistant pathogens has forced a reappraisal of that strategy and a greater emphasis now is being placed on the development of new vaccines.
FOCU S ON L EA RN IN G
1 Compare and contrast infection rates in Australia and New Zealand with rates in developing countries. 2 Provide definitions for the terms microorganisms and pathogens. 3 List and describe 3 factors associated with pathogens causing infections. 4 Differentiate between bacteria, viruses and fungi.
Antimicrobials Since initiation of the widespread use of penicillin during World War II, antibiotics have had the greatest impact on successful resistance to infection. Antibiotics are natural
Symptom severity
CHAPTER 14 Infection
RESEARCH IN F
Specific symptoms of the disease
Viral replication
Type of symptoms Incubation period Disease Respiratory illness Koplik Virus growth on spots body surfaces Virus seeded to body surfaces Spread growth in lymphoid tissue 1
2
3
4
5
6
7
8
Initial respiratory infection
CUS
Antimicrobial beds
General symptoms (e.g. malaise)
Lag (assymptomatic)
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Rash
Antibody
Shedding
9 10 11 12 13 14 15 16 17 18
Time (days)
FIGURE 14.11
The progression of measles. The measles virus enters through the oropharynx, from where it infects the regional lymph nodes. After 5 to 7 days, virus enters the blood (viraemia) and spreads to the body surfaces (respiratory, gastrointestinal and urinary tracts, and the skin). The virus replicates in these tissues, leading to upper respiratory tract symptoms, and the appearance of red spots with bluish-white specks (Koplik spots) in the oral mucosa and later to an extensive rash involving most parts of the skin. At or near the onset of overt symptoms, the infected individual is shedding virus and is highly infectious to others. Antibodies against the measles virus are primarily responsible for resolving the infection. They are produced within 10 to 11 days but immediately bind to viral particles in the blood so that free antibody is not measurable until about 2 weeks after the initial infection.
products of fungi, bacteria and related microorganisms that kill or inhibit the growth of other microorganisms. Numerous chemicals or antimicrobials have been identified that either prevent the growth of microorganisms or directly destroy them (see Fig. 14.12). Antibiotics generally act by preventing the function of enzymes or cell structures that are unique to the infecting agent. Antiviral agents have been developed more recently than antibiotics. As viruses reside in the host’s cells, using a drug to interfere or stop viral replication will also interfere with the host’s cellular reproduction. Since the advent of human immunodeficiency virus (HIV) in the early 1980s, an enormous amount of research has been conducted into antiviral medication. Antiviral drugs have now been developed to treat influenza, HIV, hepatitis and herpesvirus,
Hospital surfaces harbor microorganisms that can cause healthcare acquired infections (HAIs), when the hands of healthcare workers become contaminated through contact with those surfaces. Metals such as copper have antimicrobial properties. One hospital investigated the impact of copper equipment on the incidence of HAIs in two paediatric units. In the intervention rooms, bed rails, sink handles, intravenous poles, and the nurses’ station had copper surfaces, while control rooms had standard equipment. Infants treated in rooms with copper surfaces had a 19% reduction in risk of a HAI, while the risk declined by 26% when the data were adjusted for age and use of invasive devices. These strategies can complement standard infection control practices such as hand hygiene.
although the majority suppress viral replication by mimicking a section of viral DNA, or blocking enzymes required for replication, rather than providing a cure. Fig. 14.13 provides an example of the antiviral drug aciclovir, which is used to treat genital herpes and shingles. At the present time, no vaccines are available to prevent fungal disease effectively. Many of the antifungal drugs (e.g. amphotericin B, ketoconazole, fluconazole) used to treat deep or systemic infections can cause toxicity because the fungal cell composition is similar to the host (human) cells, although newer drugs such as flucytosine are less toxic.
Vaccines The purpose of vaccination is to induce long-lasting protective immune responses under conditions that will not result in disease in a healthy recipient of the vaccine. The primary immune response from vaccination is generally short lived for many vaccines; therefore, booster injections are used to push the immune response through multiple secondary responses, resulting in large numbers of memory cells and sustained and increased protective levels of antibody or T cells, or both. This principle of the enhanced secondary response is somewhat similar to the body’s natural defence mechanisms to infection for which no vaccine was used — the first exposure to the microorganism produced a primary immune response, which takes some time to develop and usually results in the full symptoms of the disease being experienced. Importantly, this can result in activation of memory cells which become activated immediately upon a future exposure to the same microorganism. This means that the immune system is primed and able to act very quickly and powerfully upon a second exposure to the same microorganism, and this powerful secondary response results in much less severity
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FIGURE 14.12
Mechanism of action and type of antibiotics. Antibiotics can be bactericidal (directly kill bacteria) or bacteriostatic (neutralise further bacterial growth). The four main classes of antibiotics break down the cell wall, interfere with nucleic acid activity, stop protein production or interfere with cellular metabolic activities.
of illness — sometimes with no distinct symptoms even appearing. Development of a successful vaccine is costly and depends on several factors. These include identification of the protective immune response and the appropriate antigen to induce that response. For instance, individuals with ongoing HIV infection produce a great deal of antibody against several HIV antigens. But, for development of a successful vaccine, we must first understand which antibody will protect against an initial infection. When an antigen is identified that can be used in a vaccine, it must be developed into an effective, cost-efficient, stable and safe vaccine. For instance, most vaccines against viral infection (measles, mumps, rubella and varicella (chickenpox)) contain live viruses that are attenuated (weakened so as to not cause infection when administered to the recipient) so they continue to express appropriate antigens but establish only a limited and easily controlled infection. For most common vaccines against viral infections, limited replication of the virus appears to afford better long-term protection than using a viral antigen. One current exception is the hepatitis B vaccine, which uses a recombinant
viral protein. The hepatitis A vaccine is an inactivated (killed) virus and normally should not cause an infection. Even attenuated viruses can establish life-threatening infections in individuals whose immune system is congenitally deficient or suppressed.7 The risk of infection by the vaccine strain of virus is extremely small, but it may affect the choice of recommended vaccines. For instance, two different vaccines were developed against poliovirus, which causes poliomyelitis: • The Sabin vaccine was an attenuated virus that was administered orally. It provided systemic protection and induced a secretory immune response to prevent growth of the poliovirus in the intestinal tract. Being a live virus, the vaccine could cause poliomyelitis in some children who had unsuspected immune deficiencies (about 1 case in 2.4 million doses). • The Salk vaccine was a completely inactivated virus administered by injection. It induced protective systemic immunity but did not provide adequate secretory immunity. Therefore, even if the individual was protected from systemic infection by poliovirus, the virus could
CHAPTER 14 Infection
Aciclovir
Herpesvirus
Aciclovir is converted to a form that can bind to the virus DNA
DNA T C G C
P
A G
C
Cellular enzymes
ACV Binds to the DNA T and has a blocking effect A
P P P
FIGURE 14.13
The mechanism of action for the antiviral drug aciclovir. Aciclovir binds with an enzyme that combines with the viral DNA to block viral replication.
transiently infect their intestinal mucosa, be shed and spread to others. When poliomyelitis was epidemic, the oral vaccine was preferred. Vaccination programs have been extremely effective against poliovirus. Poliovirus has been eliminated from Western countries — the Western Pacific region, including Australia and New Zealand, was declared to be completely free in October 2000. As of 2013, only three countries (Pakistan, Afghanistan and Nigeria) were classified as endemic, with 222 new cases of polio in 2012, a 66% decline compared to 2011.8 In contrast, in 1988, 125 countries on five continents were considered endemic for polio and more than 1000 children per day were paralysed due to poliovirus.9 This huge reduction is due to the World Health Organization (WHO) charter to eradicate poliovirus globally. Some common bacterial vaccines are killed microorganisms or extracts of bacterial antigens. The vaccine against pneumococcal pneumonia consists of a mixture of capsular polysaccharides from 10 strains of Streptococcus pneumoniae. Of the more than 90 known strains of this microorganism, only these 10 cause the most severe illnesses. However, the capsular vaccine is not very immunogenic in young children. A conjugated vaccine is available that contains capsular polysaccharides from seven strains that are conjugated (linked chemically) to carrier proteins in
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order to increase immunogenicity. A similar vaccine is available for Haemophilus influenzae type b (Hib). Some bacterial pathogens are not invasive, but do colonise mucosal membranes or wounds and release potent toxins that act locally or systemically. These include the bacteria that cause diphtheria, cholera and tetanus. Vaccination against systemic toxins (e.g. diphtheria, tetanus) has been achieved using toxoids — purified toxins that have been chemically detoxified without loss of immunogenicity. Pertussis (whooping cough) vaccine has been changed from a killed whole-cell vaccine to a cellular extract (acellular) vaccine that contains the pertussis toxin and additional bacterial antigens. This change has dramatically reduced the adverse side effects of the previous vaccine (fever and local inflammatory reactions). Additional difficulties associated with vaccination include allergic reactions to the vaccine antigen itself or other components of the preparation. For instance, some viral vaccines are grown in chicken eggs and many elicit a reaction in individuals who are allergic to eggs. Thiomersal is a mercury-containing compound that was used as a preservative in vaccines. Although no cases of mercury toxicity have been reported secondary to vaccination, thiomersal was removed from all childhood vaccines in 2000.10 A more common problem is compliance of the susceptible population. Depending on the microorganism, a certain percentage of the population should be immunised to protect the total population. If this level of immunisation is not achieved, outbreaks of infection can occur. For instance, in the United States, an effective measles vaccine was made available in 1963 and resulted in a dramatic decrease in the number of measles cases. Many parents became complacent and did not obtain measles vaccination for their preschool children. As a result, a large increase occurred in the number of cases and deaths in 1989 and 1990, which initiated a re-emphasis on complete immunisation before children could start school. Even with successful development of a vaccine, however, a certain percentage of the population will be genetically unresponsive to vaccination and therefore will not produce a protective immune response. With most vaccines, the percentage of unresponsive individuals is low and they will benefit from successful immunisation of the rest of the population. Australia and New Zealand have extensive childhood immunisation programs.11,12 These health programs have high immunisation rates. The vaccination programs of Australia and New Zealand are detailed in Tables 14.6 and 14.7. FOCU S ON L EA RN IN G
1 Define the term antimicrobial and explain how antimicrobials work. 2 Explain what a vaccine is. 3 Provide details of the national immunisation program for either Australia or New Zealand.
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TABLE 14.6 Recommended immunisation schedule of Australia AGE
DISEASES/CONDITIONS
VACCINE
AGE
DISEASES/CONDITIONS
VACCINE
Diphtheria, tetanus, whooping cough (pertussis), polio
Infanrix® IPV or Quadracel®
Pneumococcal
Pneumovax 23®
HPV (human papillomavirus)
Gardasil® 9
Diphtheria, tetanus, whooping cough (pertussis)
Boostrix®
4 years
Birth Hepatitis B
H-B-Vax® II Paediatric or Engerix B Paediatric
2 months
10–15 years
Diphtheria, tetanus, whooping cough (pertussis), hepatitis B, polio, Hib (haemophilus influenzae type b)
Infanrix® hexa
Pneumococcal
Prevenar 13®
Pneumococcal
Pneumovax 23®
Rotavirus
Rotarix®
Shingles (herpes zoster)
Zostavax®
Diphtheria, tetanus, whooping cough (pertussis), hepatitis B, polio, Hib (haemophilus influenzae type b)
Infanrix® hexa
Pneumococcal
Prevenar 13®
Rotavirus
Rotarix®
Diphtheria, tetanus, whooping cough (pertussis), hepatitis B, polio, Hib (haemophilus influenzae type b)
Infanrix® hexa
Pneumococcal
Prevenar 13®
Measles, mumps, rubella
M-M-R® II or Priorix®
Aboriginal and Torres Strait Islander children 6 months to less than 5 years
Hib (haemophilus influenzae type b), meningococcal C
Menitorix®
Aboriginal and Torres Strait Islander peoples 15 years and over
Pneumococcal
Prevenar 13®
Measles, mumps, rubella, chickenpox (varicella)
Priorix-Tetra® or ProQuad®
Diphtheria, tetanus, whooping cough (pertussis)
Infanrix® or Tripacel®
65 years and over
4 months
6 months
12 months
Extra vaccines for Aboriginal and Torres Strait Islander peoples 12 months Hepatitis A
Vaqta® Paediatric
12–18 months
Prevenar 13®
Pneumococcal
18 months Hepatitis A
Vaqta® Paediatric
15–49 Pneumococcal years with medical risk factors
Pneumovax 23®
50 years and over
Pneumovax 23®
Pneumococcal
Flu (influenza) vaccines 6 months and over with medical risk factors
18 months
Infections Common infections
In this section we outline some of the more common infections in children and adults in Australia and New Zealand. The majority of these common infections do not cause sustainable harm — the severity of most infections ranges from mild irritation to serious bed-bound conditions that take days or weeks to overcome. However, a tremendous amount of research is being conducted into the links between infection and other conditions. For instance, it has been
65 years and over Pregnant women any trimester during pregnancy
suggested that the common acute infections of childhood (cough, cold, fever and sore throat) are linked to endothelial dysfunction and that this may lead to the pathogenesis of early atherosclerosis lesions.13 This is an area of our knowledge that is growing and clinicians need to keep abreast of advancements. More serious infections can be quite problematic, especially in the young and the elderly, as their capacity to combat infection is limited. As we have discussed, there are a variety of antimicrobial agents and their prescription and administration should be limited to known causes of
CHAPTER 14 Infection
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TABLE 14.7 Recommended immunisation schedule of New Zealand AGE
DISEASES COVERED AND VACCINES
6 weeks
Diphtheria/tetanus/pertussis/polio/ hepatitis B/Haemophilus influenzae type b 1 injection Pneumococcal 1 injection Rotavirus
3 months
Diphtheria/tetanus/pertussis/polio/ Hepatitis B/Haemophilus influenzae type b 1 injection Pneumococcal 1 injection Rotavirus
5 months
Diphtheria/tetanus/pertussis/polio/ Hepatitis B/Haemophilus influenzae type b 1 injection Pneumococcal 1 injection Rotavirus
15 months
Haemophilus influenzae type b 1 injection Measles/mumps/rubella 1 injection Pneumococcal 1 injection
4 years
Diphtheria/tetanus/pertussis/polio 1 injection Measles/mumps/rubella 1 injection
11 years
Diphtheria/tetanus/pertussis 1 injection
12 years (girls only)
Human papillomavirus 3 doses over 6 months
45 years
Adult diphtheria tetanus
65 years
Adult diphtheria tetanus Influenza (annually)
infection and when infection is incapacitating. The overuse of prescriptions for and unwarranted administration of antibiotics has led to a major problem in healthcare settings — the emergence of drug-resistant microorganisms. Indeed, infections within a hospital setting are a major battle for patients and staff, and the ability to prevent unwarranted infections and treat and contain existing infections is one of the core domains of nursing practice. The following sections look at some common microorganisms and associated infections and injury. We have limited the scope of infections in the examples listed here, as others are covered in specific chapters elsewhere in the text.
The common cold
The common cold is one of the most frequent infections in humans. It is usually a viral infection, caused by a wide range of pathogens such as rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus (RSV) or adenovirus. RSV infection is the single most common cause
FIGURE 14.14
Gastritis. In the body of the stomach, thickened mucosal folds (arrows), the result of inflammation, can be seen.
of upper respiratory tract infections in children up to the age of 2 years.14 Such viruses are spread easily and so large numbers of community members are infected, such as in schools and workplaces. Diagnosis is made using the clinical signs and symptoms, rather than by identification of the pathogen, as specific viral detection is unwarranted in most cases. It has been suggested that antibiotics are incorrectly prescribed to common cold infections caused by a virus around 30% of the time.15 Treatment involves managing symptoms, and measures to promote the immune response such as remaining warm, extra fluid intake and additional sleep, are usually sufficient to promote good recovery.
Helicobacter pylori infection
Helicobacter pylori are gram-negative rod bacteria that are found in individuals with chronic inflammation of the stomach lining (gastritis; see Fig. 14.14). They are the predominant causative agent in the development of peptic ulcers of the stomach and duodenum and gastric adenocarcinoma.16 Infection with H. pylori is extremely common. In developing countries, most of the population are colonised before the age of 10 years and by the age of 50, 80% are colonised. In developed countries, H. pylori colonisation is uncommon prior to age 10, and the prevalence of H. pylori infection increases with age, with half of the population infected at age 60 years.16 The transmission
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appears to be mainly person to person, demonstrating the importance of basic hygiene, although contaminated water supplies are another mode of transmission in developing countries.16 The causal link between H. pylori colonisation and gastritis was found in the 1980s by the Australian researchers Professor Barry Marshall and Dr Robin Warren (who were awarded a Nobel prize for this research in 2005). The exact pathogenesis of chronic gastritis due to H. pylori is not fully understood, but the bacteria blocks acid production in the stomach by producing an enzyme (urease) that breaks down urea and neutralises the gastric acids. The bacteria also cause apoptosis (programmed cell death) of gastric epithelial cells, accelerating the inflammatory process. Diagnosis is made by endoscopic biopsy or a non-invasive test that measures urease in an individual’s breath. Pharmacological treatment is very successful with the use of a proton pump inhibitor and antibiotics. In most cases this will cure the individual of the bacteria. Research is currently underway to develop a safe and effective vaccine against H. pylori.
Urinary tract infection
Urinary tract infection (UTI) is another of the most common infections acquired by humans both in the community and when hospitalised.17 A urinary tract infection occurs when there are significant numbers of bacteria in the urinary tract, which can cause lower and upper tract infections. Urinary tract infections afflict the young and the old and, after infancy, females are more commonly infected than males. Forty per cent of females will experience a UTI in their lifetime, and 33% of those will have recurrent UTIs.18 Such infections are common in young females who are sexually active, as the pressure around the genital region during intercourse can force local bacteria into the urethra, which is very close anatomically to the opening of the vagina. The risk of developing a UTI increases with age. Bacteriuria (bacteria in the urine) is usually asymptomatic in older individuals. The gram-negative anaerobe, Escherichia coli, part of the normal intestinal flora, accounts for the majority of uncomplicated community-based urinary tract infections.18 Contamination occurs due to the close proximity of the anus to the urethral opening. Signs and symptoms include dysuria (painful urination), fever, urinary urgency and frequency (wanting to urinate frequently and needing to pass urine quickly), haematuria (blood in the urine) and bacteriuria accompanied by smelly, cloudy urine.17,18 The treatment depends on the severity of the infection, the number of infections and other complications (e.g. possible renal infection). Antibiotics that are prescribed include penicillin and cephalosporins.19
Infection control and healthcare-acquired infections
The considerable decline in infectious disease in Australia and New Zealand in recent years is attributable to many
factors, with one key aspect being increased infection control measures. Infection control is now a major responsibility of all healthcare nurses, to minimise the spread of infection between patients, and also between staff and patients. The procedures to be followed by all healthcare professionals are known as standard precautions, and these provide important protection not only for patients, but also for prevention of infection of healthcare staff. Some of the main aspects of these include:20 • appropriate hand-washing known as hand hygiene practices, including before and after touching a patient, and after an exposure risk, and after removing gloves • use of gloves in each invasive procedure and any activity which brings a risk of exposure to blood, body substances, secretions and excretions • use of aprons, gowns, and facial protection for procedures that bring increased risk of exposure • safe handling of sharps, such as not passing sharps from hand to hand, and safe disposal of sharps • regular and appropriate cleaning of surfaces and equipment. This summarises only the main aspects, with various other specific information on infection control forming an important part of the education of healthcare professionals. Despite our best efforts, a breakdown in infection control procedures costs the Australasian health systems hundreds of millions of dollars per year and serious morbidity and mortality to thousands of patients. This morbidity and mortality is largely preventable. As such, these infections are a scourge of modern healthcare facilities. Australia has about 200 000 healthcare-acquired infections (HAIs) per year, that take up approximately 2 million bed days.21 Healthcare-acquired infections are acquired by individuals during a stay in a healthcare setting, and in some cases may not become apparent until months after discharge from hospital. Such infections are relatively common in Australian hospitals, particularly those on the eastern seaboard. Furthermore, they may be caused by microorganisms from an endogenous source (a body site of the individual, such as the skin, nose, mouth, gastrointestinal tract) or an exogenous source (external to the patient, such as healthcare personnel, visitors, patient care equipment, medical devices or the healthcare environment).22 Urinary tract infections are the most common HAIs, usually related to the length of time indwelling urinary catheters remain in hospitalised patients.19,23 However, the four priority HAIs in Australian hospitals in terms of the seriousness and associated costs are: • surgical site infection (SSI) • Staphylococcus aureus blood stream infection (SABSI) • Clostridium difficile infection (CDI) • central line acquired blood stream infection (CLABSI).24 Surgical wound infections significantly contribute to an increased duration of hospital stay, and increased mortality and healthcare costs.25
CHAPTER 14 Infection
One of the main HAIs and multi-resistant bacteria in Australian and New Zealand hospitals is methicillin-resistant Staphylococcus aureus (MRSA).26,27 Because Australia does not have a standardised system of hospital surveillance for antibiotic-resistant pathogens it is difficult to estimate the incidence of such infections in Australia. There is certainly an increase in the proportion of community-acquired S. aureus infections that are methicillin-resistant, although internationally the incidence of invasive S. aureus infections in the healthcare setting has been declining since 2001, probably as a result of improved infection prevention and control programs.27 The prevention of MRSA contamination in hospitals should be fundamental. Simple infection-control procedures, such as hand hygiene before and after contact with patients or their immediate surroundings, use of personal protective equipment, and isolating MRSA-infected patients, should be enough to prevent the spread. However, these precautions are not always followed. Fortunately, MRSA remains treatable with antibiotics (vancomycin); however, there are rare cases of high level vancomycin resistance emerging. Clostridium difficile is the most common cause of hospital-acquired diarrhoea.28 C. difficile tends to occur following broad-spectrum antibiotic therapy that kills off normal gut flora, allowing overgrowth of this species and leading to inflammation of the bowel. Such infections greatly increase healthcare costs and length of hospital stay. An epidemic antibiotic resistant strain of C. difficile emerged in Australia in 2010.29 Spread of this disease is often via contaminated hands and equipment although more novel modes of transmission are proposed (see Research in Focus below). Up to 30% of HAIs occur in intensive care units in Australia, and CLABSI is an important infection in this environment.24
RESEARCH IN F
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Cover when flushing! Hospital toilets rarely have lids. Flushing a toilet creates aerosols contaminated with faecal pathogens that can settle on surrounding surfaces over periods of up to 8 hours. Clostridium difficile is the most common cause of healthcareacquired diarrhoeal infection. Faecal suspensions containing C. difficile were placed in the toilet bowl, and following flushing, air samples were taken over time and contamination of surfaces was assessed. After flushing, C. difficile bacteria were recovered from air samples taken above the toilet, and environmental contamination continued for 90 minutes as aerosols settled. This provides another mechanism for transmission of pathogens between patients. Lidless toilets should be avoided, and if present, patients should be encouraged to close the lid before flushing.
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FOCU S ON L EA RN IN G
1 List sources of common infections and provide an explanation of one in detail. 2 Describe the term healthcare-acquired infections. 3 Explain how methicillin-resistant Staphylococcus aureus (MRSA) has become one of the most virulent healthcareacquired infections in Australia and New Zealand.
Antimicrobial resistance Microbial pathogens have developed mechanisms for circumventing mechanisms for destroying or controlling infection. These include attacking the immune system (e.g. HIV) and resistance to multiple antibiotics (e.g. MRSA). HIV directly attacks the central processes involved in the development of an immune response and is discussed in Chapter 15. Many pathogens have mutated and developed resistance to particular antibiotics.30 Resistance occurs primarily through inactivation of the drug, alteration of the bacterial membrane that prevents the antibiotic from being taken up, alteration of the target molecule, or reduced uptake or active efflux of the antibiotic. These changes result from genetic mutations and can be transmitted directly to neighbouring microorganisms. Penicillin resistance, for example, results from the production of an enzyme (beta (β)-lactamase) that breaks down the antibiotic. A rapid emergence of multiple antibiotic-resistant bacteria has been observed, and the speed at which resistance develops has been accelerating.30 These microorganisms are resistant to almost all currently available antibiotics. For example, Streptococcus pneumoniae, which causes pneumonia, meningitis and acute otitis media (ear infections), was once routinely susceptible to penicillin. Since the 1980s, however, the incidence of penicillin-resistant microorganisms in Australia has risen dramatically.31 In some areas, more than 20% of tuberculosis cases are caused by multiple antibiotic-resistant Mycobacterium tuberculosis. Also, the incidence of drug-resistant gonorrhoea, malaria, pneumococcal disease, salmonellosis, shigellosis and staphylococcal infections has increased dramatically. More recently a new bacterial resistance enzyme (New Delhi metallo-β-lactamase) that makes gram-negative bacteria virtually untreatable has been isolated in India. Up to 200 million Indians are thought to be carrying bacteria with this enzyme, and it has already spread to multiple countries.32 Previous experience with resistant organisms suggests this strain will eventually spread worldwide. Why have multiple antibiotic-resistant microorganisms appeared? Overuse of antibiotics in both the human population and in animal husbandry can lead to the destruction of the normal flora, allowing the selective overgrowth of antibiotic-resistant strains or pathogens that had previously been kept under control. For example, an
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individual develops a cough and fever, necessitating a visit to their doctor and the doctor prescribes an antibiotic to treat the infection. In reality, perhaps the individual was infected with a virus, a frequent cause of upper respiratory tract infection. Therefore, this individual was unnecessarily exposed to an antibiotic, providing an opportunity for bacteria to develop resistance. The antibiotics amoxicillin and cephalexin are two of the most prescribed medications in Australia. When all antibiotics are taken as a group, they are the most frequently prescribed medications by general practitioners in Australia.33 Unfortunately, bacterial resistance to treatment is likely to develop over time. For instance, according to the World Health Organization, when fluroquinolones were introduced in the 1980s, resistance was rare, while now resistance is so widespread that the drugs are not effective in over 50% of persons who require them.34 Therefore, the need to be vigilant in the prescription of antimicrobial drugs is crucial, and measures to guide the practitioner in many cases are now in place. Strategies to reduce the development of resistance include: • better surveillance of antimicrobial resistance • reduction in the use of antimicrobials for animal husbandry • more attention to infection control and vaccination • regulations and education to promote more rational use of antimicrobials.30
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Scrutiny improves performance! Overuse/misuse of antibiotics drives the development of antimicrobial resistance. Antibiotic stewardship via specific programs to improve the appropriate use of antimicrobial drugs can help to reduce misuse. While there are guidelines to indicate in what circumstances antimicrobial drugs should be used, these are frequently not followed despite delivery of education to staff. One hospital trialled an audit of prescriptions of prophylactic antibiotics for surgery against performance indicators, followed by feedback on inappropriate use to prescribers. A previous pilot study had shown that inappropriate antibiotic regimens occurred in almost 53% of surgeries. Following the intervention, compliance with prescribing protocols was greater than 90%. Other studies have similarly found that observation and performance feedback can improve healthcare worker compliance with various guidelines.
FOCU S ON L EA RN IN G
Describe the mechanisms of antimicrobial resistance.
chapter SUMMARY Infection rates • The mortality rate from infectious diseases in Australia and New Zealand is very low compared to other causes of death.
Microorganisms • A microorganism is a term used to describe bacteria, viruses, fungi and parasites. Many microorganisms do not harm humans, but others cause infections that range from being irritating to the individual to life threatening. • Normal flora are microorganisms that reside either on or in the human body. • Pathogens are microorganisms that are harmful to the host and cause infection. • Pathogens enter the body through a variety of means, including direct contact, inhalation, ingestion and direct penetration of the skin. • Bacteria lack a discrete nucleus and are relatively small. They can be aerobic or anaerobic, motile or non-motile.
• Bacteria are identified according to their shape: cocci, bacilli and sphirochete. In addition, bacteria are classified according to a gram stain as gram-positive or gramnegative. • Septicaemia refers to the presence of microorganisms in the blood and can be life threatening. • Viruses are simple structures with a protein layer, called a capsid, surrounding one type of nucleic acid. • Viruses can survive for extended periods of time but infect people when they enter the host cells. They can bypass many defence mechanisms by developing intracellularly. • Viral diseases are the most common illnesses in humans. • Fungi are relatively large microorganisms with thick walls that grow as either single-celled yeasts (spheres) or multicelled moulds (filaments or hyphae). • Diseases caused by fungi are called mycoses. Mycoses can be superficial, deep or opportunistic.
• Deep fungal infections involving internal organs can be life threatening and are most common in association with other diseases or as an opportunistic infection in immunosuppressed individuals. • Clinical manifestations of infectious diseases vary, depending on the pathogen and the organ system affected. • Clinical manifestations may arise directly from the infecting microorganism or its products; the majority of clinical symptoms result from the host’s inflammatory and immune responses.
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• Australia and New Zealand both have broad-based, effective immunisation schedules that significantly reduce infections in the population.
Infections
• Antibiotics are natural products of fungi, bacteria and related microorganisms that kill or inhibit the growth of other microorganisms. • Many antiviral agents insert a fake nucleotide into the viral nucleic acids, blocking viral replication. • Many antifungal drugs used to treat deep or systemic infections are toxic to the host because the fungal cell composition is similar to that of the host cell.
• The common cold is one of the most frequent infections in humans. It is usually a viral infection, such as rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus and adenovirus. • Urinary tract infection is another common infection affecting humans. The gram-negative anaerobe, Escherichia coli, a normal bowel flora, accounts for up to 90% of uncomplicated community-based urinary tract infections in both adults and children. • Healthcare-acquired infections are acquired by individuals either during or after a stay in a healthcare setting. • Simple infection control procedures, such as hand hygiene before and after contact with patients or their immediate surroundings, use of personal protective equipment, and isolating MRSA-infected patients, should be enough to prevent the spread of MRSA infections.
Vaccines
Antimicrobial resistance
• Vaccines are administered to induce long-lasting protective immune responses.
• Many pathogens have mutated and developed resistance to particular antibiotics.
Antimicrobials
CASE STUDY
ADULT John, a 19-year-old male, sustains a fractured femur and a large area of skin loss following a motor-bike accident on a gravel road. John was not wearing protective clothing at the time. Following debridement of the wounds in the Accident and Emergency ward to remove grit and dirt, he was admitted to the surgical ward for a reduction of his fracture. One of his wound sites subsequently develops a purulent ooze. Swabs are taken and methicillin-resistant Staphylococcus aureus infection is diagnosed.
1
Describe the characteristics of this organism. Describe the steps involved in a gram stain. 3 Describe the implications of John’s infection in terms of length of hospital stay, hospital costs and prognosis. 4 Describe the infection control precautions that will be required to prevent the spread of this organism to other patients within the hospital. 5 Describe a drug that is likely to be used to treat John’s infection and the mode of action of that drug. 2
CASE STUDY
AGEING Leila is a 76-year-old woman who is experiencing a urinary tract infection. She has had a fever for 2 days, painful urination (dysuria), foul-smelling urine that is cloudy and, on occasions, leaking urine (urinary incontinence). Leila has five children and 10 years ago was diagnosed with diabetes mellitus type 2. This is her third urinary tract infection for the year. Her previous infections resulted from Escherichia coli, which was cultured from the urine.
1 2 3 4 5
Explain why individuals may develop a urinary tract infection. Describe why Leila is more prone to urinary tract infections. Describe why Leila has the clinical manifestations of dysuria and urinary incontinence. Discuss how diabetes mellitus may complicate recovery from infection. Discuss treatment options for Leila.
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REVIEW QUESTIONS 1 Explain why Australia and New Zealand have significantly lower rates of infectious diseases than developing countries. 2 Describe the differences between microorganisms, pathogens and infections. 3 Discuss how virulence and pathogenicity influence pathogens’ ability to cause infections. 4 Discuss differences in bacteria, including shape, gram stain and aerobic or anaerobic requirements.
5 Describe why endotoxins are harmful to the body. 6 Outline the method of viral transmission and infection. 7 Differentiate between antimicrobials and note whether they kill the microorganism. 8 Describe the action of vaccines. 9 Discuss how healthcare-acquired infections arise. 10 Discuss the rise in antimicrobial resistance and the reasons for this rise.
Key terms ABO blood group, 364 acquired immunodeficiency syndrome (AIDS), 371 acute rejection, 364 allergy, 358 anaphylactic shock, 361 anaphylaxis, 361 atopic, 360 autoantibodies, 367 autoimmunity, 358 chronic rejection, 364 delayed hypersensitivity reactions, 358 histamine, 359 hyperacute rejection, 364 hypersensitivity, 358 immediate hypersensitivity reactions, 358 immune deficiencies, 370 primary immune deficiencies, 370 Rhesus (Rh) blood group, 366 secondary immune deficiencies, 371 systemic lupus erythematosus (SLE), 367 universal donor, 366 urticaria, 360
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Lynne Hendrick Chapter outline Introduction, 358 Hypersensitivity reactions, 358 Type I: IgE-mediated hypersensitivity reactions, 358 Type II: tissue-specific hypersensitivity reactions, 361 Type III: immune complex–mediated hypersensitivity reactions, 361 Type IV: cell-mediated hypersensitivity reactions, 362 Transplantation, 363 Transplantation rejection, 364 Blood transfusion reactions, 364
The ABO blood group system, 364 The Rhesus system, 366 The universal donor, 366 Autoimmune diseases, 367 The breakdown of tolerance, 367 Systemic lupus erythematosus, 367 Immune deficiencies, 370 Primary immune deficiencies, 370 Secondary immune deficiencies, 371 Ageing and alterations of immune function, 379
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Introduction Immunity is a complex interrelated series of events that provides constant protection for the body. Even when an individual’s immune system is functioning normally, the person may still experience infection if they are exposed to a sufficient enough load of a pathogenic microorganism, or a strain that is particularly virulent. It should be stressed that, although the individual will exhibit signs and symptoms, their immune system is responding appropriately. In the majority of cases, the immune system will be able to combat the pathogenic microorganism and restore the individual back to homeostasis. However, sometimes the immune system does not respond appropriately — there may not be enough immunity or the response may be excessive and inappropriate. Inappropriate immune responses may be: • exaggerated against environmental antigens (this is commonly referred to as an allergy) • directed against transplanted foreign tissues, such as blood transfusions or organ transplants • misdirected against the body’s own cells (termed autoimmune diseases) • insufficient to protect the host (either a primary or an acquired immune deficiency disease). All these responses can be serious or life threatening. The first part of this chapter explores diseases where immunity is either exaggerated or inappropriate; while the second part looks at the less prevalent, but devastating, diseases that cause immunodeficiency. We start by examining hypersensitivity reactions, which are likely to be the most commonly encountered altered immune responses across different healthcare settings.
Hypersensitivity reactions Hypersensitivity refers to an immune response that is exaggerated or activated inappropriately, resulting in disease or damage to the individual. Hypersensitivity reactions are the most common altered immune responses, but fortunately they are usually the least life threatening. There are four different types of hypersensitivity reactions: • type I: immunoglobulin E-mediated reactions • type II: tissue-specific reactions • type III: immune complex-mediated reactions • type IV: cell-mediated reactions. The four mechanisms are interrelated and in most hypersensitivity reactions several mechanisms may be at work simultaneously or sequentially. Autoimmunity arises when the immune system attacks the body’s own cells because there is a failure to recognise self-antigens. Autoimmune responses can be caused by hypersensitivity mechanisms, but hypersensitivity reactions can occur without autoimmunity. Therefore, for the purposes of clarity, autoimmunity is discussed later in the chapter in the discussion on autoimmune diseases.
As with all immune responses, hypersensitivity reactions require sensitisation against a particular antigen, which results in a primary immune response. Disease symptoms appear after an adequate secondary immune response occurs. Hypersensitivity reactions are immediate or delayed, depending on the time required to elicit clinical symptoms after re-exposure to the antigen. Reactions that occur within minutes to a few hours after exposure to an antigen are termed immediate hypersensitivity reactions. Delayed hypersensitivity reactions may take several hours to appear and are at maximum severity days after re-exposure to the antigen. Allergy refers to a hypersensitivity to environmental antigens called allergens. It is not known why some antigens are allergens and others are not. Typical allergens include pollens, moulds and fungi, foods, animals, cigarette smoke and components of house dust. Often the allergen is contained within a particle that is too large to be phagocytosed or is surrounded by a protective non-allergenic coat. The actual allergen is released after enzymatic breakdown (usually by lysozyme in secretions) of the larger particle. Allergies are the most common hypersensitivity diseases. The majority of allergies are type I reactions that lead to annoying symptoms such as a runny nose, sneezing and other relatively mild reactions.
RESEARCH IN F CUS The incidence of allergies in Australia and New Zealand Allergies are among the fastest growing chronic conditions, and Australia and New Zealand have some of the highest rates of allergy in the world. Allergies are a major cause of disability and are a major public health problem, costing an estimated $7 billion per year. It is thought that approximately 20% of the population have at least one allergy, with most sufferers aged between 15 and 64 years of age. In addition, many children have allergies: in children aged 6–7 years, 1 in 6 have eczema and 1 in 10 have allergic rhinitis. Food allergies are also high and have been estimated to affect approximately 10% of children. Most alarming is the rapid increase in the number of children suffering from peanut allergy. Food-induced anaphylaxis has doubled in the last 10 years, although death from this type of anaphylaxis is rare. However, drug-related anaphylaxis and subsequent deaths have increased dramatically. The exact reasons for the high prevalence of allergies in Australia and New Zealand remain unknown. It is predicted that the number of patients affected by allergic diseases in Australia will increase from 4.1 million (19.6% of the population) in 2007 to 7.7 million (26.1% of the population) by 2050.
Type I: IgE-mediated hypersensitivity reactions
Type I reactions are the most common reactions and are mediated by antigen-specific immunoglobulin E (IgE) and
CHAPTER 15 Alterations of immune function across the life span
the products of tissue mast cells (see Fig. 15.1).1 In addition, most type I reactions occur against environmental antigens and are therefore allergic. Because of this strong association, many healthcare professionals use the term allergy to indicate only IgE-mediated reactions. However, IgE can contribute to some autoimmune diseases, and many common allergies (e.g. cow’s milk causing enteropathy) are not mediated by IgE. Before an IgE-mediated hypersensitivity reaction occurs, the allergen is digested by an antigen-presenting cell (such as a macrophage), which presents the antigen fragment to helper T cells. The helper T cells assist the B lymphocytes to convert into plasma cells, which produce IgE. Immunoglobulin E has a relatively short life span in the blood because it rapidly binds to receptors on mast cells. In predisposed individuals, large amounts of IgE are produced by the plasma cells which bind to mast cells and basophils, with the individual considered to be sensitised. Upon further exposure of the sensitised individual to the allergen, degranulation of the mast cell occurs with the release of mast cell products (discussed in Chapter 13) (see Fig. 15.1). A flood of substances are released from the mast cells, which cause the signs and symptoms of the type I hypersensitivity reaction.
Allergen
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First exposure
B lymphocyte
Plasma cell
Macrophage (antigen-presenting cell) IgE (binds to mast cell) Second exposure Oxygen
Sensitised mast cell
Mechanisms of IgE-mediated hypersensitivity
The most potent mediator of IgE-mediated hypersensitivity is histamine, which affects several key target cells.2 Histamine contracts bronchial smooth muscles (bronchial constriction), increases vascular permeability (oedema) and causes vasodilation (increased blood flow) (see Chapter 16). In addition, the interaction of histamine with receptors in the stomach results in increased gastric acid secretion. Some type I allergic responses can be controlled by blocking histamine receptors with antihistamines.
Allergic reaction Antigen-antibody binding
Degranulated mast cell
Histamine
Oedema
CLINICAL MANIFESTATIONS
The clinical manifestations of type I reactions are attributable mostly to the biological effects of histamine. The tissues most commonly affected by type I responses contain large numbers of mast cells and are sensitive to the effects of histamine released from them. These tissues are found in the gastrointestinal tract, the skin and the respiratory tract (see Fig. 15.2). Gastrointestinal allergy is caused primarily by allergens that enter through the mouth — usually foods or oral medications. Symptoms include vomiting, diarrhoea or abdominal pain. Foods most often implicated in gastrointestinal allergies are peanuts, milk, chocolate, citrus fruits, eggs, wheat, nuts and fish. When food is the allergen, the active immunogen may be an unidentifiable product of food breakdown by digestive enzymes. Sometimes the allergen is a drug, an additive or a preservative in the food. For example, cows are sometimes given penicillin to treat infection and trace amounts of the antibiotic can be present in the milk. Thus, hypersensitivity apparently caused by milk proteins may instead be the result of an allergy to penicillin.
Blood vessel
FIGURE 15.1
The mechanism of type I IgE-mediated hypersensitivity reactions. First exposure to an allergen stimulates B lymphocytes to mature into plasma cells that produce IgE. The IgE attaches to the surface of the mast cell by binding with IgE-specific receptors. When an adequate amount of IgE is bound, the mast cell is ‘sensitised’. During a second exposure, the allergen cross-links the surfacebound IgE and causes degranulation of the mast cell. The initial phase is characterised by vasodilation, vascular leakage and smooth muscle spasm or glandular secretions, usually within 5–30 minutes after exposure to the antigen. The late phase occurs 2–8 hours later without additional exposure to the antigen and results from infiltration of tissues with inflammatory cells, including eosinophils, neutrophils and basophils.
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Itching Conjunctivitis Rhinitis Laryngeal oedema Urticaria
Angio-oedema Hypotension
Bronchospasm (asthma) Arrhythmias
Gastrointestinal cramps and malabsorption Angio-oedema Swelling of the dermal and subcutaneous layers due to dilation and increased permeability of the capillaries FIGURE 15.2
Clinical manifestations of type I hypersensitivity reactions. Main reactions include vomiting, diarrhoea and gastrointestinal pain, and swelling of the respiratory system causing breathing difficulties, and hypotension.
Urticaria, or hives, is a dermal (skin) manifestation of allergic reactions (see Fig. 15.3). The underlying mechanism is the localised release of histamine and increased vascular permeability, resulting in limited areas of oedema. Urticaria is characterised by white fluid-filled blisters surrounded by areas of redness. This is usually accompanied by itching. Urticaria is not only caused by immunological reactions, but it can also result from exposure to cold temperatures, emotional stress, medications, systemic diseases or malignancies (e.g. lymphomas). Allergens can also cause rhinitis (inflammation of the mucous membrane of the nose) and conjunctivitis (inflammation of the membrane lining the eyelids). The more serious effects of type I hypersensitivity reactions are vasodilation, hypersecretion of mucus, oedema and swelling of the respiratory mucosa (see Fig. 15.2). Because the mucous membranes lining the respiratory tract are continuous, they are all adversely affected. This can cause obstruction of the large and small airways (bronchi) of the lower respiratory tract by bronchospasm (constriction of smooth muscle in airway walls), oedema and thick secretions. This leads to ventilatory insufficiency, wheezing and difficult or laboured breathing.
FIGURE 15.3
Urticaria due to type I hypersensitivity reaction. The skin lesions have raised edges and develop within minutes or hours, with resolution occurring after about 12 hours.
Certain individuals are genetically predisposed to develop allergies and are called atopic. In families in which one parent has an allergy, allergies develop in about 40% of the offspring. If both parents have allergies, the incidence may be as high as 80%. Atopic individuals tend to produce higher quantities of IgE and to have more receptors for IgE on their mast cells. The airways and skin of atopic individuals have increased responsiveness to a wide variety of both specific and nonspecific stimuli. EVALUATION AND TREATMENT
It must be emphasised that the majority of allergic reactions are not life threatening, but often the individual affected feels quite debilitated. For instance, allergic rhinitis affects the eyes and nasal passages and causes itching, swelling and increased mucus production. Hay fever, which affects a large percentage of the population, occurs when pollen enters the upper airway and causes a type I reaction. These conditions can be treated with antihistamines to primarily alleviate the symptoms, or individuals can undergo allergy testing to identify the specific allergen. Clinical desensitisation to allergens can be achieved in some individuals. Minute quantities of the allergen to which the person is sensitive are injected in increasing doses over a prolonged period. This procedure may reduce the severity of the allergic reaction in the treated individual. In some cases, an allergic reaction can be life threatening; therefore, it is essential that severely allergic individuals be made aware of the specific allergen against which they are
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sensitised and instructed to avoid contact with that material. If these individuals are exposed to that specific allergen, it may induce a severe allergic reaction that can be life threatening, and immediate treatment is required.
Anaphylaxis
The most rapid and severe immediate hypersensitivity reaction is anaphylaxis. Anaphylaxis occurs within minutes of re-exposure to the antigen and produces a severe reaction. Anaphylactic shock is a life-threatening condition that causes contraction of bronchial smooth muscle, oedema of the throat, breathing difficulties, decreased blood pressure and ultimately death without immediate rescue therapy. One of the main problems with anaphylaxis is that it results in widespread vasodilation. The circulatory system usually works by a combination of vasoconstriction and vasodilation in different organs at any one time, to redirect blood flow to areas of most need. However, with mass vasodilation all blood vessels have a much wider diameter than usual, which results in low blood pressure and an insufficient amount of blood going to the vital organs of the brain, heart and lungs. To try to compensate for this, the heart rate becomes rapid (tachycardia). An example of systemic anaphylaxis is an allergic reaction to peanuts, which has a high prevalence in children (greater than 1% in school aged children) and continues to rise.3 Accordingly, health- and child-care workers should be aware of children’s susceptibility to peanut allergy and many institutions prohibit peanuts and other nuts from their facilities. Individuals with severe systemic anaphylaxis are required to avoid exposure to the particular environmental trigger. In addition, they may need to carry adrenaline with them at all times, in case of a life-threatening allergic episode. An auto-injector called an Epi-Pen® (Epi indicates epinephrine — the American term for adrenaline) is a self-injecting ‘pen’ that is given subcutaneously or intramuscularly in the case of anaphylaxis. Adrenaline is an adrenergic agonist that when administered provides bronchodilation to correct breathing difficulties, as well as vasoconstriction to increase cardiac output and provide adequate blood flow back to the vital organs, thereby temporarily alleviating the effects of the anaphylactic reaction. Prompt hospitalisation is also required. Individuals are taught how to self-inject with the pen, which reduces the intervention time and has been shown to decrease mortality.4
Type II: tissue-specific hypersensitivity reactions
Type II hypersensitivities are generally reactions against a specific cell or tissue. Cells express a variety of antigens on their surfaces, some of which are called tissue-specific antigens because they are expressed on the plasma membranes of only certain cells. Antibodies are produced that bind to the antigen on these tissues that cause the hypersensitivity reaction. The symptoms of many type II diseases are
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determined by which tissue or organ expresses the particular antigen. Environmental antigens (e.g. drugs) may bind to the plasma membranes of specific cells (especially erythrocytes and platelets) and function as targets of type II reactions. There are four general mechanisms by which type II hypersensitivity reactions can affect cells (see also Fig. 15.4): • The cell may be destroyed by the antibody (IgM or IgG) reacting with the surface antigen causing activation of the complement system (see Chapter 13). This process destroys erythrocytes (red blood cells) in individuals who have haemolytic anaemia (see Chapter 17). • The antibody–antigen complex may be destroyed through phagocytosis by macrophages. An example of this occurs when antibodies against platelets cause the removal of platelets in the spleen, termed immune thrombocytopenia purpura (the individual has a decreased number of platelets — thrombocytopenia — and bruises easily, creating purple discolourations on the skin called purpura). Phagocytosis is enhanced by opsonisation, a process in which the target cell is coated with antibody or complement protein, allowing the macrophage to bind to the target cell. • The antibody on the target cell is recognised by natural killer cells, which release toxic substances that destroy the target cell. • The antibody binds to the target cell receptor and alters the function of the cell because the receptor cannot bind to substances that are required by the cell. This mechanism does not activate the complement, phagocytes or cytotoxic cells but rather destroys the cell by interfering with usual functions. This occurs in Graves’ disease, where the antibody binds to the receptor that stimulates the production of thyroxine. The hyperthyroidism triggers a range of clinical manifestations, including goitre formation, tachycardia, irritability and an anterior bulging of the eyes (proptosis or exophthalmos).
Type III: immune complex–mediated hypersensitivity reactions
Most type III hypersensitivity diseases are caused by antigen-antibody (immune) complexes that are formed in the circulation and deposited later in vessel walls or other tissues5 (see Fig. 15.5). The primary difference between type II and type III mechanisms is that in type II hypersensitivity the antibody binds to the antigen on the cell surface, whereas in type III the antibody binds to soluble antigen that was released into the blood or body fluids and the complex is then deposited in the tissues. Type III reactions are not organ-specific and symptoms have little to do with the particular antigenic target of the antibody. The harmful effects of immune complex deposition are caused by activation of the complement system, particularly through the generation of chemotactic factors (chemicals that attract immune cells) for neutrophils. The neutrophils bind to the antibody and C3b (a component
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A
Activation of complement system
C1
C
Antibody
Target cell
Antibody
Antigen Target cell
Natural killer cell
Target cell
B
Antibody
Macrophage (phagocytosis)
D
Antibody Surface receptor
Target cell
FIGURE 15.4
The mechanisms of type II tissue-specific hypersensitivity reactions. A The antigen-antibody (immune) complex causes activation of the complement system. B Phagocytosis of the targeted cell occurs when bound with antibody. C The antibody attracts natural killer cells, which cause lysis of the cell when attached. D The antibody binds to a surface receptor and inhibits usual cell function, which destroys the receptor and target cell.
1
IgG
Complement system activated
Antigen C1
Neutrophil
3 Granules
2 Target tissues/cells
5
4
C3b
Cell destruction
FIGURE 15.5
The mechanism of type III immune-complex-mediated hypersensitivity reactions. 1 Immune complexes form in the blood from circulating antigen and antibody and 2 are deposited in certain target tissues. 3 The complexes activate the complement system via C1 and generate fragments that attract neutrophils to the site. 4 The neutrophils attach to the IgG and C3b in the immune complexes and 5 release a variety of degradative enzymes that destroy the healthy tissues.
of the complement system) contained in the complexes and attempt to ingest the immune complexes. They are often unsuccessful because the complexes are bound to large areas of tissue. During the attempted phagocytosis, large quantities of lysosomal enzymes are released into the
inflammatory site. The attraction of neutrophils and the subsequent release of lysosomal enzymes cause most of the resulting tissue damage. Type III hypersensitivity reactions are the cause of many of the conditions seen in systemic lupus erythematosus, an autoimmune disease discussed later in the chapter.
Type IV: cell-mediated hypersensitivity reactions
Whereas types I, II and III hypersensitivity reactions are mediated by antibody, type IV reactions are mediated by T lymphocytes and do not involve antibody (see Fig. 15.6). Type IV mechanisms occur through either cytotoxic T lymphocytes or cytokine-producing helper T (TH1) cells.6 Cytotoxic T cells attack and destroy cellular targets directly. TH1 cells produce cytokines that recruit and activate phagocytes, especially macrophages. Destruction of the tissue is usually caused by direct killing by cytotoxic T cells or the release of soluble factors, such as lysosomal enzymes from activated macrophages. Clinical examples of type IV hypersensitivity reactions include graft rejection, the skin test for tuberculosis (Mantoux test) and allergic reactions resulting from contact with such substances as nickel, plants and latex. These are called allergic contact dermatitis and examples can be seen in Fig. 15.7. A type IV component also may be present in many autoimmune diseases. For example, T cells against the protein collagen contribute to the destruction of joints
CHAPTER 15 Alterations of immune function across the life span
Helper T cell
T cytotoxic cell
363
A
T cell receptor
Target cell
Cytokines
Apoptosis
B
Antigen Lysosomal granules Activated macrophage FIGURE 15.6
The mechanism of type IV cell-mediated hypersensitivity reactions. Antigens from target cells stimulate T cells to differentiate into T cytotoxic cells, which have direct cytotoxic activity, and helper T cells, which produce cytokines (especially interferon-gamma) that activate macrophages. The macrophages can attach to targets and release enzymes that induce apoptosis of the target cell.
C
RESEARCH IN F CUS Latex allergy in healthcare workers Latex is a natural rubber derived from the rubber tree, Hevea brasiliensis. The protein concentration in raw latex is very low, but is associated with several allergens. In the general population, the prevalence of latex allergy is low. However, in healthcare workers, especially nurses, the prevalence of latex allergy is considerably higher and is estimated to be between 5% and 15% — it is also expected to increase. The primary reason for the higher rate among healthcare workers is their increased exposure to latex compared to the general population. Healthcare workers routinely apply gloves during numerous clinical procedures and this greater usage of latex gloves increases the risk of developing a latex allergy. The most common reported symptoms include erythema, itch and swelling, typical of IgE-mediated allergy clinical manifestations. In addition, type IV cell-mediated hypersensitivity reactions are common and are related to contact dermatitis. It has been reported that many individuals with a positive latex skin-prick test are asymptomatic upon latex exposure with the skin. The reasons for this are unclear. The best treatment to date is the avoidance of latex gloves and it is recommended that healthcare workers use non-latex powdered gloves to decrease the possibility of latex allergy.
FIGURE 15.7
Allergic contact dermatitis from different allergens. A Nickel is the most common cause of contact dermatitis in Australia. B Skin-contacting nicotine patches can cause allergic dermatitis. C Latex glove contact can cause allergic dermatitis, especially in healthcare workers (see ‘Research in Focus: Latex allergy in healthcare workers’).
in rheumatoid arthritis, and T cells against an antigen on the surface of pancreatic beta cells (the cells that normally produce insulin) are responsible for beta cell destruction in insulin-dependent (type 1) diabetes mellitus. Therefore, type IV reactions are delayed hypersensitivity reactions as they take hours to days to appear, whereas type I reactions exhibit immediate allergic hypersensitivity reactions.
Transplantation Despite Australia and New Zealand having low rates of organ donation, the numbers of donors are increasing each
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F OCU S O N L E ARN IN G
1 Describe the terms hypersensitivity and allergy. 2 Distinguish between the 4 types of hypersensitivity mechanisms. 3 Describe the pathogenesis of IgE-mediated hypersensitivity reactions. 4 Distinguish between allergic and anaphylactic reactions. Outline the treatment for anaphylaxis. 5 Explain why some autoimmune diseases are associated with type III hypersensitivity reactions. 6 Discuss why type IV hypersensitivity reactions are delayed reactions.
year in both countries.7–9 Approximately 46 000 tissue and organ transplants have occurred in Australia since 1963.7–9 Australia is a world leader for successful transplant outcomes.7 For these transplants to be successful, recipients need to be closely tissue-matched with the donor, meaning that the major histocompatibility complex (MHC), the molecules found on all nucleated cells that are self-antigens, must be closely matched between the donor and recipient. This reduces the capacity of the recipient’s immune system to attack the transplanted organ, because it is less ‘foreign’. In addition, the recipient receives immunosuppressive medication to reduce their immune system’s response to the transplanted organ. Blood also needs to be matched between the recipient and donor to avoid serious immune reactions. In most clinical situations, the transfusion of blood is not associated with any major immune reactions. Organ transplantation is successful because technology enables close matching of tissue types between the donor and recipient and the level of immunosuppressive medication is carefully calculated to achieve optimal health for the recipient. However, the recipient’s immune system does mount a response to transplanted tissues and we now examine this in more detail.
Transplantation rejection
The MHC molecules, also referred to as human leucocyte antigens (HLA), are responsible for displaying proteins on the surface of every nucleated cell in the body, so that the immune system can recognise the cells as ‘self ’ — that is, normal cells. Every individual has unique MHC molecules. Within the human population, the number of possible different MHC combinations is enormous and so finding two individuals with similar MHC antigens is difficult. The diversity of MHC molecules becomes clinically relevant during organ transplantation. The recipient of a transplant can mount an immune response against the foreign MHC antigens on the donor tissue, resulting in rejection. To minimise the chance of tissue rejection, the donor and recipient are required to have the same blood group and are tissue-typed to identify differences in MHC
antigens.10,11 Because of the large number of different MHC antigen combinations, it is highly unlikely that a perfect match will be found between an individual who needs a transplant and a potential donor from the general population. However, the more similar two individuals are in their MHC antigen tissue type, the more likely a transplant from one to the other will be successful. Because MHC antigens are inherited from parents, siblings are usually closely matched and identical twins are genetically similar and therefore the closest match. Transplant rejection may be classified as hyperacute, acute or chronic, depending on the amount of time that elapses between transplantation and rejection. • Hyperacute rejection is immediate and rare. When the circulation is re-established to the grafted area, the graft may immediately turn white (so-called white graft) instead of a normal pink colour. Hyperacute rejection usually occurs because of preexisting antibody (type II reaction) to antigens on the vascular endothelial cells in the grafted tissue. • Acute rejection is a cell-mediated immune response that occurs within days to months after transplantation. This type of rejection occurs when the recipient develops an immune response against unmatched HLAs after transplantation. A biopsy of the rejected organ usually shows an infiltration of lymphocytes and macrophages characteristic of a type IV reaction. • Chronic rejection may occur after a period of months or years of normal function. It is characterised by slow, progressive organ failure. Chronic rejection may result from a weak cell-mediated (type IV) reaction against minor histocompatibility antigens on the grafted tissue.
Blood transfusion reactions
Erythrocytes (red blood cells) express several important surface antigens, known collectively as the blood group antigens, which can be targets of immune reactions.12 More than 80 different red cell antigens are grouped into several dozen blood group systems. The most important of these, because they provoke the strongest immune response, are the ABO and Rhesus systems.
The ABO blood group system The ABO blood group consists of two major carbohydrate antigens, labelled A and B (see Fig. 15.8). These are co-dominant alleles so that both A and B can be simultaneously expressed, resulting in an individual having any one of four different blood types: type A, type B, type AB or type O. The ABO blood groups are determined by the presence or absence of certain sugar molecules attached to the surface of red blood cells. Individuals with the A antigen (N-acetygalactosamine) attached to their red blood cells are type A. Individuals with the B antigen (galactose) are type B. Some individuals have both A and B antigens
CHAPTER 15 Alterations of immune function across the life span
Blood type
A Antigen A
B Antigen B
AB Antigens A and B
O Neither antigen
Anti-B antibody
Anti-A antibody
Neither antibody
Anti-A and B antibodies
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Erythrocytes (red blood cells)
Antibodies
FIGURE 15.8
The ABO blood group. The relationship of antigens and antibodies associated with the ABO blood groups. The surfaces of erythrocytes of individuals with blood group A have the A antigenic carbohydrate. The blood of these individuals has IgM antibodies against the B antigen. In individuals with blood group B, the red blood cells have the B antigenic carbohydrate, and the blood contains IgM antibodies against the A antigen. In individuals with blood group AB, the same cells have both the A and B antigens. These individuals do not have antibody to either A or B antigens. The erythrocytes of blood group O individuals have neither antigen, but their blood contains antibodies to both A and B.
on their red blood cells and hence are type AB. Finally, individuals with neither antigen are type O (refer to Table 15.1). The inheritance of the ABO blood groups is discussed in Chapter 5. At birth, antibodies to ABO antigens are not found in the plasma. Ingestion of bacteria with food or from the surrounding environment exposes the immune system to antigens that are almost identical to the ABO antigens found on erythrocytes. If an individual is exposed to an antigen that they do not possess, an antibody to that antigen will be made. For example, type A individuals do not possess the B antigen and therefore will manufacture an antibody to the B antigen (known as an anti-B antibody). Type B individuals will similarly acquire an anti-A antibody. Type O individuals, lacking both A and B antigens, will acquire both anti-A and anti-B antibodies, whereas type AB individuals, having both A and B antigens, will not acquire any ABO antibodies. Antibodies that are acquired in this way are known as naturally occurring antibodies. Table 15.1 provides a summary of the ABO blood group system and shows the different ABO antibodies that are found in the plasma of individuals of different ABO blood groups. The presence of naturally occurring ABO blood group system antibodies creates a potentially dangerous situation with respect to blood transfusions. For example, if a type A recipient is given type B or type AB blood, a severe transfusion reaction will occur, because the recipient already possesses anti-B antibodies in their plasma. These antibodies
TABLE 15.1 Description of the ABO blood group system GROUP
GENOTYPE
ANTIGENS (ON RED CELLS)
ANTIBODIES (IN PLASMA)
O
OO
None
Anti-A
FREQUENCY IN AUSTRALIA
49%
Anti-B A
AA or AO
A
Anti-B
38%
B
BB or BO
B
Anti-A
10%
AB
AB
A and B
None
3%
will bind to the B antigen on the transfused erythrocytes. The transfused erythrocytes will be destroyed by agglutination (literally clumping of the cells together, not to be confused with the blood clotting process) or complement-mediated lysis (where the cell membrane is destroyed and the cell contents leak out causing cell death). This can cause a series of physiological reactions leading to shock, coagulopathy and renal failure. An acute transfusion reaction can be fatal. Similarly, a type B individual (whose blood contains anti-A antibodies) cannot receive blood from a type A or AB donor. Type O individuals, who have neither A or B antigen but have both anti-A and anti-B antibodies, cannot accept blood from any of the other three types.
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TABLE 15.2 ABO blood group compatibility for blood transfusion PATIENT’S BLOOD GROUP
COMPATIBLE DONOR
O
O
A
A, O
B
B, O
AB
AB, B, A, O
For this reason, great care must be taken when transfusing blood to ensure that the correct blood group is given to the correct patient (i.e. the transfused blood must be compatible with the recipient’s blood). Group O blood does not have either A or B antigens and thus it is possible to transfuse this blood type to a recipient with any ABO blood type without the risk of an ABO-related acute transfusion reaction. Table 15.2 shows the donor blood groups that are compatible with recipients of different blood groups. Note that someone who is type O can receive blood only from type O, yet can donate to all types (universal donor). On the other hand, someone who is type AB can receive from all types (universal recipient), but donate only to another type AB. Transfusion reactions can be prevented only by complete and careful ABO matching between donor and recipient. In clinical practice, cross-matching of blood is routine and severe transfusion reactions occur only if an individual is transfused with an incompatible blood group.
The Rhesus system
The Rhesus (Rh) blood group is a group of antigens expressed only on red blood cells. This is the most diverse group of red cell antigens, consisting of at least 45 separate antigens, although only one is considered very important. The naming of the Rhesus (Rh) blood group system originates from the work of pioneer blood transfusion scientists who found a blood group antigen on human erythrocytes that was immunologically similar to an antigen found on the red cells of Rhesus monkeys. The human antigen is known as the D antigen. Individuals who express the D antigen on their red cells are considered Rh-positive, whereas individuals who do not express the D antigen are Rh-negative. About 85% of Caucasians are Rh-positive and these people can receive both Rh-positive and Rh-negative blood. The remaining 15% who are Rh-negative can receive only Rh-negative blood. The D antigen is the most immunogenic of the Rh antigens, meaning that if an individual who is Rh-negative is exposed to Rh-positive blood (e.g. by transfusion or pregnancy), there is a high probability that an anti-D antibody will be made by the immune system. This could cause a haemolytic reaction (lysis or destruction of erythrocytes) if there is another exposure to Rh-positive blood at a later date. The Rh blood group is checked before
individuals receive a blood transfusion. Therefore, blood to be transfused into individuals is checked for both ABO and Rh factor. A disease called haemolytic disease of the newborn is most commonly caused by IgG anti-D antibody produced by Rh-negative mothers against erythrocytes of their Rh-positive fetuses (see Chapter 17). This may occur if the maternal Rh-negative blood comes into contact with the fetus’s Rh-positive blood. The mother’s antibody will coat the fetal red blood cells and destroy them. The occurrence of this particular form of the disease has decreased dramatically because of the use of prophylactic anti-D immunoglobulin (i.e. Rhogam). By mechanisms that are still not completely understood, administration of anti-D antibody within a few days of exposure to RhD-positive erythrocytes completely prevents sensitisation against the D antigen. Because the ABO blood group is the most important in clinical practice, followed by the Rh antigen, blood grouping tests generally only test for these antigens. Other blood group antigens are tested for only if required as part of further laboratory investigation.
The universal donor
Donors with the blood type O Rh-negative are highly sought by transfusion services. This is because this blood group can be transfused to any recipient and is therefore referred to as the universal donor. Group O blood can be given to any ABO blood type recipient and because the blood is also Rh-negative there is no chance of a reaction should the recipient have a circulating anti-D antibody. Furthermore, the transfusion of Rh-negative blood will not stimulate the immune system to produce an anti-D antibody if the recipient is Rh-negative. Type O Rh-negative blood is particularly useful in emergency situations where blood needs to be transfused as a life-saving measure and there is insufficient time to perform a blood group analysis. For this reason, type O Rh-negative blood is usually kept in stock in hospitals to allow transfusion without losing time for blood typing, and ambulance and helicopter medical retrieval services in Australia carry group O Rh-negative packed cells in specially designed coolers to accident sites, so that blood transfusion can be given as quickly as possible should this be necessary.13 Care should be taken in emergency situations to monitor patients with existing hypothermia as studies have shown that transfusing cooled blood may exacerbate their condition.14
FOCU S ON L EA RN IN G
1 Explain why individuals requiring organ transplantation need to have close-matching tissue with the donor. 2 Outline the different blood groups and list the antigens and antibodies for each group.
CHAPTER 15 Alterations of immune function across the life span
Autoimmune diseases The final aspect of exaggerated or inappropriate immune responses is that related to autoimmune diseases. Autoimmunity is a disturbance in the immunological tolerance of self-antigens. The immune system normally is able to distinguish the individual’s own antigens against foreign antigens. Healthy individuals of all ages, but particularly the elderly, may produce low quantities of antibodies against their own antigens (these are termed autoantibodies) without developing overt autoimmune disease. Therefore, the presence of low quantities of autoantibodies does not necessarily indicate a disease state. Autoimmune diseases occur when the immune system reacts against self-antigens to such a degree that autoantibodies and cytotoxic T cells damage the individual’s own tissues. The reasons for the autoimmunity occurring are not entirely clear, but it appears that genetic inheritance and an environmental trigger, such as infection causing activation of antigen-presenting cells, may promote activation of cytotoxic T cells and subsequent attack on the body’s tissues (see Fig. 15.9). Many clinical disorders are associated with autoimmunity and are generally referred to as autoimmune diseases (see Table 15.3). It is well-established that autoimmune diseases can be familial. Affected family members may not all develop the same disease, but several members may have different disorders characterised by a variety of hypersensitivity reactions, including autoimmune and allergic.
Genetic susceptibility
Susceptibility genes Failure of self-tolerance
Self-reactive lymphocytes
Infection, tissue damage Necrosis, inflammation
Tissue Activation of tissue Antigenpresenting cells Influx of self-reactive lymphocytes into tissues
Activation of self-reactive lymphocytes
Tissue injury: autoimmune disease
The breakdown of tolerance
Each individual is usually tolerant to their own antigens. This is termed self-tolerance. Self-tolerance is a state of immunological control so that the individual does not make a detrimental immune response against their own cells and tissues. Autoimmune disease results from a breakdown of this tolerance. Although many theories exist concerning the initial cause of autoimmune diseases, only one example is known: acute rheumatic fever. In a small number of individuals with group A streptococcal sore throats, proteins in the bacterial capsule mimic normal heart antigens and induce antibodies that also react with proteins in the heart valve, damaging the mitral valve in particular.15 Thus, rheumatic fever is a type II autoimmune hypersensitivity. Additionally, some streptococcal skin or throat infections release bacterial antigens into the blood that form circulating immune complexes. The complexes may deposit in the kidneys and initiate an immune complex glomerulonephritis (inflammation of the kidney). Thus, streptococcal antigens (an environmental antigen) may also cause a type III allergic hypersensitivity. Many of the autoimmune disorders presented in this text are associated with a particular body system (for instance, rheumatoid arthritis is discussed in Chapter 21 on the musculoskeletal system, and rheumatic fever is discussed in Chapter 23 on the cardiovascular system).
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FIGURE 15.9
The proposed pathogenesis of autoimmunity. Autoimmunity can result from multiple factors, including susceptibility genes that may interfere with self-tolerance and environmental triggers (inflammation, other inflammatory stimuli) that promote lymphocyte entry into tissues, activation of lymphocytes and tissue injury.
However, one disease is examined in detail in this chapter as it is difficult to categorise into a single body system — systemic lupus erythematosus.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a complex and serious autoimmune disorder that affects more than 20 000 individuals in Australia and New Zealand.16 It is characterised by the production of a large variety of antibodies (autoantibodies) against self-antigens, including nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, platelets and many other self-components. The most characteristic autoantibodies are against nucleic acids (e.g. single-stranded DNA, double-stranded DNA), ribonucleoproteins and other nuclear materials.17 The blood normally contains many of these products of cellular
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TABLE 15.3 Autoimmune disorders SYSTEM DISEASE
ORGAN OR TISSUE
PROBABLE SELF-ANTIGEN
Hyperthyroidism (Graves’ disease)
Thyroid gland
Receptors for thyroid-stimulating hormone on plasma membrane of thyroid cells
Hashimoto hypothyroidism
Thyroid gland
Thyroid cell surface antigens, thyroglobulin
Insulin-dependent diabetes
Pancreas
Islet cells, insulin, insulin receptors on pancreatic cells
Addison’s disease
Adrenal gland
Surface antigens on steroid-producing cells; microsomal antigens
Pemphigus vulgaris
Skin
Intercellular substances in stratified squamous epithelium
Vitiligo
Skin
Surface antigens on melanocytes (melanin-producing cells)
Multiple sclerosis
Neural tissue
Surface antigens of nerve cells
Myasthenia gravis
Neuromuscular junction
Acetylcholine receptors; striations of skeletal and cardiac muscle
Heart
Cardiac tissue antigens that cross reaction with group A streptococcal antigen
Ulcerative colitis
Colon
Mucosal cells
Pernicious anaemia
Stomach
Surface antigens of parietal cells; intrinsic factor
Primary biliary cirrhosis
Liver
Cells of bile duct
Chronic active hepatitis
Liver
Surface antigens of hepatocytes, nuclei, smooth muscle
Ankylosing spondylitis
Joints
Sacroiliac and spinal apophyseal joint
Rheumatoid arthritis
Joints
Collagen, IgG
Systemic lupus erythematosus
Multiple sites
Numerous antigens in nuclei, organelles and extracellular matrix
Immune complex glomerulonephritis
Kidney
Numerous immune complexes
Goodpasture’s syndrome
Kidney
Glomerular basement membrane
Idiopathic neutropenia
Neutrophil
Surface antigens on polymorphonuclear neutrophils
Autoimmune haemolytic anaemia
Erythrocytes
Surface antigens on erythrocytes
Autoimmune thrombocytopenic purpura
Platelets
Surface antigens on platelets
Endocrine system
Skin
Neuromuscular tissue
Cardiovascular system Rheumatic fever
Gastrointestinal system
Connective tissue
Renal system
Haematological system
turnover and breakdown. Excessive levels of autoantibodies react with the circulating antigen and form circulating immune complexes. The deposition of circulating DNA/ anti-DNA complexes in the kidneys can cause severe kidney inflammation. Similar reactions can occur in the brain, heart, spleen, lungs, gastrointestinal tract, peritoneum and skin. Thus, some of the symptoms of SLE result from a type III hypersensitivity reaction. Other symptoms, such as destruction of red blood cells (anaemia), lymphocytes and other cells, may be type II hypersensitivity reactions. SLE, like most autoimmune diseases, occurs more often in women (approximately a 10:1 predominance of females),
especially in the 20–40-year-old age group (see ‘Research in Focus: Autoimmune diseases affect women more than men’). A genetic predisposition for the disease has been implicated based on increased incidence in twins and the existence of autoimmune disease in the families of individuals with SLE. Clinical manifestations are often many and include arthralgia (joint pain) or arthritis (90% of individuals), vasculitis and rash (70–80% of individuals), renal disease (40–50% of individuals), haematological abnormalities (50% of individuals, with anaemia being the most common complication) and cardiovascular diseases (30–50% of
CHAPTER 15 Alterations of immune function across the life span
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• oral or nasopharyngeal ulcers • non-erosive arthritis of at least two peripheral joints • serositis (inflammation of membranes of the lung (pleurisy) or heart (pericarditis)) • renal disorder (proteinuria of 0.5 g/day or cellular casts) • neurological disorders (seizures or psychosis) • haematological disorders (haemolytic anaemia, leucopenia or thrombocytopenia) • immunological disorders (positive lupus erythematosus cell preparation, anti-double stranded DNA, anti-Smith antigen, false-positive serological test for syphilis or anti-phospholipid antibodies) • presence of antinuclear antibody (ANA). There is no cure for SLE or most other autoimmune diseases. The goals of treatment are to control symptoms and prevent further damage by suppressing the autoimmune response. Non-steroidal anti-inflammatory drugs, such as aspirin, ibuprofen and naproxen, reduce inflammation and relieve pain. Corticosteroids are often prescribed for more serious active disease. Immunosuppressive drugs (e.g. methotrexate, azathioprine or cyclophosphamide) are used to treat severe symptoms involving internal organs. Ultraviolet light can worsen symptoms (known as flares) and protection from sun exposure is helpful. Improved outcomes may be available in the future with continued advances in medical research and the use of stem cell treatments.19
RESEARCH IN F CUS Autoimmune diseases affect women more than men FIGURE 15.10
Systemic clinical manifestations of systemic lupus erythematosus. The most distinct feature is the facial redness in a butterfly shape, and other symptoms extend throughout body systems.
individuals) (see Fig. 15.10). As with most autoimmune diseases, SLE is characterised by frequent remissions and exacerbations. Because the signs and symptoms affect almost every body system and tend to come and go, SLE is extremely difficult to diagnose. This has led to the development of a list of 11 common clinical findings. The serial or simultaneous presence of at least four of these indicates that the individual has SLE. They are as follows:18 • facial rash confined to the cheeks (malar rash), in a characteristic ‘butterfly’ shape on the face • discoid rash (raised patches, scaling) • photosensitivity (skin rash developed as a result of exposure to sunlight)
To explain why women are especially susceptible to autoimmune disorders, researchers are investigating whether the sex hormones oestrogen and testosterone affect the immune system. Many autoimmune diseases in females are affected by changes in hormone levels such as during pregnancy. SLE tends to worsen during pregnancy and remit after menopause whereas in multiple sclerosis many females experience remission during late pregnancy. Men with rheumatoid arthritis have been shown to have low levels of testosterone and other androgens. Although results are inconclusive, several findings support the idea that differences between genders are based on sex hormones. Genetic determinants of gender such as differences in the characteristics of the X chromosome between males and females are also being investigated.
FOCU S ON L EA RN IN G
1 Explain how autoimmune diseases arise. 2 Describe how autoimmune diseases are related to hypersensitivity reactions.
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Immune deficiencies Thus far we have explored the pathophysiology of enhanced immunity. In these conditions, the immune responses are present but they are either exaggerated or inappropriate. In contrast, immune deficiencies (or insufficient immunity) occur when the immune system or inflammatory responses fail to function normally, resulting in increased susceptibility to pathogenic microorganisms and cancers. Primary immune deficiencies are congenital — that is, they are caused by a genetic defect, whereas secondary immune deficiencies are acquired by another condition, such as cancer, infection
or normal physiological changes like ageing. Acquired forms of immune deficiency are far more prevalent than the rare primary immune deficiencies.
Primary immune deficiencies
Most primary immune deficiencies are the result of a single gene defect (Table 15.4).20 Generally, the mutations are sporadic and not inherited: a family history exists in only about 25% of individuals. The sporadic mutations occur before birth, but the onset of symptoms may be early or later, depending on the particular syndrome. In some
TABLE 15.4 Primary immune deficiencies CLASSIFICATION
EXAMPLE
IMMUNE DEFICIENCY
OUTCOME
B lymphocyte deficiencies Defective development of B cells in central lymphoid organ (bone marrow)
Bruton’s Lack of B cells, little or no agammaglobulinaemia antibody production
Recurrent, life-threatening bacterial infections
Defect in class switch
Mild infections of gastrointestinal Selective IgA deficiency Little or no production of IgA, with normal production of other and respiratory tracts classes of antibody
T lymphocyte deficiencies Defective development of T cells in central lymphoid organ (thymus)
DiGeorge’s syndrome
Lack of T cells
Recurrent, life-threatening fungal and viral infections
Defect in development of cellular immunity against a specific antigen
Chronic mucocutaneous candidiasis
Lack of T cell response to Candida
Recurrent and disseminated infections with the fungus Candida albicans
Defective development of both B and T cells
Severe combined immunodeficiencies (SCID)
Lack of both T and B cells, little or no antibody production or cellular immunity
Recurrent, life-threatening infections with a variety of microorganisms
Defects in cooperation among B cells, T cells and antigenpresenting cells
Bare lymphocyte syndrome
No antigen presentation because of lack of MHC class I or MHC class II molecules on the cell surface
Recurrent, life-threatening infections with a variety of microorganisms
A large variety of defects that affect the function of B or T cells
Wiskott-Aldrich syndrome
Cytoskeletal defect resulting in selective decrease in IgM production
Recurrent infections with select groups of microorganisms
Defective production of one early component of the complement system
C3 deficiency
Little or no C3 produced
Recurrent, life-threatening bacterial infections
Defective production of a component of the membrane attack complex
C6 deficiency
Little or no C6 produced
Recurrent disseminated infections with Neisseria gonorrhoeae or Neisseria meningitidis
Defects in production of neutrophils
Severe congenital neutropenia
Lack of neutrophils
Recurrent, life-threatening bacterial infections
Defects in bacterial killing
Chronic granulomatous Lack of production of oxygen disease products (e.g. hydrogen peroxide)
Combined immune deficiencies
Complement deficiencies
Phagocyte deficiencies
Recurrent infections with bacteria that are sensitive to killing by oxygen-dependent mechanisms
CHAPTER 15 Alterations of immune function across the life span
instances, symptoms of immune deficiency appear within the first 2 years of life. Other immune deficiencies are progressive, with the onset of symptoms appearing in the second or third decade of life. The clinical hallmark of immune deficiency is a tendency to develop unusual or recurrent severe infections.21 Preschool and school-age children may have 6–12 infections per year and adults may have 2–4 infections per year. Most of these are not severe and are limited to viral infections of the upper respiratory tract, recurrent streptococcal pharyngitis or mild otitis media (ear infections). Individually, primary immune deficiencies are rare. However, there are more than 150 different primary immunodeficiency disorders, and a central register has been established in Australia and New Zealand to account for those individuals with primary immunodeficiency diseases.22 Through the registry, the Australasian Society for Clinical Immunology and Allergy collects data which generates research into the diagnosis and treatment for those with primary immune deficiencies. Primary immune deficiencies are classified into five groups, based on which principal component of the immune or inflammatory systems is defective: • B lymphocyte deficiencies result from defect in B cell immune responses.23 This results in lower levels of circulating immunoglobulins (hypogammaglobulinaemia) or occasionally totally or nearly absent immunoglobulins (agammaglobulinaemia). • T lymphocyte deficiencies are defects in the development and function of T lymphocytes.23 Because helper T cells are obligatory in the development of many B lymphocyte responses, antibody production is often diminished, although the B cells are fully capable of producing an adequate antibody response. Immunodeficiency of T cell function contributes to failure to thrive, oral infections (e.g. candidiasis), chronic diarrhoea, pneumonia and skin rashes. • Combined immune deficiencies result from defects that directly affect the development of both T and B lymphocytes. Some combined deficiencies result in major defects in both the T and B cell immune responses, whereas others are ‘partial’ and more adversely affect T cells than B cells. The most severe are called severe combined immunodeficiencies. Most individuals with severe combined immunodeficiencies have few detectable lymphocytes in the circulation and secondary lymphoid organs (spleen, lymph nodes). The thymus usually is underdeveloped because of the absence of T cells. Immunoglobulin levels, especially IgM and IgA, are absent or greatly reduced. Children with this deficiency develop serious, life-threatening infections and usually die before the age of 5 years. • Complement deficiencies result from deficient or abnormal levels of complementary plasma proteins. Individuals with complement deficiencies have an increased risk of infection and autoimmune-like disorders. The complement system is integral to a normal immune
371
response and so individuals with genetic abnormalities that affect the complement system are not able to mount immune responses to pathogenic microorganisms. • Phagocyte deficiencies usually result in recurrent infections with the same group of microorganisms associated with antibody and complement deficiencies. FOCU S ON L EA RN IN G
1 Differentiate between primary and secondary immune deficiencies. 2 Discuss the different types of primary immune deficiencies. 3 List the clinical manifestations of primary immune deficiencies.
Secondary immune deficiencies
Secondary, or acquired, immune deficiencies are far more common than primary deficiencies. These deficiencies are not related to genetic defects but are complications of other physiological or pathophysiological conditions. Conditions associated with secondary immunodeficiencies are listed in Table 15.5. Although secondary immunodeficiencies are common, many are not clinically significant. In many cases, the degree of the immune deficiency is relatively minor and without any apparent increased susceptibility to infection. Alternatively, the immune system may be substantially suppressed, but only for a short duration, thus minimising the incidence of clinically relevant infections. However, some secondary immune deficiencies are extremely severe and may result in recurrent life-threatening infections, such as malignancy and burns. The most destructive secondary immunodeficiency is acquired immunodeficiency syndrome (AIDS). The following section explores the pathophysiology of AIDS and the virus that causes the disease, the human immunodeficiency virus (HIV).
Acquired immunodeficiency syndrome
The human immunodeficiency virus (HIV) infects and destroys helper T cells, which are necessary for the development of both plasma cells and cytotoxic T cells. Therefore, HIV suppresses the immune response against itself and secondarily creates a generalised immune deficiency by suppressing the development of immune responses against other pathogens and opportunistic microorganisms, leading to the development of acquired immunodeficiency syndrome (AIDS). An estimated 36.7 million individuals worldwide were living with HIV at the end of 2015.24 There were approximately 2.1 million new HIV infections worldwide and 1.1 million AIDS-related deaths in 2015.24 Sub-Saharan Africa remains the highest affected region in the world with 25.6 million people living with HIV in 2015, but the epidemic is worldwide and the number of new cases is alarmingly high.
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TABLE 15.5 Conditions associated with secondary immunodeficiencies GROUP
CONDITION
Normal physiological conditions
• Pregnancy
Psychological stress
• Emotional trauma
Dietary insufficiencies
• Malnutrition caused by insufficient intake of large categories of nutrients, such as protein or kilojoules
• Infancy • Ageing • Eating disorders
• Insufficient intake of specific nutrients, such as vitamins, iron or zinc • Congenital infections, such as rubella, cytomegalovirus, hepatitis B Malignancies
• Malignancies of lymphoid tissues, such as Hodgkin’s lymphoma, acute or chronic leukaemia, or myeloma • Malignancies of non-lymphoid tissues, such as sarcomas and carcinomas
Infections
• HIV/AIDS
Physical trauma
• Burns
Medical treatments
• Post-surgery
• Degloving injuries • Anaesthesia • Immunosuppressive treatment with corticosteroids or antilymphocyte antibodies • Splenectomy • Cancer treatment with cytotoxic drugs or ionising radiation
Other diseases • Diabetes mellitus or genetic • Alcoholic cirrhosis syndromes • Sickle cell disease
however, Papua New Guinea has an HIV epidemic, with approximately 40 000 of its 7 million residents living with HIV at the end of 2014, up from 28 000 in 2011.26 By comparison, the number of individuals living with HIV in Australia at the end of 2014 was approximately 27 000.27 Between the inception of HIV in Australia in 1982 and the end of 2014, Australia recorded 35 128 cases of HIV infection.27 Because of the availability of antiretroviral therapy for many years in Australia and New Zealand the development of AIDS from HIV infection rarely occurs.25
Epidemiology
HIV is a blood-borne pathogen with the typical routes of transmission: blood or blood products, intravenous drug abuse, both heterosexual and homosexual activity and maternal–child transmission before or during birth (see Table 15.6). Worldwide, the most common route of transmission is through heterosexual contact, but in Australia (see Fig. 15.11) and New Zealand homosexual contacts account for the largest proportion of new diagnoses. In 2014, 1081 new diagnoses of HIV were made in Australia,27 while 224 new diagnoses were made in New Zealand.29 The annual rate of new diagnoses in both countries had remained stable for many years but gradually increased in the period 2002–2014. Complacency regarding safe sex practices is considered to be a major contributing factor to the rise in new cases particularly amongst homosexual males. Indigenous populations have shown similar rates of HIV infections to non-Indigenous populations
TABLE 15.6 Possible transmission routes of HIV infection ROUTES
Inoculation in blood
Transfusion of blood and blood products Needle-sharing among intravenous drug users
• Systemic lupus erythematosus • Down syndrome
It is estimated that only 54% of people with HIV know their status.25 More people living with HIV are receiving antiretroviral therapy and the UNAIDS Fast-Track Strategy to end AIDS by 2030 has resulted in 17 million people being treated with antiretroviral therapy in 2015. Consequently, the number of AIDS-related deaths has decreased by 43% since 2003.24 In Oceania, which contains both Australia and New Zealand, an estimated 80 000 individuals are living with HIV.26–28 Most of the region has a relatively small number of HIV-infected individuals compared with other regions;
SPECIFIC TRANSMISSION
Known routes of transmission
Needlestick, open wound and mucous membrane exposure in healthcare workers Tattoo needles Sexual transmission
Anal and vaginal intercourse
Perinatal transmission Intrauterine transmission Peripartum transmission Breast milk
Routes not involved in transmission Close personal contact
Household members Healthcare workers not exposed to blood
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Men who have sex with men Heterosexual sex Men who have sex with men or injection drug use Injecting drug use Undetermined
0
10
20
30
40
50
60
70
80
Proportion of new HIV cases diagnosed FIGURE 15.11
The percentage of new diagnosed cases of HIV infection in Australia.
but a greater percentage of infections have been attributed to sharing needles than in non-Indigenous populations. Heterosexual transmission of HIV was also higher in Indigenous populations.27,28 However, overall the rates of HIV infection are low compared to other Western countries and reflect the effectiveness of public health campaigns instituted as early as 1987. PATHOGENESIS
HIV is a member of a family of viruses called retroviruses, which carry genetic information in the form of RNA rather than DNA. Retroviruses use a viral enzyme, reverse transcriptase, to convert RNA into double-stranded DNA. Using a second viral enzyme, an integrase, the new DNA is inserted into the infected cell’s genetic material, where it may remain dormant. If the cell is activated, translation of the viral information may be initiated, resulting in the formation of new virions, lysis and death of the infected cell, and shedding of infectious HIV particles. If, however, the cell remains relatively dormant, the viral genetic material may remain latent for years and is probably present for the life of the individual (see Fig. 15.12). The primary surface receptor on HIV is the envelope protein gp120, which binds to the molecule CD4 on the surface of helper T cells. Several other necessary co-receptors have been identified on target cells. However, the major immunological finding in AIDS is the striking decrease in the number of CD4+ helper T cells (see Fig. 15.13). Individuals who are not HIV-infected typically have a range of 600–1200 CD4+ cells per cubic millimetre of blood (count/ mm3). In individuals with HIV the initial decline reduces
the CD4+ count to about 500–600/mm3 and generally the CD4+ count declines as HIV disease progresses. The count is often used as a guide to initiating and monitoring treatment. CLINICAL MANIFESTATIONS
Depletion of CD4+ cells has a profound effect on the immune system, causing a severely diminished response to a wide array of infectious pathogens and malignant tumours (see Box 15.1). At the time of diagnosis, the individual may present with one of several different conditions: serologically negative (no detectable antibody); serologically positive (positive for antibody against HIV) but asymptomatic; or early stages of HIV disease or AIDS (see Fig. 15.14 A, B). The presence of circulating antibody against the HIV indicates infection by the replicating virus, although many of these individuals are asymptomatic. Antibody appears rather rapidly after infection through blood products, usually within 4–7 weeks. After sexual transmission, however, the individual can be infected yet seronegative for 6–14 months or, in at least one case, for years. The period between infection and the appearance of antibody is referred to as the window period. Although an individual may not have antibody, they may have virus growing, have virus in the blood and body fluids, and be infectious to others. Those with the early stages of HIV disease (early-stage disease) usually present with relatively mild symptoms resembling influenza, such as night sweats, swollen lymph glands, diarrhoea or fatigue. The early stage may last as long as 10 years. Although individuals appear to be in clinical
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Virion binding to CD4 and chemokine receptor
New HIV virion
Fusion of HIV membrane with host cell membrane; entry of viral genome into cytoplasm
HIV virion Chemokine receptor
HIV gp120/ gp41 Cytokine Cytokine receptor
Plasma membrane
Budding and release of mature virion
HIV RNA genome
CD4 Entrance inhibitors Reverse transcriptase inhibitors
Reverse transcriptase
Proviral DNA Integrase inhibitors
Cytokine activation of cell; transcription of HIV genome; transport of viral RNAs to cytoplasm
Integration of provirus into host cell genome
Nucleus
HIV DNA provirus
Synthesis of HIV proteins; assembly of virion core
HIV core structure Protease inhibitors
HIV RNA transcript
FIGURE 15.12
The life cycle and possible sites of therapeutic intervention of human immunodeficiency virus. The HIV virion consists of a core of two identical strands of viral RNA encoated in a protein structure with viral proteins gp41 and gp120 on its surface (envelope). HIV infection begins when a virion binds to CD4 and chemokine co-receptors on a susceptible cell and follows the process described here. The provirus may remain latent in the cell’s DNA until it is activated (e.g. by cytokines). The HIV life cycle is susceptible to blockage at several sites (see the text for further information) including entrance inhibitors, reverse transcriptase inhibitors, integrase inhibitors and protease inhibitors.
BOX 15.1
AIDS-defining opportunistic infections and neoplasms found in HIV-infected individuals
Infections Protozoal and helminthic infections Cryptosporidiosis or isosporiasis (enteritis) Pneumocystosis (pneumonia or disseminated infection) Toxoplasmosis (pneumonia or central nervous system infection) Fungal infections Candidiasis (oesophageal, tracheal or pulmonary) Cryptococcosis (central nervous system infection) Coccidioidomycosis (disseminated) Histoplasmosis (disseminated) Bacterial infections Mycobacteriosis (atypical, e.g. M. avium-intracellulare, disseminated or extrapulmonary; M. tuberculosis, pulmonary or extrapulmonary)
Nocardiosis (pneumonia, meningitis, disseminated) Salmonella infections (disseminated) Viral infections Cytomegalovirus (pulmonary, intestinal, retinitis or central nervous system infections) Herpes simplex virus (localised or disseminated) Varicella zoster virus (localised or disseminated) Progressive multifocal (leucoencephalopathy) Neoplasms Kaposi’s sarcoma B cell non-Hodgkin’s lymphomas Primary lymphoma of the brain Invasive cancer of the uterine cervix
CHAPTER 15 Alterations of immune function across the life span
CD4 cell
HIV
CD4 cell +
Impaired immune activation
+
Decreased lymphokine production Loss of stimulus for T and B cell activation Impaired cytotoxic activity
CD8+ cell
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Lymphopenia Decreased CD4+/CD8+ cell ratio Decreased delayed hypersensitivity
Impaired feedback Decreased chemotaxis and phagocytosis Diminished IL-1 production
Macrophage
Impaired presentation of antigen to T cells Diminished antibody production in response to antigen
B– cell
Production of immunoglobin
Increased susceptibility to opportunistic and other infections
Nonspecific increased serum immunoglobin
FIGURE 15.13
A summary of HIV infection on the immune system. HIV infection causes impairment of the immune response, leading to loss of activation of T and B cells, and decreased production of antibodies.
latency, the virus is actively proliferating in the lymph nodes (see Fig. 15.15). The currently accepted definition of AIDS relies on both laboratory tests and clinical symptoms. The most common laboratory test is for antibodies against HIV. If the individual is seropositive, the diagnosis of AIDS is made in association with various clinical symptoms (see Box 15.1 and Fig. 15.16). The symptoms include atypical or opportunistic infections and cancers, as well as indications of debilitating chronic disease (e.g. wasting syndrome, recurrent fevers). Most commonly, new cases of AIDS are diagnosed initially by decreased CD4+ T cell numbers. The average time from infection to development of AIDS has been estimated at just over 10 years. Some estimates are that approximately 99% of untreated HIV-infected individuals will eventually progress to AIDS. As the disease progresses, body systems become increasingly affected (see Fig. 15.17). Neurological and cardiac complications are detailed in Box 15.2. TREATMENT AND PREVENTION
The current regimen for treatment of HIV infection is a combination of drugs, termed highly active antiretroviral therapy (HAART). The combination includes inhibitors of
viral enzymes that are used in different stages of the replication of the human immunodeficiency virus in CD4+ helper T cells — reverse transcriptase inhibitors, integrase inhibitors and protease inhibitors (see Fig. 15.12). The clinical benefits of HAART are profound and durable. Death from AIDS-related diseases has been reduced significantly since the introduction of HAART. However, resistant variants to these drugs have been identified. Drug therapy for AIDS is difficult because, like most retroviruses, the AIDS virus incorporates into the genetic material of the host and may never be removed by antimicrobial therapy. Therefore, drug administration to control the virus may have to continue for the lifetime of the individual. Additionally, HIV may persist in regions where the antiviral drugs are not as effective, such as the central nervous system. Inhibitors of the initial viral entry into the target cell (entry or fusion inhibitors and chemokine receptor antagonists) may also be used in the combination.30 Vaccine development for preventing HIV infection is ongoing. Most of the common viral vaccines (e.g. rubella, mumps, influenza) induce protective antibodies that block the initial infection. Only one vaccine (rabies) is used after the infection has occurred. That approach is successful
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A CD4+ T cells
1200 1100 1000 900 800 700 600 500 400 300 200 100 0
B B Possible acute HIV syndrome Death Wide dissemination of virus Seeding of lymphoid organs Opportunistic 1:512 diseases 1:256 Clinical latency
Anti-envelope antibody
1:128
Anti-p24 antibody
1:64 Constitutional symptoms
1:32 1:16 1:8
CTLs specific for HIV peptides
1:4 1:2 0 3 6 9 12 Weeks
1 2 3 4 5 6 7 8 9 10 11 Years
0
0
3 6 9 12 Weeks
2
4
Viral particles in plasma 6
8 10 12 14 16 Years
Levels of virus in plasma CD4 T cells/mm3 FIGURE 15.14
Typical progression from HIV infection to AIDS in untreated individuals. A Clinical progression begins within weeks after infection; the person may experience symptoms of acute HIV syndrome. During this early period, the virus progressively infects T cells and other cells and spreads to the lymphoid organs, with a sharp decrease in circulating CD4+ T cells. During a period of clinical latency, the virus replicates and T cell destruction continues, although the person is generally asymptomatic. The individual may develop HIV-related disease (constitutional symptoms) — a variety of symptoms of acute viral infection that do not involve opportunistic infections or malignancies. When the number of CD4+ cells is critically suppressed, the individual becomes susceptible to a variety of opportunistic infections and cancers with a diagnosis of AIDS. The length of time for progression from HIV infection to AIDS may vary considerably from person to person. B Laboratory tests are changing throughout infection. Antibody and Tc cell (cytotoxic T lymphocytes (CTLs)) levels change during the progression to AIDS. During the initial phase, antibodies against HIV-1 are not yet detectable (window period), but viral products, including proteins and RNA, and infectious virus, may be detectable in the blood a few weeks after infection. Most antibodies against HIV are not detectable in the early phase. During the latent phase of infection, antibody levels against p24 and other viral proteins, as well as HIV-specific CTLs, increase, then remain constant until the development of AIDS.
because the rabies virus proliferates and spreads very slowly. Whether an HIV vaccine would successfully prevent or treat HIV infection is questionable for several reasons. First, HIV is genetically and antigenically variable, like the influenza virus, so that a vaccine created against one variant may not provide protection against another variant. Second, although individuals with AIDS have high levels of circulating antibodies against the virus, these antibodies do not appear to be protective. Therefore, even if a circulating antibody response can be induced by vaccination, that response might not be effective.
FOCU S ON L EA RN IN G
1 Provide a list of secondary immunodeficiencies differentiating between minor and severe conditions. 2 Describe the human immunodeficiency virus (HIV). 3 Outline the pathogenesis of acquired immunodeficiency syndrome (AIDS) from initial transmission of HIV. 4 Name the opportunistic infections that may arise in an individual with HIV. 5 Describe the current treatment strategies for HIV infection.
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Brain macrophages (microglial cells)
Brain glial cells
Lymph nodes
Thymus gland Bone marrow
Lung, alveolar macrophages
Colon, duodenum and rectum enterochromaffin cells
Skin, Langerhans’ cells
Lymphocytes in blood, semen and vaginal fluid
Bone marrow
FIGURE 15.15
The distribution of tissues that can be infected with HIV. HIV can infect various body systems, particularly the lymph nodes and the reproductive system. This later progresses to infecting tissues throughout the body, including the nervous system and respiratory system.
A
A B
A C
FIGURE 15.16
Clinical manifestations of acquired immunodeficiency syndrome (AIDS). A Kaposi’s sarcoma lesions over chest and arms. B Perianal lesions of herpes simplex infection. C Herpes zoster infection.
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CENTRAL NERVOUS SYSTEM • Meningitis • Encephalitis • AIDS dementia MOUTH • Herpes labialis • Thrush
LUNGS • Pneumonia
SMALL INTESTINE • Malabsorption LARGE INTESTINE • Colitis • Proctitis
LYMPH NODES • Lymphadenopathy
TUMOURS • Lymphoma
• AIDS nephropathy
• Kaposi’s sarcoma
SKIN • Dermatitis • Folliculitis • Impetigo
FIGURE 15.17
Systemic changes associated with acquired immunodeficiency syndrome (AIDS). Symptoms associated with AIDS include nervous system infection and dementia, pneumonia, Kaposi’s sarcoma, and lymphatic cancers.
BOX 15.2
Complications of AIDS
Neurological complications Some 40–60% of all individuals with AIDS have neurological complications. The most common neurological disorder is HIVassociated cognitive dysfunction (HIV encephalopathy). It may affect adults or children and is characterised by progressive cognitive dysfunction with motor and behavioural alterations. The syndrome typically develops later in the disease, but may be an early or singular manifestation in some individuals. It is believed that HIV-associated cognitive dysfunction results from direct brain tissue infection by the virus. HIV is found mostly in white matter subcortical areas causing an immune demyelinating-mediated process (literally, stripping the myelin), but some viral replication occurs in glial cells (central nervous system support cells) and, occasionally, neurons. The cognitive dysfunction is insidious in onset and unpredictable in its course. Most individuals experience a steady progression with abrupt accelerations of signs over several months to more than 1 year, although some individuals experience an abrupt onset or an accelerated course. Early clinical manifestations may be vague. Impaired concentration and memory deficits are common, and apathy, lack of motivation, social withdrawal, irritability and emotional lability appear. Later, difficulties with language, spatial or temporal disorientation and visual construction are present. Diagnosis is difficult, especially in early stages. A history with physical examination findings and supporting cerebrospinal fluid, CT scan and MRI data help establish the diagnosis. Treatment consists of antiviral agents and supportive measures.
CHAPTER 15 Alterations of immune function across the life span
BOX 15.2
379
Continued
Cardiac complications Individuals infected with HIV and AIDS are at risk for cardiac complications, including dilated cardiomyopathy, myocarditis, pericardial effusion, endocarditis, pulmonary hypertension and non-antiretroviral drug-related cardiotoxicity. In addition to HIV infection, cardiac involvement may be induced by the accompanying inflammatory response or by various bacterial, viral, protozoan, mycobacterial and fungal pathogens. Malignancies, such as lymphoma and Kaposi’s sarcoma, are often seen in individuals with AIDS and can affect the heart. Furthermore, treatment with highly active antiretroviral therapy (HAART) can cause hyperlipidaemia and atherosclerotic disease. Left heart failure is the most common complication of HIV infection and is related to left ventricular dilation and dysfunction. Pericardial effusion, ventricular arrhythmias, electrocardiographic changes and right ventricular dilation and hypertrophy are other less common findings. Opportunistic infections Opportunistic infections may be bacterial, fungal or viral in origin and may produce disease. Typically, bacterial infections are caused by unusual microorganisms. Cryptococcal infection is the most common fungal disorder and the third leading cause of neurological disease in individuals with AIDS. The symptoms are vague, such as fever, headache and malaise. Cytomegalovirus encephalitis is common in persons with AIDS. Toxoplasmosis (a protozoal infection) is a common central nervous system disorder that occurs in one-third of those with AIDS.
Allergic conditions have increased in prevalence in the last two decades in most countries, including Australia and New Zealand, and particularly in young children. Food allergy is the most common allergy in the first years of life, followed by eczema, asthma and allergic rhinitis. Food hypersensitivities can manifest as atopic dermatitis, gastrointestinal disturbances and asthma. The most common food allergies are to egg, peanut and milk. Of particular concern is the increase in prevalence of peanut allergy which is potentially fatal due to anaphylaxis. Peanut allergy is an IgE-mediated hypersensitivity reaction and can be diagnosed by skin prick testing, peanut-specific IgE levels and clinical history. The majority of food allergies and anaphylactic reactions occur in pre-school age children. However, the greater
the age of the child the greater the risk of fatality. Other factors affecting the risk of anaphylaxis include the type of food, the amount of food eaten, if the child exercises soon after eating and the presence of asthma. Despite the potential risk of anaphylaxis the majority of food allergies, including peanut allergy, do not always result in an anaphylactic reaction. In preschool age children the tendency to exchange food is high so preschools or other childcare services recommend that no child brings foods that are highly allergenic such as egg and nut products. Children who are known to be allergic to cow’s or goat milk must be carefully supervised.
PAEDIATRICS
Paediatrics and alterations of immune function
Ageing and alterations of immune function factor to immunosenescence as the thymus is involved in the production of T lymphocytes which play a vital role in both cellular and humoral immunity. Haematopoiesis in the bone marrow declines with ageing as well as lymphocyte maturation and migration, resulting in decreased numbers of new naive T and B lymphocytes. Memory cell competence also declines. Studies in the elderly have shown that there is reduced natural killer cell cytotoxicity and reduced number and function of dendritic cells.
AGEING
Immune function gradually declines with increasing age rendering the elderly more susceptible to infections and to the development of various cancers. Healing is slower and responses to vaccines are reduced. Autoimmune reactions are increased. This age-related decline in immune function is known as immunosenescence. Both cell-mediated immune responses and humoral immune responses decline. The continuing atrophy of the thymus gland that began in early adulthood is considered to be a contributing
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chapter SUMMARY Hypersensitivity reactions • Hypersensitivity is an inappropriate immune response misdirected against the host’s own tissues or directed against beneficial foreign tissues, such as transfusions or transplants; or it can be an exaggerated response against environmental antigens (allergy). • Mechanisms of hypersensitivity are classified as type I IgE-mediated hypersensitivity reactions, type II tissuespecific hypersensitivity reactions, type III immune complex-mediated hypersensitivity reactions and type IV cell-mediated hypersensitivity reactions. • Hypersensitivity reactions can be immediate (developing within seconds or hours) or delayed (developing within hours or days). • Anaphylaxis, the most rapid immediate hypersensitivity reaction, is an explosive reaction that occurs within minutes of re-exposure to the antigen and can lead to cardiovascular shock. • Allergens are antigens that cause allergic responses. • Type I hypersensitivity reactions occur after antigen reacts with IgE on mast cells, leading to mast cell degranulation and the release of histamine and other inflammatory substances. • Type II hypersensitivity reactions are caused by four possible mechanisms: complement-mediated lysis; opsonisation and phagocytosis; antibody-dependent cell-mediated cytotoxicity; and modulation of cellular function. • Type III hypersensitivity reactions are caused by the formation of immune complexes that are deposited in target tissues, where they activate the complement cascade, generating chemotactic fragments that attract neutrophils into the inflammatory site. • Type IV hypersensitivity reactions are caused by specifically sensitised T cells, which either kill target cells directly or release lymphokines that activate other cells, such as macrophages. • Allergies can be mediated by any of the four mechanisms of hypersensitivity. • Clinical manifestations of allergic reactions are usually confined to the areas of initial intake or contact with the allergen. Ingested allergens induce gastrointestinal symptoms, airborne allergens induce respiratory or skin manifestations and contact allergens induce allergic responses at the site of contact.
Transplantation • Transplantation of organs into a host causes an immune response. A transplant rejection can be hyperacute, acute or chronic, depending on the amount of time that elapses between transplantation and rejection.
• Blood groups (ABO and Rhesus) can be targets of immune reactions, if individuals are transfused with noncompatible blood groups.
The ABO blood group system • There are four ABO blood groups: O, A, B and AB. • Individuals have naturally occurring antibodies to ABO blood group antigens in their plasma according to their ABO blood group. • Because administration of an incompatible ABO blood transfusion is potentially fatal, the ABO blood group system is the most clinically important. • The Rh system is the second most clinically important blood group system. • Blood group O Rh-negative is known as the universal donor as it can be safely transfused to individuals of any ABO and Rh blood group.
Autoimmune diseases • Autoimmunity is a disturbance in the immunological tolerance of self-antigens. The immune system is normally able to distinguish the individual’s own antigens against foreign antigens. • The exact mechanisms for autoimmune diseases are unknown.
Immune deficiencies • Immunodeficiency is the failure of mechanisms of selfdefence to function in their normal capacity. • Immunodeficiencies are either primary (congenital) or secondary (acquired). Primary immunodeficiencies are caused by genetic defects that disrupt lymphocyte development, whereas acquired immunodeficiencies are secondary to disease or other physiological alterations. • The clinical hallmark of immunodeficiency is a propensity to unusual or recurrent severe infections. The type of infection usually reflects the immune system defect. • The most common infections in individuals with defects of cell-mediated immune response are fungal and viral, whereas infections in individuals with defects of the humoral immune response or complement function are primarily bacterial. • Severe combined immunodeficiency is a total lack of T cell function and a severe (either partial or total) lack of B cell function. • Defects in B cell function are diverse, ranging from a complete lack of the human bursal equivalent, the lymphoid organs required for B cell maturation, to deficiencies in a single class of immunoglobulins.
CHAPTER 15 Alterations of immune function across the life span
• Acquired immunodeficiencies are caused by superimposed conditions, such as malnutrition, medical therapies, physical or psychological trauma or infections. • Acquired immunodeficiency syndrome (AIDS) is an acquired dysfunction of the immune system caused by a retrovirus (human immunodeficiency virus (HIV)) that infects and destroys CD4+ lymphocytes (helper T cells). • Therapy for HIV infection consists of a combination of drugs to control the virus. Supportive therapy (e.g. antibiotics) is prescribed when individuals contract AIDS infections and malignancies.
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Paediatrics and alterations of immune function • Allergic conditions have increased in prevalence particularly in young children. • The majority of food allergies and anaphylactic reactions occur in pre-school age children. • The majority of food allergies, including peanut allergy, are not anaphylactic.
Ageing and alterations of immune function • Immune function gradually declines with increasing age rendering the elderly more susceptible to infections and to the development of various cancers.
CASE STUDY
P A EDIATR IC Bo is 13 months old and has eczema (atopic dermatitis). His parents first noticed that he had very dry skin and a red rash on his cheeks at the age of 5 months and he was diagnosed with infantile eczema by a paediatrician shortly afterwards. Now that Bo is a little older he often scratches the areas of dry, red skin which makes the condition worse and his parents are aware that they need to be vigilant in keeping Bo’s fingernails short to avoid further aggravation. Bo’s parents have also noticed that Bo’s eczema often flares up after eating foods containing eggs and have considered consulting a practising
dietitian with specialised knowledge of food allergies to avoid these flare-ups. 1 What type of hypersensitivity reaction is atopic dermatitis (eczema)? 2 Can eczema (atopic dermatitis) be associated with other hypersensitivity reactions? 3 Does infantile eczema have a better prognosis than childhood eczema and/or adult eczema? Discuss. 4 What triggers can aggravate atopic dermatitis? 5 Compare atopic dermatitis with contact dermatitis.
CASE STUDY
ADULT Aisha is 19 years old and is allergic to the antibiotic, penicillin. She was exposed to penicillin as a child (aged 5) when it was prescribed to treat streptococcal pharyngitis (strep throat), an infection caused by Group A streptococci. At the time she developed a whole body rash and had itchy skin — she did not have skin testing but was informed that an allergic reaction to penicillin was the most likely cause. Aisha is currently in hospital after being involved in a motor vehicle accident. She was trapped in the vehicle and sustained a fractured right femur requiring orthopaedic surgery. Her medical notes clearly document that she is allergic to penicillin. On returning to the ward after an open reduction and internal fixation to correct the fractured femur Aisha is prescribed cefazolin (intravenously), a cephalosporin antibiotic with some similarities to penicillin. Shortly after the administration of
the first dose of cefazolin she rings her buzzer, and the nurse immediately notices that she has a rash, an audible wheeze, angio-oedema and pale skin. Her blood pressure is low, heart rate is elevated and her breathing rapid and shallow. An emergency is called and Aisha is successfully resuscitated using adrenaline. 1 Discuss the likely allergic reaction that Aisha experienced. 2 Explain why the systemic signs and symptoms manifest following infusion of the antibiotic. 3 Describe why the first time Aisha was given penicillin she did not experience a similar allergic reaction to the one she experienced in hospital. 4 Why is it particularly important to administer antibiotics for Group A streptococcal infections? 5 Explain why cefazolin caused Aisha to have an allergic reaction.
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CASE STUDY
A GEING Reg is 75 years old and lives alone. He woke one morning with a cough, sore throat, runny nose, chills, fever and aching muscles. Reg called his daughter who said he had the ‘flu’ and told him to stay in bed. When Reg’s daughter arrived to visit a few hours later she found him confused and agitated and he was extremely unwell. An ambulance was called and Reg was admitted to hospital. Reg was diagnosed with seasonal influenza and was placed on fluids.
1 2 3 4 5
Explain why the elderly develop more infections of this type. What measures should the elderly take to prevent infections? Are antibiotics useful in treating influenza? Is Reg likely to have recurrence of the flu? Explain your answer. Will Reg’s immune system be able to produce antibodies in response to the influenza virus that will protect him from subsequent infections?
REVIEW QUESTIONS 1 Describe hypersensitivity reactions and the effects of the immune system response. 2 Explain what allergens are and name some potential sources. 3 List the 4 different hypersensitivities and the common features of each. 4 Describe why the immune system rejects foreign tissues transplanted into the body. 5 Explain the different blood groups and which individuals can receive which types of donor blood.
6 Discuss how autoimmunity is thought to arise. How is it related to hypersensitivity reactions? 7 Explain how primary autoimmune diseases affect B and T cells and complement and phagocytic activity. 8 List 5 different reasons why secondary immune deficiencies occur. Describe the difference between life-threatening and clinically harmless deficiencies. 9 Describe how human immunodeficiency virus (HIV) can enter the body and how it infects its host. 10 Discuss drug therapy relevant to HIV infection.
Key terms albumin, 384 antithrombin III, 401 coagulation, 384 colony-stimulating factors, 391 erythrocytes, 387 erythropoiesis, 392 fibrinolysis, 402 globulins, 384 haematopoiesis, 390 haemocytoblasts, 391 haemoglobin (Hb), 387 haemorrhage, 399 haemostasis, 397 heparin, 385 leucocytes, 387 leucopoiesis, 396 lymph nodes, 390 marginating storage pool, 391 mononuclear phagocyte system, 390 plasma, 384 platelets, 388 serum, 385 spleen, 389 thrombopoiesis, 396 thrombosis, 399
CHAPTER
The structure and function of the haematological system
16
Lynne Hendrick Chapter outline Introduction, 384 Components of the haematological system, 384 The composition of blood, 384 Lymphoid organs, 388 The mononuclear phagocyte system, 390 The development of blood cells, 390 Haematopoiesis, 390 The development of erythrocytes, 392
The development of leucocytes, 396 The development of platelets, 396 The mechanisms of haemostasis, 397 The function of platelets and blood vessels, 397 The function of clotting factors, 399 Natural substances that limit coagulation and platelet plug formation, 400 Clot retraction and fibrinolysis, 402 Ageing and the haematological system, 404
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Introduction Blood is essential for life. It consists of different types of blood cells suspended in a fluid known as plasma and is the only fluid tissue in the body. Therefore it can be considered as a specialised connective tissue despite the lack of collagen and elastin fibres that are typical of other connective tissues. An adequate supply of oxygen and nutrients is required for the survival of all body cells, and blood provides these substances to all of the body’s tissues and organs. It also transports carbon dioxide and other cellular waste products so that they can be removed from the body — waste products must be removed to prevent toxic effects. Red blood cells are the most numerous blood cells, accounting for the red appearance of blood. Oxygen diffuses from the lungs to the red blood cells to be used at body tissues, while carbon dioxide diffuses from the tissues to the red blood cells to be eliminated at the lungs. The plasma portion of blood transports the nutrients and waste products. In addition, it also contains a number of proteins involved in blood clotting. A number of different types of white blood cells provide protection from foreign invaders such as bacteria and viruses. Platelets are the smallest cellular component of the blood and are involved in preventing blood loss if blood vessels are injured. Blood flows through kilometres of vessels wound throughout the body and blood cells must adapt to the different conditions found in arteries, veins and capillaries. Like all cells in the body, blood cells have a limited life span. The spleen is an important organ in the haematological system and it is responsible for removing the majority of old or non-functional blood cells. Blood cells are manufactured in the bone marrow and under normal circumstances this process is tightly controlled so that cell production is equal to cell loss. An increase or decrease in the rate of blood cell production can occur in response to various physiological challenges or can be a primary cause of haematological disease. We start by examining what blood is made of, particularly the different cells that perform an enormous number of functions essential for homeostasis.
Components of the haematological system The composition of blood
Blood consists of various cells that circulate in the cardiovascular system suspended in plasma, which is approximately 90% water and 10% dissolved substances (solutes). The blood volume of an adult is approximately 8% of body weight or roughly 70 mL/kg. This amounts to about 4.9 L in a 70 kg adult. The continuous movement of blood around the body guarantees that critical components are available to carry out their chief functions: • delivery of substances needed for cellular metabolism in the tissues
• removal of the wastes of cellular metabolism • defence against invading microorganisms and injury • maintenance of the acid–base balance. Each of these functions is essential in contributing to homeostasis of the body.
Plasma and plasma proteins
In adults, plasma accounts for 50–55% of blood volume (see Fig. 16.1). Plasma consists of water and a variety of organic (e.g. proteins) and inorganic (e.g. electrolytes) substances. The concentration of these substances varies depending on diet, metabolic demand, hormones and vitamins. Plasma contains a large number of different plasma proteins that vary in structure and function, most of which are produced by the liver. The most abundant plasma protein is albumin (about 60% of total plasma protein). Albumin serves as a carrier molecule both for the normal components of blood and for drugs. A hormone or drug carried through the blood on albumin effectively becomes larger-sized and is therefore less able to be metabolised or filtered out of the bloodstream. In addition to albumin, other transport proteins specifically bind and carry a variety of substances including iron (transferrin), lipids and steroid hormones (lipoproteins) and vitamins (e.g. retinol-binding protein). The most essential role of albumin is control of the passage of water and solutes through the capillaries. Albumin molecules are large and do not diffuse freely through the vascular endothelium; thus they maintain the critical colloidal osmotic pressure (or oncotic pressure) that regulates the passage of water and solutes into the surrounding tissues (see Chapter 22). In the case of decreased production (e.g. some liver diseases such as cirrhosis) or excessive loss of albumin (e.g. certain kidney diseases), the reduced oncotic pressure leads to excessive movement of fluid and solutes into the tissue (oedema) and decreased blood volume. Another important group of plasma proteins is the globulins. These are not all produced in the liver — immunoglobulins are produced by plasma cells in the lymph nodes and other lymphoid tissues. Plasma cells develop from immunologically stimulated B lymphocytes. These globulins are specific to the function of the immune system and were discussed in Chapter 12. Other proteins are involved in defence or protection against infection, including other antibodies and complement proteins. One other essential constituent of plasma is the numerous clotting factors (which are proteins) that promote coagulation and stop bleeding from damaged blood vessels. Fibrinogen is the most plentiful of the clotting factors and is the precursor of the fibrin clot. The processes involved in blood clotting are discussed fully in the following sections. Plasma also contains ions (electrolytes) that participate in the control of cell function, osmotic pressure and blood pH. These include sodium, potassium, calcium, chloride
CHAPTER 16 The structure and function of the haematological system Percentage by body weight
Plasma (percentage by weight) Proteins 6%
Other fluids and tissues 92%
Percentage by volume Water 92%
385
Albumins 58% Globulins 38% Fibrinogen 4% Ions
Blood 8%
Nutrients
Plasma 55%
Other solutes 2%
Gases
Formed elements (number per mL) Formed elements 45%
Waste products
Platelets 150–450 thousand Leucocytes 4–11 thousand
Regulatory substances Leucocytes Neutrophils 54–67% Lymphocytes 25–36% Monocytes 3–8%
Erythrocytes 4.5–6.5 million
Eosinophils 1–4% Basophils 0.75–1%
FIGURE 16.1
The composition of whole blood. Approximate values for the components of blood in a normal adult.
and phosphate. Electrolytes are discussed in Chapters 1 and 29. PLASMA VERSUS SERUM
There is a significant difference between plasma and serum. Plasma is the fluid in which blood cells are suspended as blood flows around the body, whereas serum is the fluid that can be separated from blood cells after blood has been allowed to clot. Hence serum is similar to plasma except that the clotting factors (especially fibrinogen) have been consumed in the process of clot formation. Knowing the distinction between plasma and serum is important with regard to collecting blood samples for pathology tests. Some blood tests require serum, whereas others need plasma. In addition, some tests require anticoagulated whole blood as the testing material. Serum samples are required for certain laboratory tests that may be affected by the presence of fibrinogen. In order to obtain serum, a blood sample collected from a patient is placed in a plain tube. The blood in the tube will clot over time. After the blood has clotted, the tube is centrifuged
(spun at very high speed) to allow the blood cells and fluid portions to separate. The cells will occupy the lower half of the tube, while the fluid will occupy the top half — this fluid is the serum. Where plasma or whole blood is required, blood samples are collected in tubes that contain an anticoagulant to prevent the blood from clotting. When the tube is centrifuged, the fluid that separates from the blood cells is plasma. Some anticoagulants, such as EDTA (ethylene diamine tetra acetic acid) and sodium citrate, work by binding to calcium, thereby making the calcium unavailable for the blood-clotting process. Hence, when calcium is bound to the anticoagulant, clotting cannot occur. Heparin, another type of anticoagulant used in blood collection tubes, works by binding to and activating antithrombin III (a substance naturally present in the blood) to create a potent anticoagulant. The details of the anticoagulant contained within a tube are written on an exterior label on the tube. The tubes also have colour-coded caps (tops) for ease of identification. Anticoagulants that are commonly used for different types of blood tests include:
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• EDTA (purple top) — used for full blood counts • sodium citrate (light blue top) — used for coagulation studies • serum separation tube (yellow top) — used for electrolytes, liver function tests, endocrine studies • lithium heparin (green top) — used for many biochemistry and haematology tests. It is important that blood collection tubes containing an anticoagulant are filled with the correct amount of blood (indicated by a fill line on the side of the tube). Overfilled or underfilled tubes will have an incorrect RED BLOOD CELLS (ERYTHROCYTES)
concentration of anticoagulant in the sample (i.e. the proportion of anticoagulant to the proportion of blood) and this may affect the test results, especially for blood-clotting studies.
Cellular components of blood
The cellular elements of blood are broadly classified as red blood cells (erythrocytes), white blood cells (leucocytes), which have several different types, and platelets (thrombocytes) (see Fig. 16.2). The components of blood are listed in Table 16.1. PLATELETS (THROMBOCYTES)
WHITE BLOOD CELLS (LEUCOCYTES) Granular leucocytes
Basophil
Neutrophil
Eosinophil
Agranular leucocytes
Lymphocyte
Monocyte
FIGURE 16.2
The formed elements of blood. Red blood cells (erythrocytes), white blood cells (leucocytes) and platelets (thrombocytes) constitute the formed elements of blood.
TABLE 16.1 Cellular components of blood CELL
Erythrocyte (red blood cell)
STRUCTURAL CHARACTERISTICS
NORMAL AMOUNTS OF CIRCULATING BLOOD
FUNCTION
Nonnucleated Gas transport to and from tissue Males: 4.5–6.5 × 1012/L cytoplasmic disc cells and lungs 12 containing haemoglobin Females: 3.8–4.8 × 10 /L
LIFE SPAN
80–120 days
Leucocyte (white Nucleated cell blood cell)
4–11 × 109/L
Body defence mechanisms
Depends on type
Lymphocyte
25–36% of leucocyte count
Humoral and cell-mediated immunity
Days or years, depending on type
Natural killer cell Large granular lymphocyte
5–10% circulatory pool (some in spleen)
Defence against some tumours and viruses
Unknown
Monocyte and macrophage
Large mononuclear phagocyte
3–8% of leucocyte count
Phagocytosis; mononuclear phagocyte system
Months or years
Eosinophil
Segmented granulocyte
1–4% of leucocyte count
Control of inflammation, phagocytosis, defence against parasites, allergic reactions
Unknown
Neutrophil
Segmented granulocyte
54–67% of leucocyte count
Phagocytosis, particularly during early phase of inflammation
4 days
Basophil
Segmented granulocyte
0–0.75% of leucocyte count
Mast cell-like functions, associated with allergic reactions and mechanical irritation
Unknown
Platelet
Irregularly shaped cytoplasmic fragment (not a cell)
150–450 × 109/L
Haemostasis after vascular injury; normal coagulation and clot formation/retraction
8–11 days
Mononuclear immunocyte
CHAPTER 16 The structure and function of the haematological system
ERYTHROCYTES
Erythrocytes (red blood cells) are the most abundant cells of the blood, occupying approximately 48% of the blood volume in men and about 42% in women. The volume of blood occupied by red cells is known as the haematocrit or packed cell volume. It can be expressed as a percentage or as a ratio between red blood cells and whole blood. The two ways of expressing the haematocrit are easily interchangeable — 48% is the same as 0.48. The 0.48 refers to 0.48 litres of red cells per litre of whole blood. The actual number of erythrocytes is approximately 4.5–6.5 × 1012 per litre of blood in males; the value is slightly lower for females (see Table 16.1). Erythrocytes are primarily responsible for tissue oxygenation. Haemoglobin (Hb) is a specialised protein contained within erythrocytes that carries the gases oxygen and carbon dioxide. Mature erythrocytes lack a nucleus and other cytoplasmic organelles (such as mitochondria), so they cannot produce proteins or carry out the variety of cellular functions that a complete cell performs. Also, they cannot undergo mitotic division because they have no nucleus — hence they have a limited life span of approximately 120 days. Aged or damaged erythrocytes are removed from the circulation and replaced by new cells produced in the bone marrow. The erythrocyte’s size and shape are ideally suited to its function as a gas carrier. It is a small disc (see Fig. 16.3) approximately 6–8 µm in diameter (1 mm = 1000 µm) with two unique properties: • a biconcave shape • the capacity to be reversibly deformed. The flattened biconcave shape provides a relatively large surface area that is optimal for gas diffusion into and out of the cell, as there is effectively more cell membrane for the volume of the cell than there would be if the same cell
FIGURE 16.3
A scanning electron microscopy image of an erythrocyte. Red cells are smooth and concave.
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were spherical. During its life span, the erythrocyte repeatedly circulates throughout the entire circulatory system, including through leaky blood vessels in the splenic sinusoids and capillaries that are only 2 µm in diameter. Although the erythrocyte is 6–8 µm in diameter, its ability to undergo reversible deformity enables it to assume a more compact torpedo-like shape, squeeze through the microcirculation and return to normal shape afterwards when reaching larger blood vessels. LEUCOCYTES
Leucocytes (white blood cells) defend the body against organisms that cause infection and remove debris, including dead or injured host cells of all kinds. Although leucocytes are transported in the circulation, they act primarily in the tissues. The average adult has approximately 4–11 × 109 leucocytes per litre of blood. Leucocytes are classified by structure, as either granulocytes or agranulocytes (with or without granules in their cytoplasm), and according to function, as either phagocytes or immunocytes. The granulocytes, which include neutrophils, basophils and eosinophils, are all phagocytes. (Phagocytic action was described in Chapter 12.) Of the agranulocytes, monocytes and macrophages are phagocytes, whereas lymphocytes are immunocytes (cells that create immunity; see Chapter 12). Granulocytes Granulocytes have many membrane-bound granules in their cytoplasm. These granules contain enzymes capable of killing microorganisms and degrading debris ingested during phagocytosis. The granules also contain powerful substances with inflammatory and immune functions. These substances, along with the digestive enzymes, are released from granulocytes in response to specific stimuli and have vascular and intercellular effects. Granulocytes are capable of amoeboid movement, which enables migration through vessel walls (called diapedesis) and then moving to sites where their action is needed (refer to Chapter 13 for this function). Neutrophils are the most numerous and best understood of the granulocytes. Neutrophils constitute about 55% of the total leucocyte count in adults. They are important for protecting the body against bacterial infection. Neutrophils are the chief phagocytes of early inflammation. Soon after bacterial invasion or tissue injury, neutrophils migrate out of the capillaries and into the inflamed site, where they ingest and destroy microorganisms and debris and then die themselves after just 1 or 2 days. The dissolution of dead neutrophils releases digestive enzymes from their cytoplasmic granules. These enzymes dissolve cellular debris and prepare the site for healing. Eosinophils, which have large, coarse granules, constitute only 1–4% of the normal leucocyte count in adults.1 Unlike neutrophils, eosinophils ingest antigen–antibody complexes and are induced by IgE-mediated hypersensitivity reactions to attack parasites (see Chapter 15). The eosinophil granules contain a variety of enzymes that help to control inflammatory
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processes. Eosinophils circulate in the blood for up to 8 hours and then become located next to mucosal surfaces, particularly of the respiratory and gastrointestinal systems. Eosinophils have an important role in protecting the body against parasites such as worms. An individual with a parasitic infection may have a raised eosinophil count — that is, the number of eosinophils present in the blood is greater than normal; this is called eosinophilia. During type I hypersensitivity, allergic reactions and asthma are characterised by eosinophilia, which may be involved in control but may also contribute to the destructive inflammatory processes observed in the lungs of asthmatics. Basophils, which make up less than 1% of the leucocytes, are structurally and functionally similar to the mast cells found throughout extravascular tissue (see Chapter 13).2 Like mast cells, basophils have cytoplasmic granules that contain vasoactive amines (e.g. histamine) and an anticoagulant (heparin). The release of histamine promotes vasodilation and attraction of other leucocytes, which results in an increased number of leucocytes in the local area. The heparin prevents the blood from clotting, thereby encouraging blood flow that further enhances delivery of blood cells to the site of infection. Agranulocytes Agranulocytes — monocytes, macrophages and lymphocytes — have a somewhat misleading name, as they do actually contain some cytoplasmic granules, but only a few in comparison to granulocytes. Monocytes and macrophages make up the mononuclear phagocyte system. Both monocytes and macrophages participate in the immune and inflammatory response, being powerful phagocytes. They also ingest dead or defective host cells, particularly blood cells. Lymphocytes also participate in the immune and inflammatory response, but are not phagocytic. Lymphocytes, monocytes and macrophages work together to protect the body from foreign invaders. Monocytes are immature macrophages. Monocytes are formed and released by the bone marrow into the bloodstream. As they mature, monocytes migrate into a variety of tissues (e.g. liver, spleen, lymph nodes, peritoneum, gastrointestinal tract) and fully mature into tissue macrophages. Other monocytes may mature into macrophages and migrate out of the vessels in response to infection or inflammation (see Table 16.2). Lymphocytes constitute approximately 36% of the total leucocyte count and are the primary cells of the immune response (see Chapter 12). Most lymphocytes circulate in the blood for a short time and then reside in lymphoid tissues as mature T cells, B cells or plasma cells. Natural killer cells are another type of lymphocyte that kill some types of tumour cells and some virus-infected cells (see Chapter 12). They develop in the bone marrow and circulate in the blood. PLATELETS
Platelets (also called thrombocytes) are the smallest of the blood cells (see Fig. 16.4). They are not true cells, but are
TABLE 16.2 The mononuclear phagocyte system NAME OF CELL
LOCATION
Monocyte macrophages
Bone marrow and peripheral blood
Kupffer cells (macrophages)
Liver
Alveolar macrophages
Lungs
Macrophages
Bone marrow
Fixed and free macrophages
Spleen and lymph nodes
Pleural and peritoneal macrophages
Serous cavities
Microglial cells
Nervous system
Mesangial cells
Kidneys
Osteoclasts
Bone
Langerhans cells
Skin
Dendritic cells
Lymphoid tissue
disc-shaped cytoplasmic fragments of a large cell that resides in the bone marrow known as a megakaryocyte. Platelets are essential for blood coagulation and control of bleeding. They lack a nucleus and therefore have no DNA and are incapable of mitotic division. They do, however, contain cytoplasmic granules capable of releasing substances when stimulated by injury to a blood vessel to facilitate haemostasis. There are approximately 150–450 × 109 platelets per litre of circulating blood. An additional one-third of the body’s available platelets are in a reserve pool in the spleen, which can be released into the circulation if necessary to enhance the process of haemostasis. A platelet circulates for approximately 10 days, then ages or is involved in the formation of haemostatic plugs, and then is removed by macrophages of the mononuclear phagocytic system (discussed in the next section), mostly in the spleen.
FOCU S ON L EA RN IN G
1 Describe the composition of blood. 2 Explain the difference between plasma and serum. 3 List the different types of blood cells found in the circulation. 4 Discuss the function of leucocytes. 5 List the phagocytic cells found in the blood. 6 Describe the role of platelets in the blood.
Lymphoid organs
The lymphoid system is closely integrated with the circulatory system. The role of lymphoid organs in the immune response is discussed in Chapter 12. Lymphoid organs are sites of residence, proliferation, differentiation, or a function of
CHAPTER 16 The structure and function of the haematological system
A
RESEARCH IN F
389
CUS
Towards safer antithrombotic therapies
B
C
FIGURE 16.4
Scanning electron micrograph images of platelets. A Free platelets. B Platelet adhesion. C Platelet activation.
lymphocytes and mononuclear phagocytes (monocytes, namely the macrophages). The liver also has important haematological functions, including the production of clotting factors (described in Chapter 26).
The spleen
The spleen is one of the largest of the lymphoid organs. It is a site of fetal haematopoiesis (blood cell production), phagocytes within the spleen filter and cleanse the blood, splenic lymphocytes mount an immune response to blood-borne microorganisms and it serves as a blood reservoir. The spleen is a concave organ that weighs approximately 150 g and is about the size of a fist. It is located in the left upper abdominal cavity, curved around a portion of the stomach. Strands of connective tissue (trabeculae) extend throughout the spleen from the splenic capsule, dividing
Current antithrombotic therapies — antiplatelet drugs or anticoagulant drugs — are associated with an increased risk of bleeding especially in the elderly. Antiplatelet drugs inhibit platelet aggregation by inhibiting the production of thromboxane A2. Anticoagulant drugs inhibit the formation of fibrin by inhibiting thrombin or clotting factors in the coagulation system. Antiplatelet drugs are used in a greater population group for the prevention of thrombosis and consequently there are many investigations targeted at developing different classes of antiplatelet drugs with reduced risk of bleeding. There are many research teams worldwide investigating antithrombotic drugs. Australian research teams are investigating haematopoiesis of platelets and ‘plateletspecific’ procoagulant pathways in the quest for safer antithrombotic therapies.
it into compartments that contain masses of lymphoid tissue called splenic pulp. The spleen is interlaced with many blood vessels, some of which can distend to store blood. Blood that circulates through the spleen first encounters the white splenic pulp, which consists of masses of lymphoid tissue containing lymphocytes and macrophages. The white pulp forms clumps around the splenic arterioles and is the chief site of immune and phagocytic function within the spleen. Here blood-borne antigens encounter lymphocytes, initiating an immune response (see Chapter 12). Some of the blood continues through the microcirculation and enters highly distensible storage areas called venous sinuses. Most of the blood, however, oozes through the capillary walls into the principal site of splenic filtration, the red pulp. Here the resident macrophages of the mononuclear phagocytic system phagocytose damaged or old blood cells of all kinds (but mainly erythrocytes), microorganisms and particles of debris. Haemoglobin from phagocytosed erythrocytes is broken down, as discussed in the section on normal destruction of aged erythrocytes. Blood that filters through the red pulp of the spleen then moves through the venous sinuses and into the portal circulation. The venous sinuses (and the red pulp) can store more than 300 mL of blood. Sudden reductions in blood pressure cause the sympathetic nervous system to stimulate constriction of the sinuses and expel as much as 200 mL of blood into the venous circulation, helping to restore blood volume or pressure in the circulation. You can survive without a spleen and there are many individuals without a spleen who live healthy lives. If the spleen is removed surgically (known as a splenectomy), a number of haematological effects may be seen. For example, leucocytosis (high levels of circulating leucocytes) often occurs after splenectomy, so the spleen may exert some control over the rate of proliferation of leucocyte cells. After
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splenectomy, iron levels in the circulation are decreased, immune function is diminished and the blood contains more structurally defective blood cells than normal.
lymphoid tissue. Lymph enters the node, slowly filters through its sinuses and leaves through the efferent lymphatic vessel.
Lymph nodes
The mononuclear phagocyte system
Structurally, lymph nodes are part of the lymphatic system (see Chapter 22). Thousands of lymph nodes are clustered around the lymphatic veins, which collect interstitial fluid from the tissues and transport it as fluid, known as lymph, back into the cardiovascular system near the heart. Although the lymph nodes are structurally associated with the cardiovascular system, functionally lymph nodes are part of the haematological and immune systems because large numbers of lymphocytes, monocytes and macrophages develop or function within the lymph nodes. As the lymph filters through the bean-shaped lymph nodes clustered in the inguinal, axillary and cervical regions of the body, it is cleansed of foreign particles and microorganisms by the monocytes and macrophages. The microorganisms in lymph stimulate the resident lymphocytes to develop into antibody-producing plasma cells. During an infection, the rate of proliferation of macrophages within the nodes is so great that the nodes enlarge and become tender. Each lymph node is enclosed in a fibrous capsule (see Fig. 16.5), with strands of connective tissue (trabeculae) extending inwards, dividing the node into several compartments. Reticular fibres divide the compartments into smaller sections and trap and store large numbers of lymphocytes, monocytes and macrophages. The node has an outer cortex area and an inner medullary area. Within the cortex are germinal centres or separate masses of
The mononuclear phagocyte system consists of the cells that originate in the bone marrow, differentiate to monocytes that are transported by the bloodstream and finally settle in the tissues as mature macrophages.3 The main examples of these cells are the monocytes and macrophages. Table 16.2 lists the various names given to macrophages localised in specific tissues. The cells of the mononuclear phagocyte system are mostly in the liver and spleen, and function by ingesting and destroying (phagocytic process) foreign substances. They are important in the defence against bacteria and other microorganisms in the bloodstream. In addition, they cleanse the blood of old, injured or dead erythrocytes, leucocytes, platelets, coagulation products, antigen-antibody complexes and macromolecules. These cells also process and present foreign antigens to the immune system (see Chapter 12). The origin and life span of all the tissue macrophages named in Table 16.2 are not precisely known. Once monocytes leave the circulation, they do not return. In the tissues, monocytes differentiate into macrophages without dividing and can survive for many months or perhaps even years. Under normal circumstances, macrophages show little evidence of mitotic division, but production can be rapidly elevated in response to need, as in infection. FOCU S ON L EA RN IN G
1 List the functions of the spleen.
Capsule
Afferent lymph vessels
2 Discuss why lymph nodes are considered part of the haematological system.
Lymph
Sinuses Germinal centre Medullary cords
Cortical nodules Trabeculae
Medullary sinus Hilus Efferent lymph vessel FIGURE 16.5
Cross-section of lymph node. Several afferent-valved lymphatics bring lymph to the node. A single efferent lymphatic leaves the node at the hilus. Note that the artery and vein also enter and leave at the hilus. Arrows show direction of lymph flow.
3 Describe the mononuclear phagocyte system. Why is it important?
The development of blood cells We now turn to the development of blood cells, which when altered can cause systemic problems that affect many body functions.
Haematopoiesis
The typical adult requires about 100 billion new blood cells per day. Blood cell production, termed haematopoiesis, is constantly ongoing, occurring in the liver and spleen of the fetus and in the bone marrow after birth. This process involves the stimulation of populations of young undeveloped cells (i.e. undifferentiated) to undergo mitotic division (i.e. proliferation) and maturation into mature haematological
CHAPTER 16 The structure and function of the haematological system
cells.4 The process of cells changing their appearance (morphology) and function as they develop is known as differentiation. During the stages of production of blood cell types, proliferation occurs a few times and then ceases, while differentiation continues. Erythrocytes and neutrophils generally differentiate fully before entering the blood, but monocytes and lymphocytes do not. When considering the process of cell development, it is possible to visualise a line of growth from a stem cell through to immature forms and eventually to the mature end-stage cell. A collection of cells at different stages of development for a particular cell type (from stem cell to immature cell to mature cell) is known as a cell line, or lineage. Haematopoiesis continues throughout life and importantly increases in response to disease and certain conditions. For instance, haemorrhage, haemolytic anaemia (in which erythrocytes are destroyed), chronic infection and other disorders that deplete blood cells all cause an increase in blood cell production. This response is a homeostatic mechanism that can be investigated by clinicians to determine the severity of a condition or as a general guide to locating alterations such as the source of infection. In general, long-term stimuli, such as chronic disease, cause a greater increase in haematopoiesis than acute conditions, such as haemorrhage.
Bone marrow
Bone marrow is confined to the cavities of bone. It consists of blood vessels, nerves, mononuclear phagocytes, blood cells in various stages of differentiation and fatty tissue. Adults have two kinds of bone marrow: (1) red or active (haematopoietic) marrow (also called myeloid tissue); and (2) yellow or inactive marrow. The large quantities of fat in inactive marrow make it yellow. Not all bones contain active marrow. In adults, active marrow is found primarily in the flat bones of the pelvis (34%), vertebrae (28%), cranium and mandible (13%), sternum and ribs (10%) and in the extreme proximal portions of the humerus and femur (4–8%). Inactive marrow predominates in cavities of other bones. (Bones are discussed further in Chapter 20.) Haematopoietic marrow receives oxygen and nutrients needed for cellular differentiation from the primary arteries of the bones. Branches of these arteries terminate in a capillary network that coalesces into large venous sinuses, which eventually drain into a central vein. Haematopoietic marrow and fat fill the spaces surrounding the network of venous sinuses. Newly produced blood cells traverse narrow openings in the venous sinus walls and thus enter the circulation. Normally, cells do not enter the circulation until they have differentiated to a certain extent, but premature release occurs in certain diseases.
Cellular differentiation
The bone marrow contains a population of haematopoietic stem cells known as haemocytoblasts. These are stem cells that have partially differentiated (see Fig. 16.6)5,6 such that they are committed to become a blood cell — they have the capacity to differentiate into any of the haematological
391
cell populations, but can no longer differentiate into other cell types, like nerve or muscle cells. As with all stem cells, haematopoietic stem cells are self-renewing (they have the ability to proliferate or reproduce, without further differentiation or maturation) so that a relatively constant population of stem cells is available. This means that when production of blood cells is necessary, the haematopoietic stem cell will proliferate into two cells: one remains in the bone marrow, while the other undergoes differentiation into a mature blood cell. The haematopoietic stem cell may develop into a myeloid stem cell, whereby the cell undergoes development and maturation within the bone marrow, or a lymphoid stem cell, whereby the cell undergoes maturation outside the bone marrow. During further stages of differentiation, some haematopoietic stem cells will become haematopoietic progenitor (immature) cells. Progenitor cells retain the capacity to continue proliferating, but are committed to further differentiation into particular types of haematological cells: lymphoid (B cells, T cells, natural killer cells), granulocyte/monocyte (granulocytes, monocytes, macrophages) and megakaryocyte/ erythroid (platelets, erythrocytes) progenitor cells. These progenitor cells are also referred to as colony-forming units. Several cytokines participate in haematopoiesis, particularly colony-stimulating factors (or haematopoietic growth factors), which stimulate the proliferation of progenitor cells and their progeny and initiate the maturation events necessary to produce fully mature cells. Multiple cell types, including endothelial cells, fibroblasts and lymphocytes, produce these important colony-stimulating factors. In addition, the hormones erythropoietin and thrombopoietin stimulate the production of erythrocytes and platelets, respectively. When neutrophils are released to the peripheral blood they either circulate or adhere to the walls of the blood vessels (often called the marginating storage pool), mainly in areas where blood flow is slow. These cells can be rapidly mobilised to move into tissues and mucous membranes when needed, such as during bacterial infection. Cells from the circulating pool join the marginating pool to replace the cells that have migrated out of the capillaries. In addition, immature neutrophils can be released from the bone marrow when the body is challenged by infection, and in this way the bone marrow can be considered as having a storage component for the neutrophil cell line. Thus a raised white cell count (leucocytosis) can be seen in response to bacterial infection. In this case, the increase in the white cell count is due to an increase in the numbers of neutrophils circulating in the blood (known as neutrophilia). Approximately one-third of platelets are stored in the spleen (known as splenic sequestration) while the remainder circulate. Under certain conditions, the level of circulating haematological cells needs to be rapidly replenished. Haematopoiesis in the bone marrow can be accelerated by expansion of the bone marrow, faster differentiation of the daughter cells or faster proliferation of stem cells.
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Haematopietic stem cell: haemocytoblast
Myeloid stem cell
Proerythroblast
Megakaryoblast
Reticulocyte
Megakaryocyte
Red blood cells (RBCs; erythrocytes)
Platelets (thrombocytes)
Lymphoid stem cell
Myeloblast
Monoblast
Lymphoblast
Progranulocyte
Neutrophil Eosinophil
Basophil
Monocyte/ macrophage
Granulocytes
T lymphocyte
B lymphocyte
Agranulocytes White blood cells (WBCs; leucocytes)
FIGURE 16.6
Differentiation of a stem cell into red blood cells, platelets and white blood cells.
The development of erythrocytes F OC US O N L E ARN IN G
1 Describe the role of the bone marrow in the production of blood cells. 2 Discuss the role of haematopoietic stem cells. 3 Outline the role of colony-stimulating factors in the production of blood cells. 4 Discuss the distribution of neutrophils in the body.
For almost 100 years it was believed that erythrocytes developed from lymphocytes that were transformed in the spleen. It was not until the 1950s that the bone marrow was identified as the site of erythropoiesis, or development of red blood cells (see Fig. 16.7). Approximately 1% of the body’s circulating erythrocyte mass normally is generated every 24 hours. In the confines of the bone marrow some haematopoietic stem cells will differentiate into large, nucleated proerythroblasts, which are committed to producing
CHAPTER 16 The structure and function of the haematological system
Haematopoietic stem cell: haemocytoblast
Committed proerythroblast
Normoblast (nucleus shrinks and is reabsorbed)
Erythropoietin
Reticulocyte (cell leaves marrow and enters bloodstream)
393
Erythrocyte (cell achieves final size and shape: haemoglobin synthesis ceases)
FIGURE 16.7
Erythrocyte differentiation. Erythrocyte differentiation from large, nucleated stem cell to small, nonnucleated erythrocyte.
erythrocytes. The proerythroblast differentiates through several intermediate forms of erythroblast and normoblast while progressively eliminating most intracellular structures, including the nucleus. Haemoglobin will be produced in large quantities and the cell becomes more compact as it matures, eventually taking on the shape and characteristics of an erythrocyte. The last immature form is the reticulocyte, which contains a mesh-like (reticular) network of ribosomal RNA that is visible microscopically after staining with certain dyes. Reticulocytes remain in the marrow for approximately 1 day and are released into the venous sinuses. They continue to mature in the bloodstream and may travel to the spleen for several days of additional maturation. The normal reticulocyte count is 1% of the total red blood cell count. Therefore, the reticulocyte count is a useful clinical index of erythropoietic activity: a raised reticulocyte count would be consistent with increased production of red cells in the bone marrow, whereas a low reticulocyte count indicates a failure to produce sufficient new red cells. Most steps of this process are primarily under the control of the hormone erythropoietin.7 In healthy humans, the total volume of circulating erythrocytes remains surprisingly constant. In conditions of tissue hypoxia, erythropoietin is secreted by the kidneys (see Fig. 16.8). It causes a compensatory increase in erythrocyte production if the oxygen content of blood decreases because of anaemia, high altitude or pulmonary disease. The normal rate of production (an amazing 2.5 million erythrocytes per second) can increase (to an even more startling 17 million per second) under anaemic or low-oxygen states. The body responds to reduced oxygenation of blood in two ways: • increasing the intake of oxygen through increased ventilation • increasing the oxygen-carrying capacity of the blood through increased erythropoiesis.
Haemoglobin production
Haemoglobin is the protein contained within red cells that is responsible for carrying oxygen from the lungs to the tissues. Under normal circumstances red cells are saturated with haemoglobin and a single erythrocyte may contain as many as 300 million haemoglobin molecules. Haemoglobin consists of four globin protein chains, each of which contains a haem group — hence the name. Each haem group contains an iron atom. It is the iron contained within the haem of haemoglobin that binds to and releases oxygen. Haemoglobin is responsible for the red colour of erythrocytes. As erythrocytes are much more numerous than other blood cells, blood appears red in colour. Arterial blood contains oxyhaemoglobin and has a bright red colour, whereas venous blood has more deoxyhaemoglobin and has a darker red colour by comparison. Haemoglobin A is the specific type of haemoglobin that occurs in adults. A form of haemoglobin with a slightly different structure, haemoglobin F, is found in the fetus. Haemoglobin F in the fetus has a stronger attraction for oxygen than haemoglobin A found in the mother, facilitating the movement of oxygen from the mother’s erythrocytes to those of the fetus. These (and other) types of haemoglobin exist to cope with the different oxygenation conditions found in the embryo, fetus and atmospheric environment. Molecules other than oxygen can competitively bind to haemoglobin. Carbon monoxide (CO) directly competes with oxygen to bind to iron, with an ability that is about 200-fold greater than oxygen. Thus, even a small amount of CO can dramatically decrease the ability of haemoglobin to bind and transport oxygen. Haemoglobin also binds carbon dioxide (CO2), but at a binding site separate from where oxygen binds. Therefore, oxygen and carbon dioxide do not directly compete for binding sites on the haemoglobin. In addition to transporting oxygen, haemoglobin has an important role to play in transporting carbon dioxide produced in the tissues back to the lungs for expiration, as
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CONCEPT MAP
Decreased population of mature RBCs
Decreased haemoglobin synthesis
Decreased blood flow
Haemorrhage
Increased oxygen consumption by tissues
results in Decreased arterial O2 content and Decreased O2 content of tissue cells
negative feedback: further release of erythropoietin not needed
this stimulates Secretion of erythropoietin by kidney cells which leads to Increased proliferation of erythroblasts in bone marrow and leads to Increased population of mature erythrocytes in circulation homeostasis is now restored, as there is Normal arterial O2 content
FIGURE 16.8
The role of erythropoietin in the regulation of erythropoiesis.
well as in maintaining the acid–base balance in the blood (buffering). The role of haemoglobin in the transport of oxygen and carbon dioxide is discussed in detail in Chapter 24, while acid–base balance is explored in Chapter 29. Erythrocytes may play a role in the maintenance of vascular relaxation. Nitric oxide (NO) produced by blood vessels is a major mediator of relaxation and dilation of the vessel walls. In the lungs, haemoglobin can bind oxygen to iron and nitric oxide to globin. As haemoglobin transfers its oxygen to tissues, it may also shed small amounts of nitric oxide, contributing to dilation of the blood vessels and assisting oxygen delivery. (See Chapter 13 for the role of nitric oxide in inflammation.)
Nutritional requirements for erythropoiesis
Normal development of erythrocytes and production (synthesis) of haemoglobin depend on an optimal biochemical state and adequate supplies of protein, vitamins and minerals. Additional specific nutritional requirements for the production of erythrocytes are iron, vitamin B12
(cobalamin) and folate. It is important to note that these minerals and vitamins are required by other cells of the body as well as erythrocytes. If these components are lacking for a prolonged time, erythrocyte production slows and anaemia (an insufficient number of functional erythrocytes) may result (see Chapter 17). IRON CYCLE
Approximately 67% of total body iron is bound to haem in erythrocytes (haemoglobin) and muscle cells (myoglobin) and approximately 30% is stored in mononuclear phagocytes (i.e. macrophages) and hepatic cells as either ferritin or haemosiderin. The remaining 3% (less than 1 mg) is lost daily in urine, sweat, bile and epithelial cells shed from the gut. Iron is transported in the blood bound to transferrin, a glycoprotein produced primarily by the liver. Iron that will be used for haemoglobin production is carried by transferrin to the bone marrow, where it binds to transferrin receptors on erythroblasts. The iron is transported inside the erythroblast to the mitochondria, the site of haemoglobin
CHAPTER 16 The structure and function of the haematological system
production, where an enzyme incorporates it into a molecule to form haem. Aged or damaged erythrocytes are removed from the bloodstream by macrophages of the mononuclear phagocyte system (described above), largely in the spleen. Here, macrophages undergo phagocytosis of the erythrocytes, which results in release of the haemoglobin. The haemoglobin molecule is broken down and the iron is stored as ferritin or haemosiderin. The stored iron is released into the bloodstream, where it binds to transferrin so that it can be recycled (see Fig. 16.9). Iron balance is maintained through controlled absorption at the intestines. Regulation of iron transport across the plasma membrane of gastrointestinal epithelial cells is related to the cell’s iron content and the overall rate of erythropoiesis. If the body’s iron stores are low or the demand for erythropoiesis increases, iron is transported rapidly through the intestinal epithelial cell and into the plasma. If body stores are high and erythropoiesis is not increased, iron crosses the epithelial cell plasma membrane passively and is temporarily stored as ferritin. Excretion of iron occurs when the epithelial cells of the intestinal mucosa slough off.
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Normal destruction of aged erythrocytes
Although mature erythrocytes lack nuclei, mitochondria and endoplasmic reticulum, they do have cytoplasmic enzymes capable of producing small quantities of ATP. ATP provides the energy required to maintain cell function and cell membrane flexibility, which is needed to allow the erythrocyte to fold on entering small blood vessels. As the erythrocyte ages, less ATP is available to maintain cell membrane function. The older (senescent) red cell becomes increasingly fragile and loses its reversible deformability, becoming susceptible to rupture while passing through the narrow regions of the microcirculation. Additionally, the cell membrane of aged erythrocytes undergoes rearrangement such that phospholipid normally only found within the cell membrane is exposed on the cell surface. This is recognised by receptors on macrophages (primarily in the spleen), which selectively remove the red cells. If the spleen has reduced function or is absent, macrophages in the liver (Kupffer cells) take over. During digestion of haemoglobin in the macrophage, the breakdown of haem produces the waste product bilirubin (unconjugated form), which is transported to the liver and metabolised into the conjugated form further to be secreted
CONCEPT MAP
FIGURE 16.9
The breakdown of haemoglobin.
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Part 3 Alterations to protection and movement
with the bile into the intestines (see Fig. 16.9). Bacteria in the intestinal lumen transform conjugated bilirubin into urobilinogen. Most urobilinogen is excreted in faeces, although some also reaches the blood and is excreted by the kidneys in the urine, which can be detected by urinalysis.
The development of leucocytes
All leucocytes arise from stem cells in the bone marrow (their pathways of differentiation are shown in Fig. 16.6). The process of leucocyte production is known as leucopoiesis. Lymphoid progenitor cells develop into lymphocytes, which are released into the bloodstream to undergo further maturation in the primary and secondary lymphoid organs (see Chapter 12). Monocyte progenitors develop into monocytic cells, which continue maturing into macrophages after release into the bloodstream and entrance into various tissues. Progenitor cells for granulocytes fully mature in the marrow into neutrophils, eosinophils and basophils and are released into the blood. The bone marrow selectively retains immature granulocytes as a reserve pool that can be rapidly mobilised in response to the body’s needs. Further maturation is under the control of several haematopoietic growth factors, including interleukins, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). Leucocyte production increases in response to infection, to the presence of steroids and to the reduction or depletion of reserves in the marrow. It is also associated with strenuous exercise, convulsive seizures, heat, intense radiation, increased heart rate, pain, nausea and vomiting and stress.
The development of platelets
Platelets are derived from large cells found in the bone marrow known as megakaryocytes. As with other blood cells megakaryocytes originate from a stem cell and have a number of progenitor stages (see Fig. 16.6).8 The process of platelet production is known as thrombopoiesis. During thrombopoiesis, the megakaryocyte progenitor is programmed to undergo a cell cycle during which DNA replication occurs, but anaphase and cytokinesis are blocked (see Chapter 5). Thus, the megakaryocyte nucleus enlarges (containing up to 100-fold more than the normal amount of DNA) without cellular division. Concurrently, the numbers of cytoplasmic organelles (e.g. internal membranes, granules) increase and the cell develops cellular surface elongations and branches that progressively fragment into platelets. Like erythrocytes, platelets released from the bone marrow lack nuclei. Thrombopoietin, a hormone growth factor, is the main regulator of the circulating platelet mass. Thrombopoietin is primarily produced by the liver and induces platelet production in the bone marrow. Platelets express receptors for thrombopoietin and when circulating platelet levels are normal, thrombopoietin is adsorbed onto the platelet surface
and prevented from accessing the bone marrow and stimulating further platelet production. An optimal number of platelets and committed platelet precursors (megakaryoblasts) in the bone marrow is maintained primarily by thrombopoietin produced by the liver and kidneys, together with other factors such as GM-CSF. These factors affect the rate of differentiation into megakaryocytes and the rate of platelet release. About two-thirds of platelets enter the circulation and the remainder reside in the splenic pool. Platelets circulate in the blood stream for about 10 days before beginning to lose their ability to carry out biochemical processes. These senescent (ageing) platelets are removed from the circulation in the spleen by mononuclear cell phagocytosis.
FOCU S ON L EA RN IN G
1 Discuss the role of the kidneys in erythropoiesis. 2 List the functions of haemoglobin. 3 Describe the importance of iron in red cell function. 4 Describe the processes associated with red cell ageing. 5 Explain how a reticulocyte count can provide information about red cell development. 6 Distinguish between erythropoiesis, leucopoiesis and thrombopoiesis.
RESEARCH IN F
CUS
The use of induced pluripotent stem cells to find new treatments for leukaemia Bone marrow transplants have been used for decades to treat the different types of leukaemia but not all transplants are successful. Bone marrow transplants involve the transplant of haematopoietic stem cells from an HLA-matched donor or from the person’s own stem cells (autologous transplant). The shortage of matched donors means that many people with leukaemia do not survive the disease. The development of new technologies such as the ability to generate pluripotent stem cells (embryonic stem cells) from adult cells by genetic engineering has created many new opportunities in medical research. The use of induced pluripotent stem cells overcomes ethical issues associated with embryonic stem cells. Induced pluripotent stem cells are enabling researchers to study leukaemic cells in vitro from people suffering from leukaemia. Researchers are looking at possible sites of mutation in the process of haematopoiesis which will hopefully lead to the development of less toxic treatments for leukaemia than are currently being used. Another benefit is the use of induced pluripotent stem cells from a leukaemia patient’s own cells may overcome the problems of transplant rejection reactions.
CHAPTER 16 The structure and function of the haematological system
The mechanisms of haemostasis Haemostasis means the arrest of bleeding within a damaged blood vessel. As a result of haemostasis, damaged blood vessels may maintain a relatively steady state of blood volume, pressure and flow. Without haemostasis even a small cut could result in death from massive blood loss. Three main processes occur in haemostasis to prevent further loss of blood: 1 localised vasoconstriction (narrowing of the blood vessel lumen) to reduce blood flow to the damaged site 2 platelet plug formation 3 coagulation or clotting (using proteins in plasma manufactured by the liver, as well as the endothelial cells and subendothelial structures of the blood vessels). Although damage to small vessels can be repaired relatively quickly with limited blood loss, damage to large vessels depends on powerful vasoconstriction to decrease the blood flow and hence blood loss (see Table 16.3). In the following sections, we discuss how the blood vessels, platelets and clotting factors achieve haemostasis.
The function of platelets and blood vessels
The role of platelets is to: • contribute to regulation of blood flow at a damaged site through induction of vasoconstriction (vasospasm) • adhere to damaged blood vessels and initiate platelet-toplatelet interactions resulting in the formation of a platelet plug to stop further bleeding • provide a surface for the coagulation (or clotting) cascade to form a stable fibrin clot • initiate repair processes including clot retraction. Platelets normally circulate freely as disc-shaped particles, suspended in plasma, in an unactivated state, which means that they are ready to be involved in haemostasis, but do not undergo any changes unless stimulated. Endothelial cells lining the vessels produce nitric oxide and prostacyclin I2 (PGI2) to inhibit platelet activation allowing free circulation. This is very important, because in this way,
397
platelets are able to travel through the blood, while not contributing to haemostasis unless it is necessary; therefore, unwanted clotting is prevented. When a vessel is damaged, platelet activation may be initiated.9,10 Activated platelets radically change shape, develop spikes termed pseudopod-like cytoplasmic extensions and become sticky. Activation proceeds through a process of increasing platelet adhesion, aggregation and activation. Initially, platelets adhere weakly to the vessel wall, followed by increased strength of adherence to the vessels and aggregation between platelets. This creates a platelet plug at the site of injury. The process of platelet plug formation is known as primary haemostasis. The platelet plug is not secure and can be easily dislodged, so a more permanent meshwork of platelets and fibrin subsequently develops (see Fig. 16.10). The blood coagulation system that produces insoluble fibrin strands at the wound site is known as secondary haemostasis. The primary and secondary haemostasis systems work together to prevent blood loss at sites of vascular injury. The process of platelet activation can begin in several ways. If the vessel lining remains intact in an area of inflammation, the endothelial cells may become activated and begin expressing new proteins on their surface, which enable platelets to adhere to the endothelium. As inflammation progresses, the platelets adhere to each other by binding to this fibrinogen. Platelets are therefore able to aggregate together by forming platelet-fibrinogen-platelet bridges. Rupture of the endothelial layer during blood vessel damage results in exposure of the underlying matrix that contains collagen and von Willebrand factor (vWF) (see Fig. 16.10). Platelets adhere strongly to both collagen and vWF, so exposure of the subendothelium initiates platelet adhesion. Progressively the platelets undergo further aggregation through platelet-to-platelet adhesion involving further fibrinogen bridging between adjacent platelets. As a result of interactions with the subendothelial matrix, as well as exposure to inflammatory mediators produced by the endothelium and other cells, the platelets become activated. Activation results in dynamic changes in platelet shape from smooth spheres to those with spiny projections and also causes the granules contained within platelets to release their contents (known as degranulation, or the
TABLE 16.3 Types of bleeding: sources, vessel size and sealing requirements TYPE AND SOURCES OF BLEEDING
INVOLVED VESSEL
SIZE
SEALING REQUIREMENTS
Pinpoint petechial haemorrhage (blood leakage from small vessels)
Capillary
Smallest
Generally direct-sealing
Venule
Platelet plug
Arteriole Ecchymosis (large, soft tissue bleeding)
Vein
Rapidly expanding ‘blowout’ haemorrhage
Artery
Vascular contraction, fused platelets, perivascular and intravascular haemostatic factor activation (see Fig. 16.10) Largest
Greater vascular contraction, greater platelet plug, greater perivascular and intravascular haemostatic factor activation
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Part 3 Alterations to protection and movement
Endothelial sloughing
1 Subendothelial exposure • Occurs after endothelial sloughing • Platelets begin to fill endothelial gaps • Promoted by thromboxane A2 (TXA2) • Inhibited by prostacyclin I2 (PGI2) • Platelet function depends on many factors, especially calcium 2 Adhesion • Adhesion is initiated by loss of endothelial cells (or rupture or erosion of atherosclerotic plaque) which exposes adhesive glycoproteins such as collagen and von Willebrand factor (vWF) in the subendothelium. vWF and, perhaps, other adhesive glycoproteins in the plasma deposit on the damaged area. Platelets adhere to the subendothelium through receptors that bind to the adhesive glycoproteins (GPIb, GPIa/IIa, GPIIb/IIIa) 3 Activation • After platelets adhere they undergo an activation process that leads to a conformational change in GPIIb/IIIa receptors, resulting in their ability to bind adhesive proteins, including fibrinogen and von Willebrand factor • Changes in platelet shape • Formation of pseudopods • Activation of arachidonic pathway
Platelets
PGI2
Collagen
GPIa/IIa
GPIIb/IIIa
Endothelium
Sticky platelets
GPIb
Collagen
vWF
ACTIVATION
vWF
Fibrinogen
Collagen
Collagen Platelets
Collagen RBC
4 Aggregation • Induced by release of TXA2 • Adhesive glycoproteins bind simultaneously to GPIIb/IIIa on two different platelets • Stabilisation of the platelet plug (blood clot) occurs by activation of the coagulation factors, thrombin and fibrin • Heparin-neutralising factor enhances clot formation
Platelets
Fibrin mesh
Fibrin
Thrombin
5 Platelet plug formation • RBCs and platelets enmeshed in fibrin
Platelet plug (blood clot) 6 Clot retraction and clot dissolution • Clot retraction, using large number of platelets, joins the edges of the injured vessel • Clot dissolution is regulated by thrombin and plasminogen activators
FIGURE 16.10
Platelet degranulation, plug formation and clot dissolution.
Thrombin
Fibrin degradation Plasmin
Plasminogen activators
Activated protein
CHAPTER 16 The structure and function of the haematological system
platelet-release reaction). This results in various potent substances being shed from platelets into the surrounding environment. Many of these molecules have roles to play in haemostasis. Platelets are capable of releasing numerous substances that contribute to haemostasis. These include ADP, serotonin and calcium: • ADP reacts with specific receptors on platelets to induce further adherence (and subsequent release-reaction) of nearby platelets. The activated platelets aggregate together to cause a platelet plug to seal the injured endothelium. • Serotonin functions like histamine and has immediate effects on smooth muscle in the vascular endothelium, causing an immediate temporary constriction of the injured vessel (see Chapters 13 and 22). Vasoconstriction reduces blood flow and diminishes bleeding. However, this lasts for only a short time (up to 30 minutes), as vasodilation soon follows, permitting the inflammatory response to proceed. • Calcium is necessary for many of the intracellular signalling mechanisms that control platelet activation and is essential for the blood coagulation of the secondary haemostasis system to function. Activated platelets also produce thromboxane A2 (TXA2), which causes vasoconstriction and promotes attraction of additional platelets to contribute to plug formation. In addition, platelets release some clotting factors (such as fibrinogen and factor V), which enhance the process of coagulation. If blood vessel injury is minor, haemostasis is achieved temporarily by formation of the platelet plug, which usually forms within 3–5 minutes of injury. Platelet plugs seal the many tiny ruptures that occur daily in the microcirculation, particularly in capillaries. If there are too few platelets or if platelets do not function properly, damaged capillaries may leak, resulting in numerous small haemorrhagic areas under the skin and tissues. When this occurs under the skin a purple discolouration results (purpura).
F O CUS O N L E A R N IN G
1 Discuss the role of platelets in haemostasis. 2 Describe some basic changes that occur to platelets when they become activated. 3 Outline the events that occur when platelets encounter a damaged blood vessel. 4 List some of the substances that are released from activated platelets.
The function of clotting factors
A blood clot is a meshwork of protein strands that stabilises the platelet plug. Although other cells such as
399
erythrocytes and leucocytes may become trapped in the clot, they do not contribute to its formation (see Fig. 16.11). The strands are made of fibrin, which is produced by secondary haemostasis (coagulation).11 This system is traditionally described by the coagulation cascade model, comprising inactive enzymes or coagulation factors that are produced by the liver and are circulating in the blood; these coagulation factors activate each other in a sequence of complex reactions after an initiating event (e.g. blood vessel damage). The end result of this series of reactions is the conversion of fibrinogen to fibrin to form a stable blood clot. This is important, as the platelet plug formed by primary haemostasis is not stable and can be dislodged easily. While it is necessary that an efficient system exists to prevent blood loss, it is equally important that clot formation can be stopped when required. Although excessive bleeding (haemorrhage) can be life threatening — as blood volume will be dramatically reduced and the individual will not be able to adequately oxygenate — in clinical practice unwanted clotting is far more common. Unwanted clot formation (thrombosis) can have serious and fatal consequences. For instance, clot formation in the coronary arteries can lead to acute myocardial infarction (discussed in Chapter 23), pulmonary system clots can cause infarction of lung tissue (see Chapter 25) and clots in cerebral arteries can lead to stroke (refer to Chapter 9). All these conditions can be fatal. Therefore, the coagulation system has many intricate control mechanisms to either promote or inhibit clot formation and under normal circumstances a balance exists between these processes. The coagulation system is usually presented as two pathways of initiation (intrinsic and extrinsic pathways) that join in a common pathway (see Fig. 16.12). The intrinsic pathway is activated when factor XII in plasma contacts subendothelial substances such as collagen, which are exposed by vascular injury. Factor XIIa becomes activated and can then activate factor XI and a sequence of reactions follows. The extrinsic pathway is activated when tissue factor, a substance exposed by vascular damage, reacts with clotting factor VII. Both the intrinsic and extrinsic pathways lead to the common pathway and activation of factor X, which converts prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin. Thrombin also activates factor XIII, which cross-links the fibrin strands to form a stable clot formed of a meshwork of fibrin. This fibrin mesh traps the blood components and prevents them from exiting the vessel wound. The coagulation system is complex, with a large number of alternative activators and inhibitors. There is also interaction between the intrinsic and extrinsic pathways so that an activated member of one pathway may activate a member of the other pathway (e.g. activated factor VII of the extrinsic pathway can directly activate factor IX of the intrinsic pathway). Tissue factor is a powerful stimulant of the coagulation system and produces a greater amount of fibrin clot at a faster rate than the intrinsic system.
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Part 3 Alterations to protection and movement
1
2
Damaged tissue cells
Prothrombin Clotting factors
Injury
Prothrombin activator Sticky platelets
Calcium
Fibrin mesh (blood clot)
Platelet plug
A A
Thrombin Fibrin Fibrinogen 3 RBCs enmeshed in fibrin
B
Blood clot FIGURE 16.11
The blood-clotting mechanism. A The clotting mechanism involves release of platelet factors at the injury site, formation of thrombin and trapping of red blood cells (RBCs) in fibrin to form a clot. B An electron micrograph showing entrapped red blood cells in a fibrin clot.
Activated platelets are important participants in clotting. During activation, phospholipids in the platelet cell membrane undergo change resulting in the formation of several important complexes of clotting factors. In this way, platelets contribute to coagulation. The interaction of the different contributing mechanisms in blood clot formation is shown in Fig. 16.13.
Natural substances that limit coagulation and platelet plug formation
A variety of substances, some of which are products of the coagulation system itself, control coagulation.12 For example, thrombin can bind to the endothelial cell surface to activate
CHAPTER 16 The structure and function of the haematological system
Extrinsic pathway
Intrinsic pathway
Damaged tissues
Damaged blood vessel (exposure of collagen)
cause release of
401
leads to activation of factor XII Factor XII becomes factor XIIa
Tissue factor which forms a complex with factor VII Tissue factor – factor VIIa complex
leads to activation of factor XI Factor XI becomes factor XIa leads to activation of factor IX Factor IX becomes factor IXa which forms a complex with factor VIII Factor IXa–factor VIIIa complex
which activates factor X
which activates factor X Factor X becomes factor Xa which leads to prothrombin activation Prothrombin becomes thrombin which converts soluble fibrinogen to fibrin strands Fibrinogen becomes fibrin
thrombin activates factor XIII
fibrin with factor XIIIa forms Cross-linked fibrin mesh FIGURE 16.12
A simplified schematic of the steps involved in blood clotting. The intrinsic pathway is initiated by processes within (intrinsic to) the blood vessel lumen. The extrinsic pathway is initiated by processes outside the blood vessel lining, such as the collagen underneath the blood vessel endothelium. Damage to a blood vessel would usually activate both pathways. The common pathway starts with activation of factor X, and leads to the conversion of soluble fibrinogen into fibrin strands that become cross-linked into a stable fibrin mesh. Importantly, several steps in all three pathways are dependent on calcium (available in the blood). Furthermore, several steps are enhanced by substances from platelets, such that processes in the formation of the platelet plug and the fibrin mesh overlap to contribute to haemostasis. The small ‘a’ beside the factor number indicates the active form.
protein C in plasma. This leads to inhibition of some coagulation factors, which serves to control fibrin production. Thrombin therefore not only promotes clot formation by converting fibrinogen to fibrin, but also acts to control the clotting process. Antithrombin III is a powerful naturally occurring anticoagulant. As suggested by its name, this molecule inhibits thrombin; however, it also inhibits most other coagulation enzymes as well. When antithrombin III combines with heparin, the inhibitory activity to thrombin is increased 2000–10 000 times. Heparin is found naturally in the body and is secreted from intact endothelial cells
and mast cells; in addition, heparin is also administered therapeutically as a rapid-acting anticoagulant. Tissue factor pathway inhibitor is another naturally occurring anticoagulant that helps to control coagulation. It is produced in the liver, like most proteins associated with coagulation, but is also found in platelets. Tissue factor pathway inhibitor inhibits the extrinsic coagulation pathway by acting against the tissue factor — activated factor VII complex. It can also inhibit activated factor X. Prostacyclin is produced by intact endothelial cells. It promotes vasodilation and inhibits platelet activation processes when there is no endothelial cell damage; in this
CONCEPT MAP
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Part 3 Alterations to protection and movement
causes
Vessel injury activates
activates Contraction of smooth muscle in blood vessel: vasoconstriction
causes
Serotonin
releases
causes
provides Phospholipid amplifies Primary Secondary surface haemostasis: haemostasis: platelet coagulation cascade activates generates adhesion leads to formation Thrombin leads to of fibrin clot formation of platelet plug leads to
Decreased blood flow
assists
leads to Stable haemostatic plug (blood clot)
FIGURE 16.13
An overview of haemostasis. Interaction between the blood vessels and primary (platelet) and secondary (coagulation) haemostasis systems results in the production of a stable blood clot.
way, unnecessary platelet plug formation is prevented. In addition, when endothelial cells are intact the underlying collagen is not exposed, which means that the platelets are unable to adhere to the vessel wall. In platelets, an enzyme called cyclooxygenase (COX-1) converts arachidonic acid to TXA2. Aspirin irreversibly inhibits COX-1 in platelets, decreasing production of TXA2 and decreasing platelet activation, making it an effective antiplatelet drug in patients at risk of arterial thrombosis. However, aspirin also affects other body cells, leading to side effects such as gastric irritation. Hence, when aspirin is used to prevent thrombosis, it is given in low doses.
Clot retraction and fibrinolysis
After a clot is formed, it undergoes clot retraction as it ‘solidifies’. Fibrin strands shorten, becoming denser and stronger, which pulls the edges of the injured vessel wall closer and seals the site of injury. Retraction is facilitated by the large numbers of platelets trapped within the fibrin meshwork. The platelets contract and ‘pull’ the fibrin threads closer together while releasing a factor that stabilises the fibrin. Contraction expels protein-free serum from the fibrin meshwork. This process usually begins within a few minutes after a clot has formed, and most of the serum is expressed within 20–60 minutes. The process of clot retraction is important in making the clot more secure. Fibrinolysis (breakdown) of blood clots is necessary in order to remove a clot once the vessel is undergoing repair. It is carried out by the fibrinolytic system (see Fig. 16.14). Another plasma protein, plasminogen, is converted
Damaged endothelial cell
Fibrin
t-PA
Factor Xlla EXTRINSIC
INTRINSIC u-PA
Plasminogen
Plasmin
Fibrin Fibrin degradation products FIGURE 16.14
The fibrinolytic system. The central reaction is the conversion of plasminogen to the enzyme plasmin. Conversion of plasminogen is achieved by the action of tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) as well as activated factor XII (factor XIIa). Plasmin splits fibrin in the clot into fibrin-degradation products.
CHAPTER 16 The structure and function of the haematological system
to plasmin by plasminogen activator13 as well as activated factor XII. Plasmin is an enzyme that dissolves clots by degrading fibrin into fibrin-degradation products. The fibrinolytic system removes clotted blood from tissues and dissolves small clots (thrombi) in blood vessels. This is important for the restoration of normal blood flow. A balance between the amounts of thrombin and plasmin in the circulation maintains normal coagulation and fibrinolysis.
403
FOCU S ON L EA RN IN G
1 Describe the constituents of a blood clot. 2 Distinguish between haemorrhage and thrombosis. 3 Discuss the role of tissue factor in haemostasis. 4 List some molecules in the body that help to control coagulation. 5 Outline how aspirin affects platelets. 6 Explain how blood clots are removed from the body.
Blood cell counts tend to be higher than adult levels at birth and then decline gradually throughout childhood. Table 16.4 lists normal ranges during infancy and childhood. The immediate rise in values at birth is the result of accelerated haematopoiesis during fetal life, the increased numbers of cells that result from the trauma of birth and cutting of the umbilical cord. Average blood volume in the full-term neonate is 85 mL/ kg of body weight, higher than adults (about 70 mL/kg). The premature infant has a slightly larger blood volume of 90 mL/kg of body weight, with the mean increasing to 150 mL/kg during the first few days after birth. In both full-term and premature infants, blood volume decreases during the first few months. Thereafter, the average blood volume is 75–77 mL/kg, which is similar to that of older children and adults. The hypoxic intrauterine environment prior to birth stimulates erythropoietin production in the fetus and
accelerates fetal erythropoiesis, producing polycythaemia (excessive proliferation of erythrocyte precursors) in the newborn. After birth, the oxygen from the lungs saturates arterial blood and more oxygen is delivered to the tissues. In response to the change from a placental to a pulmonary oxygen supply during the first few days of life, levels of erythropoietin and the rate of blood cell formation decrease. The fall in haemoglobin and haematocrit values after birth is more marked in premature infants than it is in full-term infants. The active rate of fetal erythropoiesis is reflected by the large numbers of immature erythrocytes (reticulocytes) in the peripheral blood of full-term neonates. After birth, the number of reticulocytes decreases about 50% every 12 hours, so it is rare to find an elevated reticulocyte count after the first week of life. During this period of rapid growth, the rate of erythrocyte destruction is greater than that in later childhood and adulthood. In full-term infants, the normal erythrocyte life span is 60–80 days
TABLE 16.4 Haematological values from birth to adulthood DIFFERENTIAL COUNTS
Age
Haemoglobin Haematocrit Leucocytes Neutrophils Lymphocytes Eosinophils Monocytes Platelets (g/L) (L/L) (× 109/L) (%) (%) (%) (%) (× 109/L)
Newborn (cord blood)
135–195
0.55
18
61
31
2
6
290
2 weeks
135–195
0.50
12
40
48
3
9
252
3 months
95–135
0.36
12
30
63
2
5
150–450
6 months– 6 years
105–140
0.37
10
45
48
2
5
150–450
7–12 years
115–145
0.38
8
55
38
2
5
150–450
Adult female
115–165
0.41
7.4
54–62
25–33
1–4
3–7
150–450
Adult male
130–180
0.47
7.4
54–62
25–33
1–4
3–7
150–450
Averages (means) are given for each measurement. Continued
PAEDIATRICS
Paediatrics and the haematological system
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Part 3 Alterations to protection and movement
and in premature infants it may be as short as 20–30 days. In children and adolescents erythrocyte life span is the same as that in adults — 120 days. In preschool and school-aged children, haemoglobin, haematocrit and red blood cell counts gradually rise. Metabolic processes within erythrocytes of neonates differ significantly from those found in erythrocytes of normal adults. The relatively young population of erythrocytes in newborns consumes greater quantities of glucose than do erythrocytes in adults. The lymphocytes of children tend to have more cytoplasm and less compact nuclear chromatin than do the lymphocytes of adults. A possible explanation is that children tend to have more frequent viral infections, which are associated with atypical lymphocytes. Minor infections, in which the child fails to exhibit clinical manifestations of illness, and the administration of immunisations may also account for the lymphocyte
changes. At birth the lymphocyte count is high and it continues to rise during the first year of life. Then it steadily declines until the lower value seen in adults is reached. It is unknown whether these developmental variations are physiological or a pathological response to frequent viral infection and immunisations in children. The neutrophil count, like the lymphocyte count, is high at birth and rises during the first days of life. The cause is unknown but may be a result of stress from labour. After 2 weeks, the neutrophil count falls to within or below the normal adult range. By approximately 4 years of age, the neutrophil count is the same as that of an adult. The eosinophil count is high in the first year of life and higher in children than in teenagers or adults. Monocyte counts too are high in the first year of life but then decrease to adult levels. Platelet counts in full-term neonates are comparable with platelet counts in adults and remain so throughout infancy and childhood.
Ageing and the haematological system
F OCU S O N L E ARN IN G
1 Describe the changes in erythrocyte life span from birth through to old age. 2 Describe the changes in haemoglobin levels that occur over the life span. 3 Discuss some of the haematological changes that are found in the elderly.
erythropoietin to anaemia and a subsequent reduction in red blood cell production. Lymphocyte function decreases with age (see Chapter 12), causing changes in cellular immunity and some decline in T cell function. The humoral immune system is less able to respond to challenges to the immune system. The ageing haematopoietic system has a reduced capacity to regenerate and return to normal homeostasis after injury or stress. No changes in platelet numbers or structure have been observed in the elderly, yet evidence shows that platelet adhesiveness probably increases. Although fibrinogen levels and factors V, VII and IX tend to be increased in the elderly, evidence concerning hypercoagulability is inconclusive.
AGEING
Blood composition changes little with age. Erythrocyte life span in the elderly is normal, although erythrocytes are replenished more slowly after bleeding, probably because of iron depletion. Total serum iron, total ironbinding capacity and intestinal iron absorption are all decreased somewhat in the elderly. Iron deficiency is often responsible for the low haemoglobin levels noted in the elderly. Blood circulation in the elderly may be affected by decreased body fluid levels, hypertension and atherosclerosis. The plasma membranes of erythrocytes become increasingly fragile, with portions being lost, presumably because of physical trauma inflicted during circulation. Atrophic gastritis is more common in the elderly leading to vitamin B12 deficiency and possible megaloblastic anaemia. Declining kidney function in the ageing population can cause a decreased response of
CHAPTER 16 The structure and function of the haematological system
405
chapter SUMMARY Components of the haematological system • Blood consists of blood cells suspended in a protein-rich fluid called plasma. • The major functions of blood are the delivery of oxygen and nutrients to the tissues, the removal of wastes from tissues, providing protection against microorganisms and injury, and the maintenance of acid–base balance. • Plasma proteins are involved in blood clotting, microbial defence, transportation of molecules and regulation of biological processes. • Plasma is the fluid found in non-clotted blood, whereas serum is the fluid obtained from clotted blood. • Erythrocytes are the most abundant blood cell and their main role is to provide oxygen to the tissues. • The main role of leucocytes is to defend the body against foreign organisms, but they also have roles in destroying tumour cells and dead or dying cells. • Leucocytes can be classified according to structure as granulocytes (neutrophils, eosinophils and basophils) or agranulocytes (monocytes and lymphocytes) or according to function as phagocytes (neutrophils, eosinophils, basophils, monocytes) or immunocytes (lymphocytes). • Platelets are small blood cells that are important in blood coagulation. • The spleen is one of the largest lymphoid organs and is important for the removal of old or damaged blood cells, microorganisms and debris. • The lymph nodes are part of the haematological and immune systems. Lymphocytes, monocytes and macrophages operate within the lymph nodes to protect the body against foreign invaders. • The mononuclear phagocyte system is the term given to the collection of monocytes and macrophages distributed around the body to remove dead or injured cells and microorganisms.
The development of blood cells • Haematopoiesis is the term used to describe the production of blood cells. • Under normal circumstances haematopoiesis is confined to the bone marrow. • The different types of blood cells all originate from haematopoietic stem cells, which are stimulated by cytokines to develop along a particular pathway. • Erythropoiesis refers to the development of red blood cells.
• Erythropoietin is an important hormone for regulating the production of red blood cells. • Red blood cells are saturated with haemoglobin, a specialised protein that binds to oxygen. • Iron, vitamin B12 and folate are the three most important nutritional requirements for red blood cell development. • Leucopoiesis refers to the production of leucocytes. The rate of leucopoiesis increases in response to infection, stress and other environmental factors. • Thrombopoiesis refers to the production of platelets. Thrombopoietin is the main regulatory hormone in this process.
The mechanisms of haemostasis • The components that are important in haemostasis are platelets, the clotting factors, the fibrinolytic system, natural anticoagulants and the vasculature. • Primary haemostasis involves the formation of a platelet plug at a site of vascular injury. • Activated platelets release numerous substances that can activate further platelets or are involved in haemostasis. • Secondary haemostasis consists of a system of plasma enzymes that result in the formation of a stable fibrin clot. • Tissue factor is the main activator of secondary haemostasis. • Protein C and protein S, antithrombin III and tissue factor pathway inhibitor are naturally occurring anticoagulants that help to control fibrin clot formation. • Plasmin is a fibrinolytic enzyme that removes blood clots. • Heparin is an anticoagulant commonly used to prevent unwanted blood clot formation.
Paediatrics and the haematological function • Blood cell counts tend to rise above adult levels at birth and then decline gradually throughout childhood. • The lymphocytes of children tend to have more cytoplasm and less compact nuclear chromatin than do the lymphocytes of adults. • After childhood, blood composition changes little with age.
Ageing and the haematological system • Lymphocyte function appears to decrease with age.
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CASE STUDY
P AEDIATRIC Brinda is 5 years old and has developed some bruises and tiny red spots on her skin. She has been in otherwise good health apart from a mild respiratory virus recently. Her concerned parents took her to a local medical centre where she was examined by a physician. As Brinda’s temperature was normal and she had no other symptoms apart from the bruising a current infection was ruled out. Palpation of lymph nodes, liver and spleen showed no enlargement. Blood samples were taken and results obtained the following day showed no abnormalities apart from a low platelet count. Brinda was diagnosed with immune thrombocytopenia and referred to a paediatric haematologist at the closest children’s hospital. After a thorough examination at the children’s hospital the haematologist assured Brinda’s parents that Brinda had no major bleeding and was therefore not in serious danger and that the condition was usually self-limiting. Brinda’s parents
were advised not to give Brinda any aspirin or other nonsteroidal anti-inflammatory drugs. A follow-up appointment was arranged for the subsequent week. 1 Define immune thrombocytopenia and discuss its relationship with a viral infection. 2 Discuss the function of platelets and why a low platelet count would cause bruising in Brinda. 3 What other possible conditions/diseases would have been ruled out by the blood tests and physical examination? 4 Discuss the reasons why Brinda should not be given aspirin or other non-steroidal anti-inflammatory drugs. 5 Brinda was not given any treatment for her condition. What treatments are available for immune thrombocytopenia and under what conditions are they given?
CASE STUDY
A DULT Louise is a 24-year-old outdoor sports enthusiast. As a consequence of falling recently while mountain biking, Louise has presented with a laceration in her leg that has become badly infected. Louise has also developed a fever. As part of the clinical management for Louise, a number of laboratory tests have been requested, including a full blood count. The haematology laboratory has completed the full blood count and the results show that Louise’s white cell count is raised well above the reference range.
1 2 3 4 5
What type of blood sample should have been collected to perform a full blood count? Explain how the anticoagulant in the blood collection tube stops the sample from clotting. Which particular type of white cell is likely to be present in increased numbers in Louise’s blood sample? Outline how Louise’s body has been able to rapidly increase the numbers of this type of cell in her blood. Explain how these cells can help Louise to fight her infection.
CASE STUDY
A GEING Van is a 71-year-old man who has been feeling tired for some time. He has put this down to old age but he has recently noticed that he has shortness of breath on exertion and the occasional bout of dizziness. Van’s wife suggests a checkup with the local physician who orders a full blood count and biochemical profile. Results of the full blood count were normal except that Van’s haemoglobin level was 115 g/L (normal for males is 135–170 g/L). Van’s doctor recommends that he includes moderate amounts of lean red meat and plenty of fresh fruit and vegetables in his diet and suggests that it may be necessary for Van to see
a gastroenterologist to investigate the possibility of a small bleed in the gastrointestinal tract. 1 Explain the function of haemoglobin. 2 Why would low haemoglobin levels cause the symptoms that Van is experiencing? 3 Explain why Van’s doctor recommended a diet that includes red meat, fruit and vegetables. 4 Explain the relationship between anaemia and bleeding in the gastrointestinal tract. 5 Discuss reasons why the elderly may be anaemic despite adequate nutrition.
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REVIEW QUESTIONS 1 Describe the fluid components of the blood, including a comparison between plasma and serum. 2 Name the different types of blood cells that are normally found in the peripheral blood. 3 Explain the functions of blood. 4 What is haematopoiesis and where does it occur? 5 What is leucopoiesis?
6 7 8 9
What is haemoglobin and what functions does it perform? Briefly describe primary haemostasis. Explain why tissue factor is important in haemostasis. Explain the processes which occur in the body to limit haemostasis. 10 What is fibrinolysis?
Key terms
CHAPTER
17
Alterations of haematological function across the life span Moira Stephens
Chapter outline Introduction, 409 Alterations of erythrocyte function, 409 Anaemia, 409 Inherited blood disorders, 415 Myeloproliferative red cell disorders, 416 Alterations of platelets and coagulation, 417 Platelet disorders, 417 Disorders of coagulation, 419 Haemostasis therapy, 424
408
Alterations of leucocytes, 424 Alterations of leucocyte count, 424 Alterations of leucocyte function, 426 Alterations of lymphoid function, 430 Lymphadenopathy, 430 Malignant lymphomas, 431
agranulocytosis, 425 anaemia, 409 aplastic anaemia, 415 B-cell neoplasms, 431 disseminated intravascular coagulation (DIC), 422 embolus, 421 folate, 414 granulocytopenia, 425 granulocytosis, 425 haemolysis, 411 haemolytic disease of the newborn, 416 haemophilia, 420 heparin-induced thrombocytopenia syndrome, 418 Hodgkin’s lymphoma, 432 hypercoagulability, 422 hypoxaemia, 410 hypoxia, 410 impaired haemostasis, 420 infectious mononucleosis, 426 iron deficiency anaemia, 411 leucocytosis, 424 leucopenia, 424 leukaemia, 426 lymphadenopathy, 430 natural killer-cell (NK-cell) neoplasms, 431 neutropenia, 425 neutrophilia, 425 pancytopenia, 428 polycythaemia, 417 post-haemorrhagic anaemia, 415 Reed-Sternberg (RS) cells, 432 T-cell neoplasms, 431 thrombocytopenia, 417 thrombus, 421 Virchow’s triad, 422
CHAPTER 17 Alterations of haematological function across the life span
Introduction Haematological function refers to both the production (haematopoiesis) and the function of blood cells. Under normal conditions, changes occur to haematological function in early life; however, beyond childhood, little variation is seen in the healthy individual. Pathological alteration to function occurs either as a consequence of haematological disease or secondary to other processes. Alterations in haematological function may be due to: an alteration of function of the bone marrow itself (thus increasing or decreasing the number of blood cells produced); alteration in the function of haematopoietic stem cells; changes in the function of the blood cell line and thus the function of the cell itself; or alterations in the immune response (such as an autoimmune disorder causing destruction of blood cells). Some kinds of disorders affecting haematological function vary with age and others occur across the life span. This chapter examines some of the important alterations to haematological function within the context of the life span and presents them in the context of the three key kinds of blood cell (erythrocytes, platelets and leucocytes) and their function.
Alterations of erythrocyte function Anaemia is the commonest manifestation of altered erythrocyte function. Anaemia is a reduction in the oxygen carrying capacity of the blood, and may be due to insufficient numbers of erythrocytes, or an insufficient amount of haemoglobin. Polycythaemia is a condition that arises from excessive levels of erythrocytes; it is much less common that anaemia. Haematocrit levels are altered by both anaemia (showing a decreased haematocrit) and by polycythaemia (showing an elevated haematocrit) (see Fig. 17.1 and Table 17.1).
Anaemia
Anaemia is defined as a reduction in the haemoglobin concentration of the blood with a decrease in the total number of circulating erythrocytes. In broad terms, inadequate numbers of erythrocytes may result from either lack of red cell production (which is the more common type) or excessive destruction of red cells. Anaemia may also arise due to loss of blood volume in haemorrhage (see Fig. 17.2). World Health Organization (WHO) definitions for anaemia differ by age, sex, and pregnancy status as follows, based on the amount of haemoglobin (Hb): for children 6 months to 5 years of age anaemia is defined as a Hb level < 110 g/L, children 5–11 years of age Hb < 115 g/L, adult males Hb < 130 g/L, non-pregnant adult females Hb < 120 g/L, and pregnant females Hb < 110 g/L. Severe anaemia is defined as Hb < 70 g/L.1 Inherited defects can cause anaemia. With the notable exception of haemolytic disease of the newborn, acquired
A
B
409
C
Plasma
Buffy coat
WBCs and platelets RBCs
FIGURE 17.1
Haematocrit tubes showing normal blood, anaemia and polycythaemia. Note the buffy coat located between the packed red blood cells (RBCs) and the plasma. A A normal percentage of red blood cells. B Anaemia (a low percentage of red blood cells). C Polycythaemia (a high percentage of red blood cells).
types of anaemia can occur at any stage of the life span. Iron deficiency, renal disease and chronic inflammation are common causes of anaemia. In the clinical setting, comorbidities may contribute to the development of anaemia, such that no single cause may be identifiable. Anaemia is a common finding in the elderly, especially men, and is frequently multifactorial in origin.
Classification of anaemia
Different types of anaemia are classified by their causes or by the changes that affect the size, shape or substance of the erythrocyte. The most common classification is based on the changes that affect the cell’s size and haemoglobin content. The mean corpuscular volume (MCV; in this context, the term ‘corpuscular’ refers to the erythrocyte) and mean corpuscular haemoglobin (MCH) are the laboratory measurements that are used respectively to determine red cell size and haemoglobin content (which gives the erythrocyte its red appearance). These measurements form part of a full blood count. Terms used to identify types of anaemia reflect these characteristics. Terms that end with cytic refer to cell size and those that end with chromic refer to haemoglobin content. Anaemia may be either microcytic (small), normocytic (normal) or macrocytic (large) in relation to red cell size and either hypochromic (pale) or normochromic in relation to red cell haemoglobin content. The term hyperchromic is not used, as red cells usually contain maximal amounts of haemoglobin. The erythrocytes may also demonstrate more general poikilocytosis (variation in shape) and anisocytosis (variation in size).
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TABLE 17.1 Blood tests for erythrocyte disorders CELL TYPE AND TEST
PROPERTY EVALUATED BY TEST
POSSIBLE HAEMATOLOGICAL CAUSE OF ABNORMAL FINDINGS
Erythrocyte Red cell count
Number (× 1012) of erythrocytes/litre of blood
Altered erythropoiesis, anaemias, haemorrhage, Hodgkin’s lymphoma, leukaemia
Mean cell volume (MCV)
Size of erythrocytes
Anaemias, thalassaemias
Mean corpuscular haemoglobin (MCH)
Amount of haemoglobin in each erythrocyte (by weight)
Anaemias
Haemoglobin determination
Amount of haemoglobin (by weight)/ litre of blood
Anaemias
Haematocrit determination
Proportion of a given volume of blood that is occupied by erythrocytes (expressed as L/L or %)
Haemorrhage, polycythaemia, erythrocytosis, anaemias, leukaemia
Reticulocyte count
Number of reticulocytes (× 109)/litre of blood
Hyperactive or hypoactive bone marrow function
Serum ferritin determination
Depletion of body iron (potential deficiency of haem production)
Iron deficiency anaemia
Total iron-building capacity (TIBC)
Amount of iron in serum plus amount of transferrin available in serum
Haemorrhage, iron deficiency anaemia, haemochromatosis, iron overload, anaemias, thalassaemia
Transferrin saturation
Percentage of transferrin that is saturated with iron
Acute haemorrhage, haemochromatosis, iron deficiency anaemia, iron overload, thalassaemia
Haemoglobin metabolism
A blood film examination can further assist in defining the type of anaemia and possible cause. Further laboratory tests (e.g. iron or ferritin studies) or a bone marrow examination (aspiration or biopsy) may be required to complete the investigation.
General clinical manifestations of anaemia
The fundamental alteration of anaemia is a reduced oxygen-carrying capacity of the blood resulting in tissue hypoxia (low oxygen content in the tissues). Symptoms of anaemia vary, depending on the body’s ability to compensate for the reduced oxygen-carrying capacity. The most common symptoms are fatigue, feeling cold and pallor (being pale), although in mild anaemia and where compensation has occurred over time, the individual may be asymptomatic. Anaemia that is mild and starts gradually is usually easier to compensate for and may cause problems for the individual only during physical exertion. As the reduction in the number and efficacy of red cells continues, symptoms become more pronounced and alterations in specific organs and compensation effects are more apparent. Compensation generally involves the cardiovascular, respiratory and haematological systems (Fig. 17.3). A reduction in the number of blood cells in the blood causes a reduction in the consistency and volume of blood. Initial compensation for cellular loss is movement of
interstitial fluid into the blood causing an increase in plasma volume (see Fig. 17.4). This movement maintains an adequate blood volume, but the viscosity (thickness) of the blood decreases. The ‘thinner’ blood flows faster and more turbulently than normal blood, causing a hyperdynamic circulatory state. This hyperdynamic state creates cardiovascular changes — increased stroke volume and heart rate. These changes may lead to cardiac dilation and heart valve insufficiency if the underlying anaemic condition is not corrected. Hypoxaemia, reduced oxygen level in the blood, further contributes to cardiovascular dysfunction by causing dilation of arterioles, capillaries and venules, thus increasing the volume of blood flow through them. Increased peripheral blood flow and venous return further contribute to an increase in heart rate and stroke volume in a continuing effort to meet normal oxygen demand and prevent cardiopulmonary congestion. These compensatory mechanisms may lead to heart failure (refer to Fig. 17.3). Tissue hypoxia creates additional demands and effects on the pulmonary and haematological systems. The rate and depth of breathing increases in an effort to increase oxygen availability and this is also accompanied by an increase in the release of oxygen from haemoglobin. All of these compensatory mechanisms may cause individuals to experience shortness of breath (dyspnoea), a rapid and
CHAPTER 17 Alterations of haematological function across the life span
NORMAL Normal production rate of new erythrocytes
Normal loss of old erythrocytes
ANAEMIA Low production rate of erythrocytes
Excessive loss of erythrocytes
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disturbances, extreme weakness, spasticity and reflex abnormalities. Decreased oxygen supply to the gastrointestinal tract often produces abdominal pain, nausea, vomiting and anorexia. Low-grade fever occurs in some anaemic individuals and may result from the release of leucocyte pyrogens from ischaemic tissues (refer to Chapter 13). When the anaemia is severe or acute in onset (e.g. due to haemorrhage), the initial compensatory mechanism is peripheral blood vessel constriction, diverting blood flow to essential vital organs (the brain, heart and lungs are the highest priority). Decreased blood flow detected by the kidneys activates the renin-angiotensin response, leading to sodium and water retention in an attempt to increase blood volume. These situations are considered to be emergencies and require immediate intervention to correct the underlying problem that caused the acute blood loss; therefore, long-term compensatory mechanisms do not develop. Therapeutic interventions for slowly developing anaemic conditions require treatment of the underlying condition and palliation of associated symptoms. Anaemia associated with chronic conditions is largely thought to be related to chronic inflammation, except in the presence of chronic kidney failure where it is due to the decline in the production of erythropoietin by the kidneys that is necessary for erythrocyte development. Therapies include transfusion, dietary correction and administration of supplemental vitamins or iron.
Anaemia due to insufficient erythrocyte production
FIGURE 17.2
Erythrocyte levels with anaemia. Erythrocyte levels are normally maintained by the rate of production balancing the rate of loss. In anaemia, there is usually insufficient production and/or excessive loss of erythrocytes.
pounding heartbeat, dizziness and fatigue. In mild chronic cases, these symptoms may be present only when there is an increased demand for oxygen (e.g. during physical exertion), but in severe cases symptoms may be experienced even at rest. Manifestations of anaemia may be seen in other parts of the body. The skin, mucous membranes, lips, nail beds and conjunctivae become either pale because of reduced haemoglobin concentration or yellowish (jaundiced) because of the accumulation of the end products of red cell destruction (haemolysis) if that is the cause of the anaemia. Tissue hypoxia of the skin results in impaired healing and loss of elasticity, as well as thinning and early greying of the hair. Nervous system manifestations may occur where the cause of anaemia is a deficiency of vitamin B12. Myelin degeneration occurs, causing a loss of nerve fibres in the spinal cord, resulting in paraesthesias (numbness), gait
There are several different causes that may lead to inability to produce adequate levels of erythrocytes. Many of these causes include lack of availability of the necessary nutrients for the steps involved in red cell production. IRON DEFICIENCY ANAEMIA
Iron deficiency anaemia is the most common type of anaemia throughout the world, occurring in both developing and developed countries but is disproportionately higher in developing countries.2 Females have a higher incidence than males for iron deficiency anaemia, with the peak incidence occurring in the reproductive years and decreasing at menopause. There are higher demands for iron during pregnancy and, as fetal iron stores are accumulated in the third trimester (the final stages of pregnancy), premature infants have a greater risk of iron deficiency. Iron deficiency anaemia is also the most common blood disorder of infancy and childhood, with the highest incidence occurring between the ages of 6 months and 2 years. Incidence is not related to gender or race, but socioeconomic factors are important because they affect nutrition. PATHOPHYSIOLOGY
Iron deficiency anaemia may result from inadequate iron intake or absorption, increased iron requirements (such as during growth) or excessive iron loss. The red cells are
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CONCEPT MAP
Causes including haemorrhage, decreased erythropoiesis and increased erythrocyte destruction increases Red blood cells, haemoglobin (anaemic condition) decreases Oxygen-carrying capacity (hypoxaemia)
Ischaemia
leads to
manifests as
Weakness, fatigue
Tissue hypoxia
manifests as
Respiratory (↑ respiratory rate, depth, ‘exertional dyspnoea’)
Skin pallor
including
Compensatory mechanisms
↑ Heart rate
Central nervous system (dizziness, fainting, lethargy)
Renal
Cardiovascular increases Stroke volume
Heart rate
increases Renin-aldosterone response Salt and H2O retention Extracellular fluid volume changes
leads to Hyperdynamic increase circulation
leads to increase
Extracellular fluid causes
leads to increase
Blood pressure
FIGURE 17.3
The progression and manifestation of anaemia. In response to a low oxygen-carrying capacity, tissue hypoxia leads to clinical symptoms ranging from skin pallor to exertional dyspnoea. Compensatory mechanisms include increased heart rate and blood pressure.
microcytic and hypochromic, so small and pale respectively as well as low in number. Iron deficiency anaemia is common in children because they need an extremely high amount of iron for normal growth to occur. During adolescence, iron deficiency anaemia is relatively common in menstruating females; menorrhagia (excessive menstrual bleeding) results in considerable iron loss with the menstrual fluid and causes iron deficiency anaemia.
Males and females may experience iron deficiency anaemia due to bleeding as a result of ulcers, hiatus hernia, oesophageal varices, cirrhosis, haemorrhoids, ulcerative colitis, drugs that cause gastrointestinal bleeding or cancer. Although iron is recycled in the body (see Chapter 16), blood loss disrupts this balance by creating a need for more iron, thus depleting the iron stores more rapidly to replace the iron lost from bleeding.
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FIGURE 17.6
Koilonychia. The nails are concave, ridged and brittle. FIGURE 17.4
Fluid shift in anaemia. A Normal proportion of erythrocytes and plasma in blood. B Fewer erythrocytes in fluid moving into plasma. Although blood volume is maintained, the blood is much less viscous (less thick).
FIGURE 17.7
FIGURE 17.5
Pallor and iron deficiency. Pallor of the skin, mucous membranes and palmar creases in an individual with haemoglobin of 90 g/L. The palmar creases become as pale as the surrounding skin when the haemoglobin level approaches 70 g/L.
Insufficient dietary intake of iron leads to iron deficiency anaemia. In addition, surgical procedures that decrease the stomach acidity, decreased intestinal transit time and intestinal abnormality (such as coeliac disease) will limit the absorption of iron. CLINICAL MANIFESTATIONS
The onset of symptoms is gradual and usually individuals do not seek medical attention until haemoglobin levels drop to 70 or 80 g/L. Early symptoms are nonspecific and include fatigue, weakness, shortness of breath, palpitations and pale ear lobes, palms and conjunctiva (see Fig. 17.5). As the condition progresses and becomes more severe, structural and functional changes occur in epithelial tissue. The fingernails become brittle and ‘spoon-shaped’ or concave (koilonychia) (see Fig. 17.6). Tongue papillae atrophy and cause soreness along with redness and burning (see Fig. 17.7). These changes can be reversed within 1 to 2 weeks of iron replacement. The corners of the mouth become dry
Glossitis. The tongue of an individual with iron deficiency anaemia has a bald, fissured appearance caused by loss of papillae and flattening.
and sore (angular stomatitis) and an individual may experience difficulty with swallowing because of a ‘web’ that develops from mucus and inflammatory cells at the opening of the oesophagus. These lesions have the potential to become cancerous. Iron is a component of many enzymes in the body and lack of iron may alter other physiological processes and contribute to the clinical manifestations. Individuals with iron deficiency anaemia exhibit gastritis, neuromuscular changes, irritability, headache, numbness, tingling and vasomotor disturbances. Gait disturbances are rare. In the elderly, mental confusion, memory loss and disorientation may be wrongly perceived as normal events associated with ageing. In children, parents generally do not note any change in the child’s behaviour or appearance until moderate anaemia has developed. General irritability, decreased activity tolerance, weakness and lack of interest in play are nonspecific indications of anaemia. When haemoglobin levels fall below 50 g/L, pallor, anorexia, tachycardia and systolic murmurs may occur. Other symptoms and signs include splenomegaly, widened skull sutures, decreased
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physical growth and developmental delays, pica (a behaviour in which non-food substances are eaten) and altered neurological and intellectual functions, especially those involving attention span, alertness and learning ability.
Neurological manifestations, if present, may be caused by thiamine deficiency, which often accompanies folate deficiency.
EVALUATION AND TREATMENT
Evaluation of folate deficiency is based on blood tests, measurement of serum folate levels and clinical manifestations. Treatment requires administration of oral folate preparations until adequate blood levels are obtained and manifestations are reduced or eliminated. Long-term therapy is not necessary except for maintaining an adequate daily intake of folate. Folate is essential for reducing blood levels of homocysteine, which has been recently recognised as a risk factor for the development of coronary artery disease.
Evaluation is based on clinical manifestations and laboratory tests. Iron stores are measured directly by bone marrow biopsy, or indirectly by tests that measure serum ferritin (circulating levels of iron in the blood), transferrin saturation (transferrin transports iron through the blood) or total iron-binding capacity. The first step in the treatment of iron deficiency anaemia is to find and eliminate potential sources of blood loss. If this is not done, replacement therapy is ineffective. Iron replacement therapy is required and very effective. Initial doses are 150–200 mg/day and are continued until the serum ferritin level reaches 50 mg/L, indicating that adequate replacement has occurred. A rapid decrease in fatigue, lethargy and other associated symptoms is generally seen within the first month of therapy. Replacement therapy usually continues for 6–12 months after the bleeding has stopped but may continue for as long as 24 months. Menstruating females may need daily therapy (325 mg/ day) until menopause. FOLATE DEFICIENCY ANAEMIA
Folate (folic acid) is an essential vitamin required for DNA production within the developing erythrocyte. Folate deficiency anaemia is also known as megaloblastic anaemia because the erythrocytes are macrocytic (very large). The cellular contents are not completely developed and may have a shorter than normal (120 days) life span. The cells may be oval in shape and, because they are abnormal, the bone marrow produces fewer of them. Humans are totally dependent on dietary intake to meet the daily requirement of 50–200 mg/day. Folate is absorbed from the upper small intestine and is then stored in the liver. Folate deficiency occurs more often than vitamin B12 deficiency (discussed next), particularly in alcoholics and individuals who are malnourished because of fad diets or diets low in vegetables. Increased amounts are required for lactating and pregnant females. Folate deficiency during pregnancy can result in the birth of infants with neural tube defect. This has led to the promotion of folic acid supplementation in women of childbearing age.3 Also, some foods are now fortified with folate in Australia and New Zealand (details in Chapter 9).
EVALUATION AND TREATMENT
PERNICIOUS ANAEMIA
Pernicious anaemia is a specific term used to define the anaemia caused by the absence of intrinsic factor. Normal levels of stomach secretions are necessary for the secretion of intrinsic factor; this travels to the intestines, along with the vitamin B12, where intrinsic factor is necessary for vitamin absorption (refer to Fig. 17.8). Pernicious anaemia may accompany chronic atrophic gastritis;4 complete or partial removal of the stomach (gastrectomy) also causes intrinsic factor deficiency and results in pernicious anaemia. Insufficient intrinsic factor affects normal red blood cell development so that they are macrocytic (large cells) and these defective cells die early, resulting in insufficient numbers of erythrocytes. As for folate deficiency anaemia, they are also normochromic in pernicious anaemia. Pernicious means highly injurious or destructive and reflects the fact that this condition was once fatal. It typically
CLINICAL MANIFESTATIONS
Clinical manifestations are similar to the malnourished appearance of individuals with pernicious anaemia (see below), except for the absence of neurological symptoms. Specific manifestations include cheilosis (scales and fissures of the mouth), stomatitis (inflammation of the mouth) and painful ulcerations of the buccal mucosa and tongue. Dysphagia, flatulence and watery diarrhoea may also be present, as well as histological changes in the gastrointestinal tract suggestive of coeliac disease (refer to Chapter 27).
FIGURE 17.8
The absorption of vitamin B12. Normal levels of intrinsic factor must be secreted in the stomach to facilitate the absorption of vitamin B12 in the small intestine.
CHAPTER 17 Alterations of haematological function across the life span
develops in middle age or later (generally after 40 years of age) and is rare in children. CLINICAL MANIFESTATIONS
Pernicious anaemia develops slowly (over 20 to 30 years), so that by the time an individual seeks treatment, it is usually severe. Early symptoms are often ignored because they are nonspecific and vague — they include infections, mood swings and gastrointestinal, cardiac or kidney ailments. When the haemoglobin has decreased to 70–80 g/L, the individual experiences the classic symptoms of anaemia: weakness, fatigue, paraesthesias of the feet and fingers, difficulty walking, loss of appetite, abdominal pain, weight loss and a sore tongue that is smooth and beefy red. The skin may become ‘lemon yellow’ (sallow), caused by a combination of pallor and jaundice (yellow colouration due to build-up of bilirubin). Neurological abnormalities may develop such as numbness, weakness and an unsteady gait. EVALUATION AND TREATMENT
Evaluation is based on blood tests, bone marrow aspiration, serological studies, gastric biopsy, clinical manifestations and the Schilling test. This test involves administering radioactive vitamin B12 to the patient and then measuring its excretion in the urine. Low urinary excretion is significant for pernicious anaemia. Serological studies reveal the presence of antibodies against gastric cells and gastric biopsy reveals achlorhydria, a total absence of hydrochloric acid. Untreated pernicious anaemia is fatal, usually because of resulting heart failure. With vitamin B12 replacement therapy, mortality has decreased significantly.5 Death from this disease is now rare and relapses are often the result of noncompliance with therapy. Initial replacement of vitamin B12 is accomplished by weekly injections until the deficiency is corrected. Monthly injections are then required for the remainder of an individual’s life. Although oral preparations were previously considered ineffective (as no intrinsic factor would prevent absorption of B12), recent practice has shown that oral administration of higher doses of B12 is beneficial. There is an association between low folate and vitamin B12 levels and ageing populations. Undiagnosed B12 deficiency in aged care is relatively common and may manifest as neurological conditions such as dementia.6,7 APLASTIC ANAEMIA
Aplastic anaemia manifests as a failure of the bone marrow to produce blood cells. Causes of aplastic anaemia are thought to be due to exposure to chemicals, drugs, radiation, infection and autoimmune disease. In about 50% of cases however, the cause is unknown and diagnosis is by exclusion of other pathologies or conditions (e.g. pancytopenia, which occurs during chemotherapy, where all blood counts are low; refer to Chapter 37). Prognosis and treatment depend on severity, response to immunosuppressive therapy, age, and the availability of a matched bone marrow transplant donor as this is usually the only option offering a long-term cure.
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RENAL ANAEMIA
Diseases affecting the kidneys can result in the impaired ability of the kidneys to detect hypoxaemia and respond by producing and secreting erythropoietin. Without adequate levels of erythropoietin, production of erythrocytes will be deficient. In this case, the anaemia is secondary to the kidney disease (see Chapter 30 for discussion of kidney disease).
Anaemia due to excessive erythrocyte loss
Loss or destruction of erythrocytes leads to anaemia. Loss of erythrocytes may occur following haemorrhage, and destruction of erythrocytes occurs with haemolysis or haemolytic anaemia. Destruction of erythrocytes also occurs with haemolytic disease of the newborn although this is now an extremely rare disease in Australia and New Zealand due to prophylactic (preventive) treatment. POST-HAEMORRHAGIC ANAEMIA
Sudden blood loss occurs too quickly for production of replacement erythrocytes. This is referred to as post-haemorrhagic anaemia. Complications arising from haemorrhage are discussed in Chapter 23. Slower losses of blood such as those due to gastric bleeds are able to be compensated. MALARIAL ANAEMIA
The highest prevalence of anaemia is in the developing world. About 40% of the world’s population is exposed to malaria and there are up to 500 million cases per year. A major complication of falciparum malaria is severe malarial anaemia. It is thought that haemolysis (destruction of red blood cells) is the primary alteration although the mechanism is not fully understood and it is the leading cause of death in people with malaria.8
Inherited blood disorders
Thalassaemia is the most common inherited disorder and affects the production of haemoglobin causing there to be less circulating haemoglobin as well as fewer circulating erythrocytes as they become weak and are destroyed. There are several different kinds of thalassaemia depending on which chain of the haemoglobin molecule is affected. The different kinds of thalassaemia vary in severity and thus in prognosis and management. Sickle cell anaemia is also an inherited disorder of the haemoglobin which is characterised by erythrocytes changing shape and becoming rigid and ‘sickle’ shaped. Manifesting with severe pain and anaemia, sickle cell anaemia also varies in severity and thus prognosis and treatment. Sickle cell anaemia is protective in malarial infection. Both of these conditions are very rare in Australia. Whereas the World Health Organization estimates that approximately 5% of the world’s population are carriers for haemoglobinopathies, the total number of affected infants per 1000 in Australia is 0.1 births per 1000 infants rising to 0.2–0.99 births per 1000 births in some parts of Victoria (for all haemoglobinopathies).9
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HAEMOLYTIC DISEASE OF THE NEWBORN
Haemolytic disease of the newborn (erythroblastosis fetalis) is an acquired congenital haemolytic anaemia. It occurs when the fetal blood type differs from that of the mother. The risk occurs when a mother who is Rh-negative carries an Rh-positive fetus. The first Rh-incompatible pregnancy generally presents no difficulties because few fetal erythrocytes cross the placental barrier. When the placenta detaches at birth, however, a large number of fetal erythrocytes usually enter the mother’s bloodstream. This can cause the mother to develop anti-Rh antibodies (see Fig. 17.9). During subsequent pregnancy, these antibodies can cross the placenta and bind to and destroy the fetal erythrocytes (haemolysis). Neonates with mild haemolytic disease of the newborn may appear healthy or slightly pale, with slight enlargement of the liver or spleen. Pronounced pallor, splenomegaly and hepatomegaly indicate severe anaemia, which predisposes the neonate to cardiovascular failure and shock. Routine evaluation of fetuses at risk for haemolytic disease of the newborn measures antibodies in the
mother’s circulation and indicates whether the fetus is at risk. The key to treatment of haemolytic disease of the newborn resulting from Rh incompatibility lies in prevention (immunoprophylaxis). One of the success stories of immunology has been the result obtained with Rh immune globulin, a preparation of IgG antibody against Rh antigen (Rhogam in Australia). If an Rh-negative woman is given Rh immune globulin within 72 hours of exposure to Rh-positive erythrocytes, she will not produce an antibody against the D antigen and the next Rh-positive baby she conceives will therefore be protected.
Myeloproliferative red cell disorders
Haematological dysfunction also results from an over-production of cells, as well as deficiency. One or more marrow elements may be produced in excess, responding to processes arising from within the body, such as a physiological compensatory response or as a result of an immune disorder. Also, external factors such as radiation
Maternal circulation
A A
Maternal Rh-negative erythrocyte
B Maternal circulation Maternal Rh-negative erythrocyte
Fetal Rh-positive erythrocyte enters maternal circulation
Fetal Rh-positive erythrocyte
Rh antibodies
Maternal circulation
C Agglutination of fetal Rh-positive erythrocytes leads to haemolytic disease of the newborn
Maternal Rh antibodies cross the placenta
FIGURE 17.9
Haemolytic disease of the newborn. A Before or during delivery, Rh-positive erythrocytes from the fetus enter the blood of the Rh-negative mother through a tear in the placenta. B The mother is sensitised to the Rh antigen and produces anti-Rh antibodies. Because this usually happens after delivery, there is no effect on the fetus in the first pregnancy. C During a subsequent pregnancy with an Rh-positive fetus, Rh-positive erythrocytes cross the placenta, enter the maternal circulation and stimulate the mother to produce antibodies against the Rh antigen. The anti-Rh antibodies from the mother cross the placenta, using agglutination and haemolysis of fetal erythrocytes, and haemolytic disease of the newborn develops.
CHAPTER 17 Alterations of haematological function across the life span
F O CUS O N L E A R N IN G
1 Describe how cell size and haemoglobin content can be used to classify anaemia. 2 List some of the physiological effects of anaemia. 3 Explain how a deficiency of vitamin B12 can cause anaemia. 4 Describe the different stages of development of iron deficiency anaemia. 5 Explain how blood group antibodies produced in a pregnant woman can cause haemolysis of fetal red cells. 6 Explain what is meant by the term polycythaemia. 7 Discuss the difference between relative and absolute polycythaemia.
and drugs can lead to haematological dysfunction. Excessive red cell production is classified as polycythaemia. Polycythaemia exists in two forms: relative and absolute. • Relative polycythaemia results from haemoconcentration of the blood associated with dehydration. It is of minor consequence and resolves with fluid administration or treatment of underlying conditions. • Absolute polycythaemia consists of two forms: primary and secondary. Secondary polycythaemia, the more common of the two, is a physiological response resulting from erythropoietin secretion caused by hypoxia. This hypoxia is noted in individuals living at high altitudes (> 3000 metres), smokers with increased blood levels of carbon monoxide and individuals with chronic obstructive pulmonary disease or coronary heart failure, or both. Abnormal types of haemoglobin, which have a greater affinity for oxygen also cause secondary polycythaemia, as does inappropriate secretion of erythropoietin by certain tumours (some renal, hepatic or brain tumours). The absolute primary form of polycythaemia is referred to as polycythaemia vera and is due to excessive production of red blood cells despite low levels of erythropoietin; this is a rare condition.
Alterations of platelets and coagulation In this section, we consider abnormalities that relate to excessive or insufficient levels of haemostasis. These may arise due to alterations in either platelet formation (which normally forms a platelet plug) or the coagulation process (which leads to the formation of the fibrin mesh). Common laboratory tests to assess platelet and clotting factor function are listed in Table 17.2.
Platelet disorders
Alterations in the number or function of platelets can interrupt normal blood coagulation and prevent haemostasis. The main abnormality in the platelet number is
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thrombocytopenia, a decrease in the number of circulating platelets. Disorders of platelet function can coexist with disorders of the number of platelets. The disorders of platelet function usually result in the prevention of platelet adherence and aggregation, thereby preventing formation of a platelet plug.
Thrombocytopenia
Thrombocytopenia is defined as a platelet count below 150 × 109/L of blood, although most clinicians do not consider the decrease significant unless it falls below 100 × 109/L. The risk for haemorrhage associated with minor trauma is not substantial until the count falls below 50 × 109/L. Spontaneous bleeding without trauma can occur with counts ranging from 10 to 15 × 109/L. When this happens, skin manifestations (petechiae, ecchymoses and larger purpuric spots) are observed or frank bleeding from mucous membranes occurs. Petechiae, ecchymoses and purpura are areas of bleeding underneath the skin causing purple discolouration that does not blanch on pressure. These skin manifestations are essentially differentiated by size: purpura measure 0.3–1 cm (3–10 mm), whereas petechiae measure less than 3 mm, and ecchymoses greater than 1 cm. Severe bleeding results if the count falls below 10 × 109/L and can be fatal if it occurs in the gastrointestinal, respiratory or central nervous systems. In the bone marrow transplant or oncology setting, a platelet count as low as 10 × 109/L can be tolerated before platelet transfusions are required. Before thrombocytopenia is diagnosed, careful attention needs to be paid to the procedures used in obtaining the blood sample. A traumatic venepuncture or incorrect mixing of blood samples after blood collection can result in platelet activation or clot formation (thus platelet aggregation) in the blood collection tube. Also, any abnormalities in the laboratory testing of the blood need to be ruled out. In approximately 1 in 1000 to 10 000 blood samples, the platelets may form an aggregate (platelet plug) after the blood sample is obtained; platelets that are incorporated into the aggregate are not available to be counted by an automated cell counter. Finally, other physiological conditions such as hypothermia (< 25°C) can predispose to a thrombocytopenic state, which is reversed when temperatures return to normal, suggesting that the platelets are being sequestered by the spleen for later release back to the blood. PATHOPHYSIOLOGY
Thrombocytopenia results from decreased platelet production, or increased consumption, or both. The condition may be either congenital or acquired and either primary or secondary to other conditions. Thrombocytopenia secondary to congenital conditions occurs in a large number of different diseases, although each is relatively rare. Acquired thrombocytopenia is more common and may occur in relationship with acute viral infections (Epstein-Barr virus, rubella and HIV), drug reactions, autoimmune diseases, nutritional deficiencies, aplastic anaemia or cancer. Thrombocytopenia that results from decreased platelet
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TABLE 17.2 Laboratory tests of haemostasis CELL TYPE AND TEST
POSSIBLE HAEMATOLOGICAL CAUSE OF ABNORMAL FINDINGS
PROPERTY EVALUATED BY TEST
Platelets and clotting factors Platelet count
Number of circulating platelets (× 109)/litre of blood
Anaemias, multiple myeloma, myelofibrosis, polycythaemia vera, leukaemia, disseminated intravascular coagulation (DIC), haemolytic disease of the newborn, transfusion reaction, lymphoproliferative disorders
Platelet function analysis
Ability of platelets to adhere and aggregate under standardised conditions simulating small blood vessel injury
Inherited and acquired platelet function disorders, storage pool disorder, von Willebrand’s disease
Platelet aggregation tests
Ability of platelets to adhere to one another (aggregate) in response to different activators
Inherited and acquired platelet function disorders, storage pool disorder, von Willebrand’s disease
Activated partial thromboplastin time (aPTT)
Effectiveness of plasma clotting factors of the intrinsic and common pathways of the coagulation cascade, as measured by the time taken for a clot to form in a test tube (in seconds)
Presence of circulating anticoagulants, DIC, clotting factor deficiencies, excessive fibrinolysis, haemorrhagic disease of the newborn, hypofibrinogenaemia, dysfibrinogenaemia and afibrinogenaemia, prothrombin deficiency, von Willebrand’s disease, acute haemorrhage
Prothrombin time
Effectiveness of plasma clotting factors of the extrinsic and common pathways of coagulation cascade, as measured by the time taken for a clot to form in a test tube (in seconds)
Hypofibrinogenaemia, dysfibrinogenaemia, and afibrinogenaemia; presence of circulating anticoagulants; DIC; clotting factor deficiency; presence of fibrin degradation products, increased fibrinolytic activity, haemolytic jaundice, haemorrhagic disease of the newborn; acute leukaemia, polycythaemia vera, multiple myeloma
Thrombin time
Quantity and activity of fibrinogen as measured in a test tube (in seconds)
Hypofibrinogenaemia, dysfibrinogenaemia, and afibrinogenaemia; presence of circulating anticoagulants; haemorrhagic disease of the newborn, polycythaemia vera; increase in fibrinogenfibrin degradation products; increased fibrinolytic activity
Fibrinogen assay
Amount of fibrinogen available for fibrin formation
Acute leukaemia, congenital hypofibrinogenaemia or afibrinogenaemia, DIC, increased fibrinolytic activity, severe haemorrhage
Fibrin-fibrinogen degradation products (fibrin-fibrinogen split products)
Transfusion reactions, DIC, internal haemorrhage Fibrinogenic activity as measured by levels of fibrin-fibrinogen degradation products (in in the newborn, deep vein thrombosis, pulmonary embolism mg/L of blood)
production is usually the result of nutritional deficiencies (vitamin B12 or folic acid), drugs (e.g. chemotherapeutic agents, alcohol), radiation therapy or bone marrow infiltration by some cancers. Most common forms of thrombocytopenia are the result of increased platelet consumption. The main examples are heparin-induced thrombocytopenia and disseminated intravascular coagulation (discussed in the section on disorders of coagulation). HEPARIN-INDUCED THROMBOCYTOPENIA SYNDROME
Heparin is used clinically prior to surgery to inactivate clotting factor X and thrombin, thereby preventing
coagulation during surgery. Specifically, it can reduce the risk of venous thromboembolism (see Chapter 23) and pulmonary embolism (see Chapter 25). Heparin is also used in the days after surgery to continue to prevent coagulation, particularly until the patient is mobilised, when the risk of unwanted clotting is lower. Approximately 4% of individuals treated with heparin develop heparin-induced thrombocytopenia syndrome. The incidence is lower (about 0.1%) with the use of low-molecular-weight heparin, a structurally different form of heparin that may be more effective in some types of surgery. Heparin-induced thrombocytopenia syndrome is an immune-mediated adverse drug reaction, as IgG antibodies bind to platelet receptors and activate platelet aggregation; this ultimately results in decreased numbers of free platelets.
CHAPTER 17 Alterations of haematological function across the life span
CLINICAL MANIFESTATIONS
The hallmark of heparin-induced thrombocytopenia syndrome is the actual thrombocytopenia. However, 30% or more individuals are also at risk for thrombosis. If the syndrome is not recognised and treated, intravascular aggregation of platelets causes rapid development of arterial and venous thrombosis. Venous thrombosis is more common and results in deep venous thrombosis and pulmonary emboli. Arterial thrombosis affects the lower extremities causing limb ischaemia (impaired oxygen delivery). Cardiovascular accidents and myocardial infarctions also may be experienced (refer to Chapter 23). EVALUATION AND TREATMENT
Diagnosis is based primarily on clinical observations. The individual presents with dropping platelet counts after 5 days or longer of heparin treatment. On average, platelet counts may reach 60 × 109/L. The onset of symptoms, including thrombosis, may be delayed until after release from the hospital. Most people are diagnosed postsurgery, therefore other possible causes of thrombocytopenia (e.g. infection, other drugs) must be considered. A number of laboratory tests are available to measure the antiplatelet antibodies and the amount of platelet aggregation. Treatment is the withdrawal of heparin and use of alternative anticoagulants. Warfarin (which blocks the action of vitamin K and hence prevents the liver from producing clotting factors) should not be used until the symptoms of heparin-induced thrombocytopenia syndrome have resolved because of an increased risk of initiating skin necrosis. The thrombocytopenia should then progressively resolve. The risk of blood clots can be diminished by using a thrombin inhibitor (such as lepirudin). Increasing concerns about the use of heparin flushing solutions and the incidence of heparin-induced thrombocytopenia syndrome has led to a move to flushing central venous access devices with 0.9% sodium chloride and has shown to not be inferior with regard to lumen patency.10,11 F O CUS O N L E A R N IN G
1 List some causes of thrombocytopenia. 2 Distinguish between essential and secondary thrombocytopenia. 3 Discuss platelet function disorders.
Alterations of platelet function
Alterations in platelet function have similar clinical effects to thrombocytopenia, irrespective of the platelet count. The diagnosis can be made on the basis of abnormal laboratory tests. As these tests require a threshold number of platelets to be present for the results to be meaningful, diagnosing platelet function abnormalities in the presence of thrombocytopenia can be difficult, if not impossible. Associated clinical manifestations include spontaneous
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petechiae and purpura, bleeding from the gastrointestinal tract, genitourinary tract, pulmonary mucosa and gums. Acquired disorders of platelet function may result from the use of drugs, with aspirin being the most common. It irreversibly inhibits cyclo-oxygenase function for several days after administration. Non-steroidal anti-inflammatory drugs also affect cyclo-oxygenase, although in a reversible fashion; this means that if the drug is not taken, the platelet function can return to normal. Foods can also alter platelet function (see Research in Focus: Cocoa and cardiovascular health). Other disorders of platelet function include some systemic disorders, such as chronic renal disease, liver disease, cardiopulmonary bypass surgery and severe deficiencies of iron or folate. Haematological disorders associated with platelet dysfunction include chronic myeloproliferative disorders, multiple myeloma, leukaemias and myelodysplastic syndromes.
Disorders of coagulation
Disorders of coagulation are usually caused by defects or deficiencies in one or more of the clotting factors. (Normal function of the clotting factors is described in Chapter 16.) The abnormalities interfere with or prevent the activation of the clotting factors, circulating as plasma proteins, into a stable fibrin clot (see Fig. 16.12). Some clotting factor defects are inherited and involve one single factor, such as haemophilia (see Table 17.3). Other defects are acquired and tend to result from deficient production of clotting factors by the liver. Causes include liver disease and dietary deficiency of vitamin K. Some coagulation disorders are attributed to pathological conditions that trigger coagulation inappropriately, engaging the clotting factors and causing detrimental clotting within blood vessels. For example, any cardiovascular abnormality
TABLE 17.3 Coagulation factors and associated disorders COAGULATION FACTOR
ASSOCIATED DISORDER
I
Fibrinogen deficiency
II
Hypoprothrombinaemia
V
Factor V deficiency
VII
Factor VII deficiency
VIII
Factor VIII deficiency (haemophilia A); von Willebrand’s disease
IX
Factor IX deficiency (haemophilia B)
X
Factor X deficiency
XI
Factor XI deficiency
XII
Hageman trait
XIII
Factor XIII deficiency (fibrin stabilising factor deficiency)
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that alters normal blood flow by speeding it up, slowing it down or obstructing it can create conditions in which coagulation proceeds within the vessels. An example of this is thromboembolic disease, in which blood clots obstruct blood vessels.
RESEARCH IN F CUS Cocoa and cardiovascular health An increasing number of foods have been reported to have platelet-inhibitory functions. A number of foods such as some teas, grape juice, wine, various berries and cocoa contain flavonols, which are thought to be important in reducing the risk of stroke and coronary heart disease. One particular flavonol is known as epicatechin and has been shown to be effective in reducing platelet reactivity as well as improving vascular function, reducing blood pressure and having other anti-inflammatory effects. A number of studies now have shown that flavonol-rich cocoa inhibits several measures of platelet activity. Cocoa has been shown to reduce platelet aggregation and reduce platelet adhesion. Dark chocolate contains much more cocoa than does light chocolate. Additional cardioprotective effects may include antioxidant properties and activation of nitric oxide (NO). Low to moderate consumption of red wine reportedly has a greater benefit than other alcoholic beverages on cardioprotective mechanisms.
Haemophilia
Awareness of a serious bleeding disorder in males was documented nearly 2000 years ago in the Babylonian Talmud, which exempted from the rite of circumcision those boys having male relatives prone to excessive bleeding. In 1803 the first description of this disorder appeared in the medical literature, where it was noted to be X chromosome-linked in nature and associated with joint bleeding and crippling. This disease, haemophilia, is caused by genetic abnormalities that are linked to deficiencies in the production of clotting factors. Being X-linked, this disorder affects predominantly males. Males have XY sex chromosomes, whereas females have XX. If a male inherits the defective factor VIII gene on the X chromosome, the disease will be expressed. If a female inherits a defective gene on an X chromosome and there is a fully functional gene on the other X chromosome, the reduction in factor VIII levels will usually not be sufficient to cause bleeding. The female in this case will, however, be a carrier of the disease. A female may be affected by haemophilia in the extremely rare instance where defective genes are inherited on both X chromosomes. Many boys with haemophilia have undergone circumcision without excessive bleeding — we now know that normal haemostasis is achieved in these infants because clotting is activated through the extrinsic coagulation cascade. Haemophilia A is a deficiency in factor VIII, while haemophilia B is a deficiency in factor
IX. Haemophilia A is the more common, but affects only approximately 1 in 4000 to 1 in 10 000 males. CLINICAL MANIFESTATIONS
Prolonged bleeding will often become apparent in the first few years of the child’s life. Easy bruising and haemarthrosis (bleeding into joints) may occur and minor cuts take a long time to clot. Haemorrhage into the elbows, knees and ankles causes pain, limits joint movement and predisposes the child to degenerative joint changes. The extent of haemorrhagic disease and the age at which symptoms manifest are related to the severity of the deficiency. Recurrent bleeding, both spontaneous and after minor trauma, is a lifelong problem. Many affected individuals experience phases or cycles of spontaneous bleeding episodes. Mechanisms that cause this phenomenon are unknown. Intracranial haemorrhage and bleeding into the tissues of the neck or abdomen constitute life-threatening emergencies. EVALUATION AND TREATMENT
Treatment options have been largely focused on transfusion of blood products, to allow the coagulation factor from the donor to enter the patient’s blood, thereby temporarily correcting the deficiency. However, in the early 1980s many haemophilia patients unfortunately became infected with blood-borne viruses such as HIV and hepatitis C. By the end of the 1980s, substantially improved screening and treatment of donated blood products led to them being safe, with minimal risk of transmitting these infections. Thus individuals can now be treated with plasma clotting factor concentrates much more safely. Haemophilia treatment may also include recombinant clotting factors, which are produced in laboratories rather than from blood products. These are safer still as there is no risk of viral contamination; however, they are more expensive. As a result of improved treatment options, it is likely that the prevalence of this disease may increase in the future, as patient survival is increasing. In the longer term, treatments of conditions for patients with haemophilia may be more complicated (see Research in Focus: The cost of success in haemophilia management).
Impaired haemostasis
Impaired haemostasis, or the inability to promote coagulation and the development of a stable fibrin clot, is commonly associated with liver dysfunction, as the liver is responsible for producing the clotting factors. This process is dependent on vitamin K and hence deficiency in this vitamin will interfere with clotting factor production. Other liver abnormalities may also contribute to impaired production of the clotting factors. VITAMIN K DEFICIENCY
Vitamin K is a fat-soluble vitamin that is required for the production of many of the clotting factors. Parenteral administration of vitamin K is the treatment of choice and usually results in correction of the deficiency. Fresh frozen
CHAPTER 17 Alterations of haematological function across the life span
RESEARCH IN F CUS The cost of success in haemophilia management Many people with haemophilia now live much longer with better treatments and management. This has made them susceptible to the normal processes of ageing including those of chronic diseases. Typical chronic conditions associated with ageing include cardiovascular disease, diabetes, hypertension and coronary heart disease. Previously this cohort of patients was thought to be protected against these conditions and the focus has always been on managing their bleeding risk but successful management has put them at risk. Prevention and health promotion arguably should become a component of haemophilia management from an early stage. Otherwise there is a risk of significant impact of obesity, exacerbated by a sedentary lifestyle due to the effects of heart failure and the long-term impact of joint bleeds; however, this may lead to common interventions such as arthroscopy and coronary procedures that are becoming high risk procedures for this cohort.
plasma also may be administered but is usually reserved for individuals with life-threatening haemorrhages or those who require emergency surgery. LIVER DISEASE
Individuals who have liver disease present with a broad range of haemostatic derangements that may be characterised by defects in the clotting or fibrinolytic system, and by platelet function. The usual sequence of events is an initial reduction in clotting factors, which parallels the degree of liver cell damage or destruction. Factor VII is the first to decline because of its rapid turnover, followed by declines in factors II and X. Factor IX levels are less affected and do not decline until liver destruction is well advanced. Protein C (an anticoagulant) levels decline early, similarly to levels of factor VII, and protein S (also an anticoagulant) levels decline in the later stages of liver disease. Declines of factor V are of special importance because factor V plasma levels appear to be a direct reflection of liver cell damage. Other alterations of haemostasis in liver disease include an increase in fibrinolytic activity that is either primary in origin or is a manifestation that is secondary to disseminated intravascular coagulation (see next section). Thrombocytopenia and thrombocytopathies are manifestations of liver disease. Thrombocytopenia is caused by splenomegaly, which often accompanies liver disease. Splenic pooling of platelets is the major cause of thrombocytopenia. Thrombocytopathies are associated with elevated levels of fibrin fragments, alcohol or drugs. Treatment of alterations to haemostasis in liver disease must be comprehensive to cover all aspects of dysfunction. Fresh frozen plasma administration is the treatment of choice; however, not all individuals tolerate the volume
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needed to adequately replace all deficient factors. Platelet concentrates may also be transfused, depending on the degree of thrombocytopenia.
Thromboembolic disorders
Certain conditions within the blood vessels predispose an individual to develop clots spontaneously. A clot attached to the vessel wall is called a thrombus (see Fig. 17.10); this may form as unwanted clotting that contributes to the formation of an atherosclerotic plaque (refer to Chapter 23). A thrombus is composed of fibrin and blood cells and can develop in either the arterial system or the venous system. Arterial clots form under conditions of high blood flow and are composed mostly of platelet aggregates held together by fibrin strands. Venous clots form in conditions of low flow and are composed mostly of red cells with larger amounts of fibrin and few platelets. A thrombus eventually reduces or obstructs blood flow to tissues or organs, such as the heart, brain or lungs, depriving them of essential nutrients critical to survival. A thrombus also has the potential of detaching from the vessel wall and circulating within the bloodstream (referred to as an embolus). The embolus may become lodged in smaller blood vessels, blocking blood flow into the local tissue or organ and leading to ischaemia. Whether episodes of thromboembolism are life threatening depends on the site of vessel occlusion. Thromboembolic disorders are mainly found in the adult population and the risk increases with age. Therapy consists of removal or breakdown of the clot and supportive measures. Anticoagulant therapy is effective in treating or preventing venous thrombosis; it is not as useful in treating or preventing arterial thrombosis. Parenteral heparin is the major anticoagulant used to treat thromboembolism. Oral coumarin drugs also are widely used, particularly for individuals not hospitalised. More aggressive therapy may be indicated for such conditions as pulmonary embolism, coronary thrombosis or thrombophlebitis. Streptokinase and urokinase activate the fibrinolytic system and are administered to accelerate the lysis of known thrombi. Thrombolytic therapy has limited uses and is prescribed with a high degree of caution because it can cause haemorrhagic complications.
FIGURE 17.10
Deep venous thrombus. A deep vein thrombus from a patient with widespread carcinoma. The portion most adherent to the vein wall (arrow) is the origin of the thrombus.
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The risk for developing spontaneous thrombi is related to three factors, referred to as Virchow’s triad: • injury to the blood vessel endothelium • abnormalities of blood flow • hypercoagulability of the blood. Virchow’s triad explains that abnormal blood clotting occurs due to abnormalities with any one of these three key determinants. Endothelial injury to blood vessels can result from atherosclerosis (plaque deposits on arterial walls; see Chapter 23). Atherosclerosis initiates platelet adhesion and aggregation, promoting the development of atherosclerotic plaques that enlarge, causing further damage and occlusion. Other causes of vessel endothelial injury may be related to haemodynamic alterations associated with hypertension and turbulent blood flow. Injury also is caused by radiation injury, exogenous chemical agents (toxins from cigarette smoke), endogenous agents (cholesterol), bacterial toxins or endotoxins, or immunological mechanisms. Whatever the precipitating cause of endothelial injury, it is a potent thrombogenic agent. Sites of turbulent blood flow in the arteries and stasis of blood flow in the veins are at risk for thrombus formation. In areas of turbulence, platelets and endothelial cells may be activated, leading to thrombosis. In sites of stasis, platelets may remain in contact with the endothelium for prolonged lengths of time and clotting factors that would normally be diluted with fresh flowing blood are not diluted and may become activated. The most common clinical conditions that predispose to venous stasis and subsequent thromboembolic phenomena are major surgery (e.g. orthopaedic surgery), acute myocardial infarction, congestive heart failure, limb paralysis, spinal injury, malignancy, advanced age, the postpartum period and bed rest longer than 1 week. Turbulence and stasis occur with ruptured atherosclerotic plaques (myocardial infarction), hyperviscosity (polycythaemia) and conditions with deformed red cells (sickle cell anaemia). The events leading to thrombus formation at sites of atherosclerotic plaque rupture are not fully understood. However, recent research shows that the effects of the mechanical forces associated with flow alteration lead to an accumulation of platelets tethered together on the downstream side of the blockage. This leads to growth of the blockage, which in turn creates a vortex or backflow immediately downstream of the platelet clump. Soluble activators released by the adhered platelets (see Chapter 16) can then accumulate in the backflow to cause platelet activation and further increasing the blockage. In blood vessels where there is no blockage the mechanism for platelet aggregation is different. In this case platelet aggregation is solely dependent on release of soluble platelet activators such ADP, thrombin and thromboxane A2. Hypercoagulability is the condition in which an individual is at risk for thrombosis, but by itself it is a rare cause of thrombosis. An individual may be in a hypercoagulable state if they are deficient in anticoagulation proteins, such that there is an increased tendency towards
coagulation. Hypercoagulability (thrombophilia) is differentiated according to whether it results from primary (hereditary) or secondary (acquired) causes. Secondary causes of hypercoagulability arise in three main conditions: venous stasis (caused by, for instance, immobility, congestive cardiac failure, obesity); coagulation factor activation (caused by, for instance, pregnancy, cancer, nephritic syndrome); and platelet activation (caused by, for instance, myeloproliferative disorders or thrombotic thrombocytopenic purpura).
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) is an acquired clinical syndrome characterised by widespread activation of coagulation resulting in the formation of fibrin clots in medium and small vessels throughout the body.12 Widespread clotting may lead to blockage of blood flow to organs, resulting in multiple organ failure. The magnitude of clotting may result in the consumption of platelets and clotting factors, which can result in severe bleeding. This is a complex systemic disorder that arises as a result of a major physiological event or trauma, such as sepsis, malignancy, complications of pregnancy and severe trauma. The clinical course of this condition is largely determined by the individual circumstances. It is characterised by subacute haemorrhage and diffuse microcirculatory thrombosis. PATHOPHYSIOLOGY
Coagulation is designed to function at local areas of vascular damage, resulting in cessation of bleeding and activation of repair to the vessels. DIC results from abnormally widespread and ongoing activation of clotting. Excessive exposure of tissue factor appears to be the trigger for activating coagulation (see Fig. 17.11). Not only is the clotting system extensively activated in DIC, but the predominant natural anticoagulants (such as tissue factor pathway inhibitor, antithrombin III) are also greatly diminished. Tissue factor pathway inhibitor in association with factor Xa inactivates the TF-VIIa complex, preventing further activation of clotting. Antithrombin III is the principal inhibitor of thrombin. The rate of fibrinolysis is also diminished in DIC, as the activity of plasmin is diminished. Although thrombosis is generalised and widespread, individuals with DIC are paradoxically at risk for haemorrhage. Haemorrhage is secondary to the abnormally high consumption of clotting factors and platelets, as well as the anticoagulant properties of fibrin degradation products. Thrombin causes platelet activation and aggregation — an event that occurs early in the development of DIC — which facilitates microcirculatory coagulation and obstruction in the initial phase. However, platelet consumption exceeds production, resulting in a thrombocytopenia that increases bleeding. The deposition of fibrin clots in the circulation interferes with blood flow, causing widespread organ hypoperfusion. This condition may lead to ischaemia, infarction and necrosis, further potentiating and complicating the existing
CHAPTER 17 Alterations of haematological function across the life span
Increased tissue factor
Thrombosis
causes
causes
contributes to
Decreased fibrinolysis contributes to consumption
Increased clot formation clot lysis
Thrombocytopenia and clotting factor deficiency
Fibrin degradation products causes
decreased clearance
Increased fibrin degradation products inhibit haemostasis
causes
CONCEPT MAP
Decreased natural anticoagulants
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Bleeding
FIGURE 17.11
The pathophysiology of disseminated intravascular coagulation (DIC). DIC is initiated by exposure of tissue factor causing clot formation. This is enhanced by a decrease in the natural anticoagulants (tissue factor pathway inhibitor, antithrombin-III and protein C). There is also a reduction in fibrinolysis by plasmin. The combined effect is to cause thrombosis. The thrombotic activity consumes coagulation factors and platelets. Slow degradation of the fibrin clots produces fibrin degradation products. These have inhibitory effects upon thrombin and platelets. The inhibition of coagulation, combined with the depletion of factors and platelets, then creates a bleeding tendency. DIC is a thrombohaemorrhagic disorder.
DIC process by causing further release of tissue factor and eventually organ failure. Whatever initiates the process of DIC, the cycle of thrombosis and haemorrhage persists until the underlying cause of the DIC is removed or appropriate therapeutic interventions are used.
hypotension, haemoptysis (coughing blood), chest pain and tachycardia. Symmetric cyanosis of fingers and toes (blue finger/toe syndrome), nose and breast may be observed and indicates macrovascular thrombosis. This may lead to infarction and gangrene that may require amputation.
CLINICAL MANIFESTATIONS
EVALUATION AND TREATMENT
Clinical signs and symptoms of DIC largely depend on whether the DIC is acute or chronic in nature. Most symptoms are the results of either bleeding or thrombosis. Acute DIC presents with rapid development of haemorrhaging (oozing) from venepuncture sites, arterial lines or surgical wounds or development of ecchymotic lesions (purpura, petechiae) and haematomas. Other sites of bleeding include the eyes (sclera, conjunctiva), nose and gums. Manifestations of thrombosis are not always as evident, even though it is often the first pathological alteration to occur. Several organ systems are susceptible to microvascular thrombosis associated with dysfunction: cardiovascular, pulmonary, central nervous, renal and hepatic systems. Acute and accurate clinical interpretations are critical to preventing progression of DIC that may lead to multisystem organ dysfunction and failure. Indicators of multisystem dysfunction include changes in the level of consciousness, behaviour and confusion, seizure activity, oliguria (low volume urine), haematuria (blood in the urine), hypoxia,
No single laboratory test can be used to effectively diagnosis DIC. Diagnosis is based primarily on clinical symptoms and confirmed by a combination of laboratory tests. The most commonly used combination of laboratory tests usually confirm thrombocytopenia or a rapidly decreasing platelet count on repeated testing, prolongation of clotting times, the presence of fibrin degradation products, reduced fibrinogen levels and decreased levels of coagulation inhibitors. Detection of fibrin degradation products is more specific for DIC. Detection of D-dimers is a widely used test for DIC. D-dimer is a molecule produced by plasmin degradation of cross-linked fibrin in clots. It is important to note that D-dimer levels may also be raised in conditions where DIC is not present (e.g. deep vein thrombosis). Treatment of DIC is directed towards: • eliminating the underlying pathology • controlling ongoing thrombosis • maintaining organ function.
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Eliminating the underlying pathology is the initial intervention in the treatment phase in order to eliminate the trigger for activation of clotting. Once the stimulus is gone, production of coagulation factors in the liver leads to restoration of normal plasma levels within 24–48 hours. Controlling ongoing thrombosis is more difficult to attain. Heparin has been used for this; however, its use is controversial because its mechanism of action is binding to and activating antithrombin III, which is deficient in many types of DIC. The anticoagulant action of heparin may also create a bleeding risk if the clotting factors are depleted. Currently, heparin is indicated only in certain types of situations related to DIC. Replacement of deficient coagulation factors, platelets and other coagulation elements is gaining recognition as an effective treatment modality. Their use is not without controversy, however, because a major concern with replacement therapy is the possible risk of adding components that will increase the rate of thrombosis. Clinical judgment is the key factor in determining whether replacement is to be used as a treatment modality. Maintaining organ function is achieved by fluid replacement to sustain adequate circulating blood volume and maintain optimal tissue and organ perfusion. Fluids may be required to restore blood pressure, cardiac output and urine output to normal parameters.
Haemostasis therapy
For many years, the only agents used to inhibit coagulation were heparin and warfarin. These drugs are still widely used to treat or prevent thrombosis. Heparin is a fast-acting anticoagulant that is administered intravenously or subcutaneously. It combines with antithrombin III to exert an anticoagulant effect. Warfarin has an advantage over heparin in that it is taken orally; however, the anticoagulant effect develops slowly over several days. Warfarin is an antagonist of vitamin K, which is required for the production of clotting factors II, VII, IX and X in the liver. An individual taking warfarin will not be able to produce functional versions of these clotting factors and so the ability of their blood to clot will be reduced. The dose of anticoagulant given to a patient needs to be sufficient to reduce the risk of thrombosis, but the anticoagulant effect should not be so great as to create a high risk of bleeding. For this reason, therapeutic ranges have been established and the degree of anticoagulation can be monitored by laboratory tests (see Table 17.2). Unfractionated heparin therapy can be monitored by the activated partial thromboplastin time (APTT). This is a clotting test that assesses the intrinsic and common pathways of the coagulation cascade and is sensitive to the anticoagulant effect of unfractionated heparin. The APTT test is not sensitive to the effect of low-molecular-weight heparin, which is sometimes used in clinical practice. Warfarin therapy is monitored by the prothrombin time (PT). This clotting test assesses the extrinsic and common pathways and is sensitive to the effect of warfarin. A calculation is applied by the laboratory to the PT test result,
such that the PT test result divided by the average time obtained for a normal control plasma produces the prothrombin ratio (PR). The INR (international normalised ratio) calculation allows test results from different laboratories and different batches to be comparable — otherwise, prothrombin time results for a patient could only be reliably compared with other prothrombin time tests prepared at a similar time, which is not achievable. By using the INR, patient results can be compared over time and from one location to another to allow effective monitoring of warfarin therapy. Because of this, the INR is one of the most frequently requested laboratory tests. New oral anticoagulants targeting activated factor X or thrombin are in advanced stages of development.11 These new drugs may not need the same level of monitoring as warfarin. Aspirin has been used successfully to inhibit platelets for many years. In more recent times other specific inhibitors of platelet activation, mostly targeting platelet glycoprotein receptors, have emerged.13 The management of individuals with bleeding disorders has been advanced by the development of recombinant factor agents, the prolonged half-life of agents or agents with reduced activation of immune responses. First introduced for haemophiliacs, recombinant factor VIIa (rFVIIa) is now used for several inherited and acquired bleeding disorders. FOCU S ON L EA RN IN G
1 Describe the pathophysiology and clinical manifestations of haemophilia. 2 Explain how liver disease can affect haemostasis. 3 List some causes of DIC and describe the clinical manifestations of this syndrome. 4 Explain the difference between a thrombus and an embolism. 5 Discuss how warfarin and heparin work as anticoagulants.
Alterations of leucocytes Leucocyte function is affected if too many or too few white cells (in general or of specific kinds) are present in the blood or if the cells that are present are structurally or functionally defective (see Table 17.4). Phagocytic cells (granulocytes, monocytes, macrophages) may lose their ability to act as effective phagocytes and lymphocytes may lose their ability to respond to antigens. Other leucocyte alterations include infectious mononucleosis and cancers of the blood — leukaemia and multiple myeloma.
Alterations of leucocyte count
Leucocytosis is used to describe a white cell count that is higher than normal, whereas leucopenia refers to
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TABLE 17.4 White blood cell counts PROPERTY EVALUATED BY TEST
POSSIBLE HAEMATOLOGICAL CAUSE OF ABNORMAL FINDINGS
Leucocytes: differential white cell count (absolute number of a type of leucocyte/ litre of blood)
See below
See below
Neutrophil count
Neutrophils (× 109)/L
Myeloproliferative disorders, haematopoietic disorders, haemolysis, infection
Lymphocyte count
Lymphocytes (× 109)/L Infectious lymphocytosis, infectious mononucleosis, haematopoietic disorders, anaemias, leukaemia, lymphosarcoma, Hodgkin’s lymphoma
Monocyte count
Monocytes (× 109)/L
Hodgkin’s lymphoma, infectious mononucleosis, monocytic leukaemia, non-Hodgkin’s lymphoma, polycythaemia vera
Eosinophil count
Eosinophils (× 109)/L
Haematopoietic disorders
CELL TYPE AND TEST
Basophil count
9
Basophils (× 10 )/L
when the count is lower than normal. Leucocytosis and leucopenia may affect a specific type of white blood cell and may result from a variety of physiological conditions and alterations. Leucocytosis occurs as a normal protective response to physiological stressors, such as invading microorganisms, strenuous exercise, emotional changes, temperature changes, anaesthesia, surgery, pregnancy and some drugs, hormones and toxins. It is also caused by pathological conditions, such as malignancies and haematological disorders. If the leucocyte count falls to less than 1 × 109/L, the risk of infection increases drastically. With counts below 0.5 × 109/L, the possibility for life-threatening infections is high. Leucopenia may be caused by radiation, anaphylactic shock, autoimmune disease (e.g. systemic lupus erythematosus), immune deficiencies and certain chemotherapeutic agents.
Granulocyte and monocyte alterations
Granulocytosis — an increase in granulocytes (neutrophils, eosinophils or basophils) — begins when stored blood cells are released. Neutrophilia is another term that may be used to describe granulocytosis because neutrophils are the most numerous of the granulocytes. Neutrophilia is seen in the early stages of infection or inflammation and is established when the absolute count exceeds 7.5 × 109/L. Release and depletion of stored neutrophils stimulates granulopoiesis to replenish neutrophil reserves. When the demand for circulating mature neutrophils exceeds the supply, immature neutrophils (and other leucocytes) are released from the bone marrow. The immature cells can be observed by microscopic examination of a blood smear. Neutropenia is a condition associated with a reduction in circulating neutrophils and exists clinically when the neutrophil count is less than 2 × 109/L. Reduction in
Chronic myeloid leukaemia, haemolytic anaemias, Hodgkin’s lymphoma, polycythaemia vera
neutrophils occurs in severe prolonged infections when production of granulocytes cannot keep up with demand. Other causes of neutropenia, in the absence of overwhelming infection, may be: • decreased neutrophil production or ineffective granulopoiesis • reduced neutrophil survival • abnormal neutrophil distribution and sequestration. Haematological disorders that cause ineffective or decreased production include hypoplastic or aplastic anaemia, megaloblastic anaemia, leukaemia or drug/ toxin-induced neutropenia. Neutropenia is also seen in starvation and anorexia nervosa because of an inadequate supply of protein. Decreased neutrophil survival is seen in autoimmune disorders (e.g. systemic lupus erythematosus, rheumatoid arthritis). Abnormal neutrophil distribution and sequestration are associated with hypersplenism and pseudoneutropenia. Viral infections (HIV, Epstein-Barr virus) also may cause neutropenia, as do chemotherapy and other toxic drugs used in cancer treatment and in transplantation. If neutrophils are drastically reduced (38°C, drenching night sweats, unexplained loss of >10% of body weight in the 6 months preceding diagnosis E: large mediastinal mass with direct extension into extranodal sites
Because of the variability in symptoms, early definitive detection may be difficult. Asymptomatic lymphadenopathy can progress undetected for several years. Careful evaluation, including chest x-ray films, positron emission tomography (PET) scans and biopsy, should be carried out for individuals with fever of unknown origin and peripheral lymphadenopathy. A lymph node biopsy with scattered RS cells and a cellular infiltrate is highly indicative of Hodgkin’s lymphoma. The effectiveness of treatment is related to the age of the individual and the extent of the disease. Approximately 75% of individuals diagnosed with Hodgkin’s lymphoma can be cured, largely because of successful treatment with irradiation and chemotherapy. Those with stage III or IV disease, bulky disease (> 10 cm mass or mediastinal disease with a transverse diameter exceeding 33% of the transthoracic diameter) or presence of B symptoms require combined chemotherapy with or without additional radiation treatment. Those with stage I or II disease are candidates for chemotherapy, combined or radiation therapy alone. The survival rate depends on many factors, including the age of the individual, the stage of the disease, gender and other variables. The 5-year survival rate with no additional factors is 87%, but drops substantially with each additional factor to about 42% with five or more factors.
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Multiple myeloma
Multiple myeloma is a B cell malignancy of the bone marrow, characterised by the uncontrolled replication (cloning) of plasma cells.22 Multiple myeloma is one of a range of plasma cell disorders that include monoclonal gammopathy of undetermined significance (MGUS); primary amyloidosis; solitary plasmacytomas; Waldenstrom’s macroglobulinaemia; polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin-changes syndrome (POEMS); and multiple myeloma. The members of this diverse group of disorders all have varying implications for treatment and survival.23 The reported incidence of multiple myeloma has doubled in the past two decades, possibly as a result of more sensitive testing used for diagnosis. In Australia, multiple myeloma accounts for 1.3% of all cancers (see Table 17.5). It rarely occurs before the age of 40 years — the peak age of incidence is about 65 years. It is slightly more common in men than women. Neoplastic cells of multiple myeloma reside in the bone marrow and are usually not found in the peripheral blood. Occasionally, however, it may spread to other tissues, especially in very advanced disease. The basic defect is genetic, which may result from chronic stimulation of B cells with bacterial or viral antigens. The duration of survival has increased in recent years, particularly for younger patients. The variation in characteristics of myeloma is clearly highlighted by differences in survival. For example, the median expected survival for standard risk patients is approximately 7 years, yet the median expected survival for higher risk patients remains significantly lower, at between 3 and 4 years. Being diagnosed at an early stage and at a younger age, and being treated with novel agents have all been shown to independently improve survival. PATHOPHYSIOLOGY
Most, if not all, multiple myelomas involve chromosomal translocations (break points), which recur in many individuals. In about half of all cases, one of the chromosomal partners is 14 (the site of genes for the immunoglobulin heavy chain), which recombines with a number of other chromosomal sites of oncogenes, most commonly located on chromosomes 11, 4, 16, 20 and 6, resulting in probable dysregulation of the oncogenes (refer to Chapter 37). Deletions in chromosome 13 are observed in about 50% of cases. The molecular pathogenesis of multiple myeloma also involves proto-oncogene mutations and, more rarely, inactivation of tumour-suppressor genes. The precise timing and reason for the genetic alteration and accumulation is unknown. Malignant plasma cells arise from one clone of B cells that produce abnormally large amounts of one class of immunoglobulin (usually IgG, occasionally IgA and rarely IgM, IgD or IgE). The malignant transformation may begin early in B cell development, possibly before encountering antigen in the secondary lymphoid organs. The myeloma cells return to either the bone marrow or
other soft tissue sites. Their return is aided by cell adhesion molecules that help them to target favourable sites that promote continued expansion and maturation. Cytokines, particularly interleukin-6 (IL-6), have been identified as essential factors that promote the growth and survival of multiple myeloma cells. (Lymphocytes and cytokines are described in Chapter 12.) Myeloma cells in the bone marrow produce several cytokines themselves (e.g. IL-6, IL-1, TNFα). IL-6 in particular acts as an osteoclast-activating factor and stimulates osteoclasts to resorb (break down and dissolve) bone, which releases calcium in the blood. This process results in bone lesions and hypercalcaemia (high calcium levels in the blood). The antibody produced by the transformed plasma cell is frequently defective, containing truncations, deletions and other abnormalities, and is frequently referred to as a paraprotein (abnormal protein in the blood). Because of the large number of malignant plasma cells, the abnormal antibody, called the M protein, becomes the most prominent protein in the blood and is readily detected by laboratory tests. Suppression of normal plasma cells by the myeloma results in diminished or absent normal antibodies. The excessive amount of M protein may also contribute to many of the clinical manifestations of the disease. If the myeloma produces IgM, the excessive amount of large-molecularweight proteins (about 900 000 daltons) can lead to abnormally high blood viscosity (hyperviscosity syndrome). Frequently, the myeloma produces free immunoglobulin light chain (Bence Jones protein) that is present in the blood and urine and contributes to damage of renal tubular cells. CLINICAL MANIFESTATIONS
Many physiological systems can be affected by myeloma (hence the name ‘multiple’ myeloma). The disease has a variety of symptoms. The most common are bone pain, infection, fatigue, renal failure and neurological problems. Up to 25% of people with myeloma present without any symptoms of the disease and are diagnosed on a routine blood test. The most common presenting symptoms are fatigue and pain. Other symptoms that are frequently reported on presentation are infection, pathological fractures, symptoms of renal failure, and spinal cord compression. Symptoms that occur less commonly on presentation are confusion, carpal tunnel symptoms, and hyperviscosity syndrome. Symptoms of myeloma are sometimes commonplace or ambiguous (e.g. back pain or fatigue). These may appear benign and thus are often ignored by patients, family and healthcare professionals. This can lead to missed opportunities for early diagnosis.22 EVALUATION AND TREATMENT
Diagnosis of multiple myeloma is made by symptoms, radiographic and laboratory studies and a bone marrow biopsy. The current definition requires the following three diagnostic criteria to be present:23
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• 10% monoclonal plasma cells in the bone marrow and/ or the presence of a biopsy-proven plasmacytoma • monoclonal protein present in the serum and/or urine • the presence of one or more of the following clinical signs: calcium, renal function, anaemia and bone lesions — these are known by the acronym ‘CRAB’, and describe myeloma-related organ dysfunction. Measurements of immunoglobulin typically demonstrate that one class of immunoglobulin (the M protein produced by the myeloma cell) is greatly increased, while the others are suppressed. Because myeloma is regarded as incurable, treatment is focused on three other health-related outcomes; to arrest the malignant process of abnormal plasma cell production; to treat and manage the systemic effects of myeloma — for example: renal failure, bone disease, pain and decreased immunity; and to treat and manage the adverse effects of treatment itself — for example: fatigue, neuropathy, and further reduced immunity. The treatment of myeloma has changed drastically over recent years. Historically, cytotoxic chemotherapy drugs, such as melphalan, doxorubicin and vincristine, as well as glucocorticosteroids, were used alone or in combination to
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provide the mainstay of myeloma therapy. More recently, better understanding of the pathophysiology of myeloma, together with knowledge about signalling pathways, has led to the development of a new class of drugs known as ‘novel agents’. These include thalidomide, bortezomib and lenalidomide. Novel agents aim to destroy myeloma cells in the microenvironment of the bone marrow. They work primarily by targeting and disrupting cell signalling pathways, and thereby cause myeloma cells to apoptose or ‘commit suicide’. Following the initial induction treatment described, the next phase of treatment may be a stem cell transplant. Stem cell transplant is an expensive, arduous and resource-intensive treatment that has been shown to improve survival in the treatment of myeloma.24 FOCU S ON L EA RN IN G
1 Discuss lymphadenopathy. 2 Contrast the principal features of Hodgkin’s lymphoma with those of non-Hodgkin’s lymphoma. 3 Explain what M protein is.
chapter SUMMARY Alterations of erythrocyte function • Anaemia is defined as a reduction in the haemoglobin concentration of the blood. • The most common classification of anaemia is based on changes in the cell size (MCV) and changes in the cell’s haemoglobin content (MCH). • Clinical manifestations of anaemia can be found in all organs and tissues throughout the body. Decreased oxygen delivery to tissues causes fatigue, dyspnoea, syncope, angina, compensatory tachycardia and organ dysfunction. • Macrocytic (megaloblastic) anaemia is caused by deficiency of vitamin B12 or folate. Pernicious anaemia can be fatal unless vitamin B12 replacement is given. • Microcytic-hypochromic anaemia is characterised by abnormally small red cells with insufficient haemoglobin content. The most common cause is iron deficiency. • Iron deficiency anaemia usually develops slowly, with a gradual insidious onset of symptoms, including fatigue, weakness, dyspnoea, alteration of various epithelial tissues and vague neuromuscular complaints.
• Iron deficiency anaemia is the most common blood disorder of infancy and childhood; the highest incidence occurs between 6 months and 2 years of age. • Iron deficiency anaemia is usually a result of a chronic blood loss or decreased iron intake. Once the source of blood loss is identified and corrected, iron replacement therapy can be initiated. • Normocytic-normochromic anaemia is characterised by insufficient numbers of normal erythrocytes. Included in this category are aplastic, post-haemorrhagic and haemolytic anaemia and anaemia of chronic inflammation. • Haemolytic disease of the newborn (HDN) results from incompatibility between the maternal and fetal blood, which involves differences in Rh antigens. • Maternal antibodies enter the fetal circulation and cause haemolysis of fetal erythrocytes. This occurs because the immature liver of the newborn is unable to conjugate and excrete the excess bilirubin that results from the haemolysis. • Polycythaemia vera is characterised by excessive proliferation of erythrocyte precursors in the bone
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marrow. Signs and symptoms result directly from increased blood volume and viscosity. • Polycythaemia vera may spontaneously covert to acute myeloid leukaemia.
Alterations of platelets and coagulation • Thrombocytopenia is characterised by a platelet count below 100 × 109/L of blood; a count below 50 × 109/L increases the potential for haemorrhage associated with minor trauma. • Thrombocytopenia exists in primary or secondary forms and is commonly associated with autoimmune diseases and viral infections; bacterial sepsis with disseminated intravascular coagulation also results in thrombocytopenia. • Alterations in platelet functions of adherence or aggregation prevent platelet plug formation and may result in prolonged bleeding times. • Platelet dysfunction results from changes in the cellular contents and integrity. • Disorders of coagulation are usually caused by defects or deficiencies of one or more clotting factors. • Haemophilia A is the most common of the inherited coagulation factor deficiencies. Because it is an X-linked disorder it mainly affects males; females are carriers. • Coagulation is impaired when there is a deficiency of vitamin K because of insufficient production of prothrombin and production of clotting factors II, VII, IX and X, often associated with liver diseases. • Disseminated intravascular coagulation (DIC) is a complex syndrome resulting from a variety of clinical conditions that release tissue factor, causing an increase in fibrin and thrombin activity in the blood producing augmented clot formation and accelerated fibrinolysis. Sepsis is a condition that is often associated with DIC. • DIC is characterised by a cycle of intravascular clotting followed by active bleeding caused by the initial consumption of coagulation factors and platelets and diffuse fibrinolysis. • Diagnosis of DIC is based on measurement in the blood of end products characteristic of dysfunctional coagulation activity. Treatment is complex and nonstandardised and focused on removing the primary cause, restoring haemostasis and preventing further organ damage. • Thromboembolic disease results from a fixed (thrombus) or moving (embolus) clot that blocks flow within a vessel, denying nutrients to tissues distal to the occlusion; death can result when clots obstruct blood flow to the heart, brain or lungs. • Hypercoagulability is the result of deficient anticoagulation proteins. Secondary causes are conditions that promote venous stasis. • The term Virchow’s triad refers to three factors that can cause thrombus formation: (a) loss of integrity of the vessel wall; (b) abnormalities of blood flow; and (c) hypercoagulability of the blood.
Alterations of leucocytes • Alterations of leucocyte numbers (too many or too few) can be caused by bone marrow dysfunction or premature destruction of cells in the circulation. Many changes in the number of leucocytes occur in response to invasion by microorganisms. • Leucocytosis is a condition in which the leucocyte count is higher than normal and is usually a response to stress and invasion of microorganisms. • Leucopenia is a condition in which the leucocyte count is lower than normal and is caused by pathological conditions, such as malignancies, and haematological disorders. • Granulocytosis (particularly as a result of an increase in neutrophils) occurs in response to infection. The marrow releases immature cells when responding to an infection that has created a demand for neutrophils that exceeds the supply in the circulation. • Eosinophilia results most commonly from parasitic invasion and ingestion or inhalation of toxic foreign particles. • Basophilia is seen in hypersensitivity reactions because of the high content of histamine and subsequent release. • Monocytosis occurs during the late or recuperative phase of infection when macrophages (mature monocytes) phagocytose surviving microorganisms and debris. • Granulocytopenia, a significant decrease in neutrophils, can be a life-threatening condition if sepsis occurs; it is often caused by chemotherapeutic agents, severe infection and radiation. • Infectious mononucleosis is an acute infection of B lymphocytes most commonly associated with the Epstein-Barr virus, a type of herpes virus. Transmission of Epstein-Barr virus is through close personal contact, commonly through saliva — thus its nickname, the kissing disease. • Two of the earliest manifestations of infectious mononucleosis are sore throat and fever caused by inflammation at the primary site of viral entry. • Most causes of Epstein-Barr virus infectious mononucleosis include fever lasting 7–10 days, sore throat and enlargement and tenderness of the cervical lymph nodes. It is self-limiting and treatment consists of rest and symptomatic treatment. • The common pathological feature of all forms of leukaemia is an uncontrolled proliferation of leucocytes, overcrowding the bone marrow and resulting in decreased production and function of the other blood cell lines. • Leukaemia is classified by the cell type involved — lymphoid or myeloid — and is differentiated by onset — acute or chronic. Thus, there are four major types of leukaemia: acute lymphoblastic leukaemia (ALL); chronic lymphocytic leukaemia (CLL); acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML).
CHAPTER 17 Alterations of haematological function across the life span
• Although the exact cause of leukaemia is unknown, it is considered a clonal disorder. A high incidence of acute leukaemia and CLL is reported in certain families, suggesting a genetic predisposition. • The major clinical manifestation of leukaemia includes fatigue caused by anaemia, bleeding caused by thrombocytopenia, fever secondary to infection, anorexia and weight loss. • Chemotherapy is the treatment of choice for leukaemia. Acute leukaemia is associated with an increasing survival rate of 80–90%, with long-term survival of 30–40%. Chronic leukaemia is associated with a longer life expectancy than acute leukaemia. • Chronic leukaemia progresses differently to acute leukaemia, advancing slowly and without warning. The presence of the Philadelphia chromosome is a diagnostic marker for CML. • ALL is the most common leukaemia of childhood and is a potentially curable disease.
Alterations of lymphoid function • The number of lymphocytes is decreased (lymphocytopenia) in most acute infections and in some immunodeficiency syndromes. • Lymphocytosis occurs in viral infections (infectious mononucleosis and infectious hepatitis, in particular), leukaemia, lymphomas and some chronic infections. • Lymphomas are tumours of primary lymphoid tissue (thymus, bone marrow) or secondary lymphoid tissue (lymph nodes, spleen, tonsils, intestinal lymphoid tissue). The two major types of malignant lymphomas are Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. • Distinctive abnormal chromosomes are present in multiple cells of the lymph nodes of an individual with Hodgkin’s lymphoma. The abnormal cell is called the Reed-Sternberg cell. • A virus might be involved in the pathogenesis of Hodgkin’s lymphoma. Some familial clustering suggests an unknown genetic mechanism.
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• An enlarged, painless mass or swelling, most commonly in the neck, is an initial sign of Hodgkin’s lymphoma. Local symptoms are produced by lymphadenopathy, usually caused by pressure or obstruction. • Treatment of Hodgkin’s lymphoma includes radiation therapy and chemotherapy. A cure is possible regardless of the stage of Hodgkin’s lymphoma; however, individuals treated with chemotherapy who relapse in less than 2 years have a poor prognosis. • The cause of lymph node enlargement and cancerous transformation in non-Hodgkin’s lymphoma is unknown. Immunosuppressed persons have a higher incidence of non-Hodgkin’s lymphoma, suggesting an immune mechanism. • Generally, with non-Hodgkin’s lymphoma, the swelling of lymph nodes is painless and the nodes enlarge and transform over a period of months or years. • Individuals with non-Hodgkin’s lymphoma can survive for long periods. The treatment used is chemotherapy. • Multiple myeloma is a neoplasm of B cells (immature plasma cells) and mature plasma cells. It is characterised by multiple malignant tumour masses of plasma cells scattered throughout the skeletal system and sometimes found in soft tissue. • The exact cause of multiple myeloma is unknown, but genetic factors and chronic stimulation of the mononuclear phagocyte system by bacteria, viral agents and chemicals have been suggested. • The major clinical manifestations for multiple myeloma include recurrent infections caused by suppression of the humoral immune response and renal disease as a result of Bence Jones proteinuria. • Chemotherapy is the treatment of choice for multiple myeloma. Survival is still only 2–3 years with chemotherapy, however. Treatment with thalidomide is showing promise as an effective therapeutic agent in producing long-term remissions.
CASE STUDY
ADU LT Damien is a 28-year-old chemical engineer. He has been feeling unwell for the past 2 weeks and has gone to see his doctor. He presents with fatigue, fever, night sweats and bruising. Damien’s doctor decides to request a full blood count. The blood sample is sent to a haematology laboratory — the laboratory report that comes back shows that Damien has normocytic-normochromic anaemia, marked leucocytosis and marked thrombocytopenia. A blood film was made from Damien’s sample and examined microscopically. The report states that numerous blast cells were present in the blood film (50% of the white cells in Damien’s blood film are blast cells).
1 2 3 4 5
Explain the terms normocytic-normochromic anaemia, marked leucocytosis and marked thrombocytopenia. What is a blast cell? Outline the significance of the presence of numerous blast cells in Damien’s blood. Explain whether the laboratory findings are consistent with Damien’s symptoms. What would the provisional diagnosis be for Damien? What additional samples would be required, and how would examination of those samples help the investigation of his illness?
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CASE STUDY
A GEING Martha is a 78-year-old woman living in a residential facility. Martha has early stage dementia and is not able to articulate clearly how she feels. Staff have noticed that Martha does not engage in all of her usual activities, seems listless at times and slightly dyspnoeic on exertion. The staff arrange for the doctor to assess Martha on her next visit. Martha has grade 1 congestive heart disease but this does not account for the recent change in her symptoms. On examination Martha has dyspnoea on exertion, conjunctival and mucosal pallor. A full blood count is sent to the laboratory and reveals: MCV < 80 ng/mL, reticulocyte count < 1% and serum ferritin < 15 ng/mL. The blood film
shows RBCs which are hypochromic together with poikilocytosis and anisocytosis. 1 Explain the terms hypochromic, poikilocytosis and anisocytosis. 2 Explain the significance of the ferritin level in Martha’s blood. 3 Explain the significance of the low reticulocyte component in Martha’s blood. 4 Explain whether the laboratory findings are consistent with Martha’s symptoms. 5 What would the provisional diagnosis be for Martha? What treatment and follow-up would be advised?
REVIEW QUESTIONS 1 Explain what anaemia is. 2 Outline some of the causes of iron deficiency anaemia and discuss treatment options. 3 Discuss the potential dangers that exist for the fetus and newborn in haemolytic disease of the newborn. 4 Outline how the numbers of different types of white cells can be affected by infections.
5 6 7 8 9 10
Describe chronic leukaemia. Discuss the pathogenesis of multiple myeloma. Describe DIC. What is meant by the term hypercoagulable state? Explain why thrombosis is a potentially serious health risk. What is the INR and why is it useful?
Key terms apocrine sweat glands, 446 bulb, 445 dermis, 443 eccrine sweat glands, 445 epidermis, 440 eponychium, 445 hypodermis, 440 keratinocytes, 440 Langerhans’ cells, 440 melanin, 440 melanocytes, 440 Merkel cells, 440 nail bed, 445 nail body, 445 nail root, 445 root, 445 sebaceous glands, 446 sebum, 444 shaft, 445 stratum basale, 440 stratum corneum, 443 stratum granulosum, 443 stratum lucidum, 443 stratum spinosum, 440
CHAPTER
The structure and function of the integumentary system
18
Adriana Tiziani Chapter outline Introduction, 440 The structure of the skin, 440 Layers of the skin, 440 Skin colour, 444 Appendages of the skin, 444 Hair, 444 Nails, 445 Sweat glands, 445 Sebaceous glands, 446
The function of the integumentary system, 447 Protection, 447 Regulation of body temperature, 447 Cutaneous sensation, 447 Production of vitamin D, 448 Excretion, 448 Ageing and the integumentary system, 449
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Introduction The integumentary system consists of the skin and its appendages including the hair, nails, sweat glands and sebaceous glands. The word integument is derived from the Latin word meaning ‘to cover’, which is precisely the main function of the integumentary system. It is the body’s first line of defence, providing a protective barrier against microorganisms, ultraviolet (UV) radiation, dehydration and pollutants in the external environment. It is also involved in a number of major functions, including temperature regulation, sensation, vitamin D production and excretion, in order to provide protection for the body and contribute to homeostasis. The functions of the skin are closely integrated to those of other systems of the body. For example, the integument functions with the skeletal and muscular systems to provide protection and support to the body; and vitamin D produced in the skin is used for absorption of calcium from the digestive tract and renal tubules. Therefore, the integumentary system is vital to many homeostatic mechanisms of other body systems. To understand how the disease process alters integumentary function, it is first necessary to appreciate the normal structure and function of the integumentary system and its normal structural changes across the life span. This is particularly important and contemporary for students in Australia and New Zealand, as these two countries have the highest rates of some skin cancers in the world. We start our exploration of the integumentary system with the anatomy of the skin.
The structure of the skin Layers of the skin
There are many amazing facts about the skin. It covers the entire body, with a surface area of approximately 1.8 m2 in the adult, and is the largest organ of the body, accounting for approximately 7% of body weight. Yet it is only approximately 1.5–4 mm thick, meaning that generally it is thin. In fact, the skin consists of two layers: (1) the epidermis, an outer layer of epithelial tissue; and (2) the dermis, an inner layer of connective tissue. Underlying these two layers is the hypodermis — this is not part of the skin. We also refer to this layer as the subcutaneous layer, which means under the skin. The hypodermis is mainly composed of adipose cells (fat), which provide insulation, preserving heat in the body and cells involved in tissue repair, and forming connective tissue (fibroblasts) (see Fig. 18.1). Both the dermis and the subcutaneous layers are important for specific types of injections (for details see Box 18.1).
The epidermis
The epidermis is composed of stratified squamous epithelium. This means that the cells are layered, squamous in shape and make up epithelial tissue, which is a protective lining tissue (see Chapter 3). Four types of cell are found in the epidermis:
• Keratinocytes. Most cells (80%) of the epidermis are keratinocytes. These cells are formed by division of the stem cells in the deepest layer of the epidermis. The newly produced keratinocytes undergo a differentiation program whereby, as they are pushed up towards the surface, they lose their nuclei and cell organelles and become filled with keratin (a protein that provides structure). This process is called keratinisation. Dead cells are continually desquamated (sloughed off) at the same rate that new cells are produced. It takes about 28 days for a new keratinocyte to be produced in the stratum basale, become keratinised and be sloughed off from the skin (see Table 18.1). Disruption to this process can occur in some skin diseases, such as psoriasis, which is discussed in Chapter 19. • Melanocytes. Melanocytes, found in the deepest layer of the epidermis, are cells that produce melanin, a skin pigment that provides an individual’s skin colour. The melanin is packaged into melanosomes that are transported into the cytoplasm of keratinocytes protecting them from ultraviolet radiation. Freckles, found on the skin of many individuals, are areas of increased melanin accumulation. • Langerhans’ cells. Langerhans’ cells arise from the bone marrow and migrate into the epidermis to help protect the body from foreign bodies, such as microorganisms that may invade the skin. These cells trap the invading foreign bodies and present them to helper T lymphocytes, activating the immune response (see Chapter 12). • Merkel cells. Merkel cells are located in the deep epidermis, mainly between the epidermis and dermis. They are closely associated with a disc-shaped sensory nerve ending. Together, the Merkel cell and its associated disc detect the sensation of touch (described in Chapter 6). There are four or five layers in the epidermis, depending on the location in the body. The thick skin found on the fingertips, palms of the hands and soles of the feet consists of five layers (see Fig. 18.3). Thick skin is free of hair and the underlying dermal papillae are raised, producing epidermal ridges on the surface of the skin. These ridges increase friction and on the fingertips form fingerprints. The thin skin covering most of the body has four layers and a smooth surface. The layers are referred to as stratum, meaning parallel layers. The layers are shown and detailed in Fig. 18.4 and Table 18.1. Let’s start with the deepest layer and work out towards the surface of the skin: • Stratum basale. The stratum basale, sometimes referred to as the stratum germinativum, is the deepest layer of the epidermis and consists of a single row of new keratinocytes. The word basale refers to base. Stem cells undergo mitosis and continually produce new keratinocytes in this layer. The layer is also populated with melanocytes and Merkel cells. • Stratum spinosum. The stratum spinosum (meaning prickly layer) consists of 8–10 rows of irregular-shaped
CHAPTER 18 The structure and function of the integumentary system
A
441
B
Sweat duct Nerve fibres
Dermoepidermal junction
Shaft of hair Dermal papillae
Hypodermis
Dermis
Epidermis
Ridges of dermal papillae
Opening of sweat duct
Blood vessels
Papillary layer of dermis
Sweat gland Subcutaneous adipose tissue
Sweat duct Sweat gland
Root of hair
Reticular layer of dermis
Hair follicle
Sebaceous gland
FIGURE 18.1
The structure of the skin. A Thick skin, found on the surface of the palms and soles of the feet. B Thin skin found on most parts of the body. The skin consists of two layers: the outer epidermis and the dermis. Underlying these layers is the hypodermis composed of fatty tissue. Note the ridges of the dermis where the epidermis has been raised.
BOX 18.1
Integumentary system injections
In clinical practice, some drugs, such as vaccines, are administered by injection into the skin or subcutaneous tissue (see Fig. 18.2). For example, insulin is administered into the subcutaneous tissue by subcutaneous injection and some vaccines are administered into the skin by intradermal injection. Subcutaneous 45°
FIGURE 18.2
Intradermal 15° Skin Subcutaneous tissue (hypodermis) Muscle
Intradermal and subcutaneous injections. Drugs may be administered into the skin (intradermal injection) or into the subcutaneous tissue (subcutaneous injection).
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TABLE 18.1 Layers of the skin STRUCTURE
DESCRIPTION
A
Surface film
Thin film coating the skin; made up of a mixture of sweat, sebum, desquamated cells/fragments, various chemicals: protects the skin
B
Epidermis
Superficial primary layer of the skin; made up of keratinised epithelium and includes hairs, sweat glands and sebaceous glands
C
Stratum corneum
Several layers of flake-like dead cells
D
Stratum lucidum
A few layers of squamous epithelium filled with eleidin — a keratin precursor that gives this layer a translucent quality (not visible in thin skin)
E
Stratum granulosum
2–5 layers of dying, somewhat flattened cells
F
Stratum spinosum
8–10 layers of cells pulled by desmosomes into a spiny appearance
G
Stratum basale
Single layer of keratinocytes capable of mitotic cell division; it is from this layer that all cells of superficial layers are derived; includes keratinocytes and some melanocytes
H
Dermal–epidermal junction
The basement membrane, a complex arrangement of adhesive components that glue the epidermis and dermis together
I
Dermis
Deep primary layer of the skin; made up of fibrous tissue; also includes some blood vessels, muscles and nerves
J
Papillary region
Connective tissue with collagen and elastin fibres and includes touch receptors
K
Reticular region
Tough network of collagen and some elastin fibres; forms most of the dermis
L
Hypodermis (subcutaneous layer)
Connective and adipose tissue; under the skin
CHAPTER 18 The structure and function of the integumentary system
A
B
FIGURE 18.3
Thick and thin skin. A The surface of the thick skin is hairless and has deep sulci (grooves) and friction ridges. B Thin skin has irregular sulci and contains hair.
Epidermis Stratum corneum
Stratum basale Dermis
FIGURE 18.4
Photomicrograph of the skin. The stratum basale and corneum are shown in the epidermis with the dermal layer underneath.
keratinocytes that are held tightly together giving strength to the skin. Langerhans’ cells are also found in this layer. • Stratum granulosum. The stratum granulosum consists of 3–5 rows of keratinocytes that are different in shape from the basale and spinosum layers. In this layer the nuclei and cell organelles begin to degenerate and the cells flatten. The cells contain keratinohyaline, a substance that assists in the formation of keratin in the layers above. In addition, there are granules that secrete a glycolipid (carbohydrate and lipid) substance that fills the spaces between the cells preventing loss and entry of water.
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This essentially waterproofs the epidermis and slows water loss from the skin. • Stratum lucidum. The stratum lucidum, the clear layer, is found only in thick skin. It consists of 2–3 rows of clear, flat keratinocytes. • Stratum corneum. The stratum corneum (horny layer), the outermost layer of the epidermis, consists of 20–30 rows of flattened, dead keratinocytes. Consisting mainly of keratin, this layer helps protect the body from water loss, injury and entry of foreign substances. Cells are continuously shed from the stratum corneum and replaced at the same rate by cells from the deeper layers. • There is a thin layer of sebum, sweat and cell fragments covering the epidermis. This surface film varies in thickness and chemical composition over different areas of the body.
The dermis
Immediately under the epidermis is the dermis. The dermis is strong and flexible and is a thicker layer than the epidermis. It consists of connective tissue and cells such as fibroblasts and macrophages. Within this tissue are fibres embedded in a semi-fluid matrix. There are collagen fibres (fibrous protein found in connective tissue), which give the skin its resilience as well as binding water to maintain skin hydration, and elastin fibres, similar to collagen but with elastic properties that cause the skin to recoil after stretching. Structures found in the dermis include blood vessels, lymphatic vessels, smooth muscles, nerve endings and hair follicles. The dermis is divided into a thinner superior layer, the papillary layer, and a deep thick layer, the reticular layer: • The papillary layer is composed of connective tissue with a rich supply of blood vessels. Its surface forms folds called papillae that extend into the epidermis (see Fig. 18.4). Diffusion of nutrients from the capillary loops located in the papillae provides nourishment to the epidermis, which has no blood supply. Also located in the papillary layer are free nerve endings (pain receptors) and touch receptors (see Chapter 6 for discussion of nerve function). • The reticular (net-like) layer forms about 80% of the dermis and is composed of dense irregular connective tissue. The dense bundles of collagen fibres provide resilience as well as binding water. Adequate water content helps maintain skin turgor (elasticity or tension produced by the water and the cell contents). The collagen and elastin fibres in each location of the body are arranged in parallel bundles that form cleavage lines. This is important when considering where to locate surgical incisions. Incisions parallel to the cleavage lines will result in less stress to the wound and therefore faster healing with less scar tissue. In contrast, overstretching of the dermis, such as during pregnancy and obesity, may damage the dermis, causing stretch marks called striae. Extending through the reticular layer are the hair follicles with arrector pili muscles attached, sebaceous glands, sweat
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glands, blood and lymphatic vessels and nerves. Cutaneous receptors located throughout the reticular layer enable the skin to receive stimuli for the sensations of touch, pressure and temperature.
The dermal–epidermal junction
The area between the dermis and epidermis, the dermal– epidermal junction, is composed of a basement membrane. The two layers are adhered together by specialised fibres and a polysaccharide gel. Downward finger-like projections of the epidermis called rete ridges fit into the upward projections of the papillary layer of the dermis. This anchors the two layers together, thereby providing resistance against shearing forces.
Skin colour
Polygenetic inheritance determines skin colour (see Chapter 5). Each individual’s skin colour results from the combination of pigments (melanin, carotene and haemoglobin) and dermal circulation. The number of melanocytes is relatively similar in all humans, so differences in skin colour are related to the amount of melanin produced and stored within each melanocyte. The melanin, once produced, is packaged into vesicles called melanosomes that are transferred to the keratinocytes. Skin colour depends on the size, number and distribution of the melanosomes rather than the density of the melanocytes.1 However, the melanocytes of darkly pigmented skin are more active and produce up to ten times more melanin than do the melanocytes of white skin. Also, in light skin, the melanosomes are transferred to keratinocytes in the lower two layers of the epidermis and the pigment is degraded by enzymes. Therefore, there is no melanin in the upper layers of the epidermis. On the other hand, the melanosomes in dark skin are transferred to keratinocytes in more layers of the epidermis and melanin persists in the stratum corneum, leaving the skin by natural desquamation.1 Dysfunction of the melanocytes may lead to pigmentation abnormalities. For example, a recessive genetic trait causing failure to produce tyrosine (an amino acid) results in the absence of melanin, a condition called albinism. Another condition in which there is an acquired loss of melanocytes in areas of the epidermis is vitiligo. This results in patchy white areas of skin (see Fig. 18.5). Damage to the melanocyte’s DNA may cause melanoma, which is discussed in Chapter 19. In addition to melanin, carotene (an orange pigment found in some vegetables such as carrots) accumulates in epidermal cells, thereby contributing to skin colour. Finally, dermal blood flow and oxygenation also contribute to skin colour. Oxygen bound to haemoglobin gives blood a bright-red colour, causing the pink colour of light skin. Deoxygenated blood is a dark-red colour and gives the skin a bluish colour, called cyanosis. Constriction of cutaneous blood vessels reduces blood flow to the skin causing skin pallor, while vasodilation causes redness (erythema).
FIGURE 18.5
Vitiligo. Areas of patchy white skin resulting from the acquired loss of melanocytes.
Often an abnormal skin colour is the sign of disease. Abnormal skin colours are summarised in Table 18.2. FOCU S ON L EA RN IN G
1 List the components of the integumentary system. 2 Name the two layers of the skin and state the type of tissue found in each. 3 Explain how the epidermis receives nourishment. 4 Compare the structure of the two layers of the dermis. 5 Describe the factors that contribute to skin colour.
Appendages of the skin Arising from the epidermis are accessory structures that include the hair, nails, sweat glands and sebaceous glands (see Fig. 18.6).
Hair
Hair is found over most of the body with the exception of the palms of the hands, the soles of the feet, the lips, nipples and parts of the external genitalia. Hairs are produced in hair follicles, cavities in the skin. The walls of the follicle consist of an internal and external root sheath, derived from the epidermis, and a dermal root sheath derived from the dermis. Attached to each hair follicle is a sebaceous gland that produces sebum to lubricate the hair and an arrector pili muscle. Contraction of this smooth muscle causes the hair to become more erect, resulting in ‘goose bumps’ when cold or frightened.
CHAPTER 18 The structure and function of the integumentary system
TABLE 18.2 Alterations of skin colour ABNORMAL SKIN COLOUR
Cyanosis A bluish colour to the skin resulting from a severe decrease in blood oxygen content
Jaundice Yellow discolouration of the skin caused by increased blood levels of bilirubin, a substance formed when haemoglobin is broken down. Jaundice may be a sign of liver dysfunction Pallor Pale skin resulting from reduced haemoglobin or temporarily reduced blood flow to the skin. Pallor may be a sign of anaemia or shock
Bruise A blue or purple discolouration of the skin resulting from blood seeping into the tissue from damaged blood vessels. A bruise may be caused by blunt tissue injury or it may be a sign of a coagulation disorder Erythema Redness resulting from increased blood flow to the skin. Erythema may be a sign of hypertension or inflammation
Hair shaft
EXAMPLE
A Epidermis
Dermis
B
C
Hair follicle Apocrine gland (sweat gland)
D
E
Each hair consists of a bulb from where the hair originates, a root that is the portion of hair in the follicle and a shaft, the portion of hair extending from the surface of the skin (see Fig. 18.7). The hair bulb contains a mass of undifferentiated cells, the matrix, which produces the hair. Extending into the bulb is the dermal papilla containing blood capillaries, which provide nourishment to the cells of the matrix. Once formed by the matrix, the cells become keratinised and push upwards as new cells are added.
Nails
Sebaceous gland
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The distal ends of the fingers and toes are protected by plates of hard keratinised epithelial cells, the fingernails and toenails. The nails consist of a distal visible section, the nail body, and a proximal section concealed under the skin, the nail root. The nail body is bounded by nail grooves
Subcutaneous layer
Eccrine gland (sweat gland)
FIGURE 18.6
Appendages of the skin. Hair and skin glands: sebaceous glands and sweat glands.
and nail folds. The proximal nail fold forms the eponychium, or cuticle. A layer of epithelium called the nail bed lies under the nail (see Fig. 18.8). As a result of the rich blood supply in the underlying dermis the nail appears pink. In clinical practice, when patients have a sudden fall in oxygen levels to the tissues, the first location that cyanosis is often observed is the nail bed. Nail growth occurs from the matrix at the base of the nail root. New cells are produced by mitosis in the stratum basale of the matrix. These cells become keratinised and move distally.
Sweat glands
Sweat glands are the most numerous glands in the skin. There are two types of sweat glands, eccrine and apocrine, which vary with location and type of secretion.
Eccrine sweat glands
Eccrine sweat glands are more numerous and widespread than apocrine sweat glands, with a particular abundance on the palms of the hands, the soles of the feet, upper limbs and forehead. Eccrine sweat glands are coiled tubular glands with the secretory portion of the gland located in the dermis. The duct opens at a pore on the skin surface. Eccrine sweat glands secrete sweat that is produced in the secretory part of the gland. Sympathetic stimulation (such as due to stress and anxiety) of the sweat glands causes the sweat to be secreted onto the surface of the skin,
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FIGURE 18.7
The structure of the hair and skin.
A AA
which is a powerful mechanism for heat loss and therefore plays an important role in the regulation of body temperature. Eccrine sweat consists primarily of water with small quantities of electrolytes (such as sodium and chloride) and some metabolic wastes (such as urea, uric acid, and ammonia) and dermacidin, an antimicrobial peptide.
Free edge Nail body Lunula Cuticle Nail root
B Nail
matrix Nail root
Apocrine sweat glands
Cuticle Nail body Nail bed Free edge
Bone
Stratum basale Stratum granulosum Stratum corneum
FIGURE 18.8
The structure of the fingernail. A Viewed from above. B Sagittal section.
Apocrine sweat glands are less numerous than eccrine glands and located in the axilla, areolar of the breast and pubic regions. They are simple branched glands whose ducts empty into hair follicles. Apocrine sweat glands are larger than eccrine sweat glands and do not develop until puberty. Apocrine sweat is more viscous and milky than eccrine sweat. As well as water and electrolytes, it also contains fatty acids and protein. Although odourless when secreted, degradation by bacteria is the cause of body odour.
Sebaceous glands
Sebaceous glands are simple branched glands whose ducts mainly open into hair follicles (known as pilosebaceous units) and found all over the body including non-hairy areas such as eyelids, nipples and around the genitals. The only areas of the body without sebaceous glands are the palms and soles. The largest number of glands and largest glands are found on the face and the scalp. The sebaceous glands secrete an oily substance, sebum, which contains triglycerides, cholesterol, cholesterol esters, wax esters and squalene. Although the exact function is unknown, it is thought that sebum’s function is to reduce water loss from
CHAPTER 18 The structure and function of the integumentary system
the skin. It also has a mild antimicrobial action, protecting the skin from bacteria and fungi. Sebaceous glands and sebum production are regulated by androgens and retinoids with a number of other factors also thought to be involved in regulation of activity.
F O CUS O N L E A R N IN G
1 Describe the structure of a hair. 2 Describe the structure of the nail. 3 Compare and contrast the structure and function of eccrine and apocrine sweat glands.
The function of the integumentary system The function of the integumentary system is to protect the underlying tissues from physical, chemical and microbial damage and to maintain homeostasis.
Protection
The skin’s primary function is to protect the body from invasion of harmful substances, damage by environmental factors such as ultraviolet radiation, and loss of fluids and electrolytes. The integument’s physical, chemical and biological barriers provide this protection.
Physical barrier
An intact skin provides a formidable barrier preventing the entry of microorganisms and is the body’s first line of defence. Constant renewal of the epidermis and desquamation with the elimination of adhering microorganisms ensures maintenance of an intact physical barrier. The barrier is created by the continuity of keratinocytes filled with the tough, insoluble protein, keratin. Keratin is the predominant component of the epithelial cells and constitutes 85% of the cellular protein in keratinised cells of the stratum corneum.2 Deeper in the epidermis (in the stratum granulosum), a water barrier is formed by lipids secreted by the keratinocytes and the tight junctions between the cells. This barrier functions to retain water in the body. Although the epidermis prevents entry by most substances, a small amount of lipid-soluble substances, organic solvents and heavy metal salts is able to penetrate the skin. In clinical practice, transdermal drug delivery systems have been developed to enable drugs to be administered through the skin to obtain systemic effects. This delivery system has advantages, such as a controlled release into the patient, reduced systemic effects and improved drug adherence. However, for the drug to be able to diffuse through the epidermis it must be soluble in the lipophilic layer as well as the more aqueous structures, have a small molecular size, and also be present in sufficient concentration
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to penetrate the epidermis.3,4 A number of drugs are now administered via this route including fentanyl (Durogesic® patch), glyceryl trinitrate (Transiderm-nitro® patch), oestradiol (Climara® transdermal patches) and nicotine.
Chemical barrier
The skin and its appendages secrete a number of chemicals that provide protection against microorganisms and other harmful substances. The pH of the skin is acidic, resulting mainly from the secretion of sweat from the eccrine glands. This ‘acid mantle’ creates an environment on the skin surface that is not conducive to microorganism growth. Secretion of antimicrobial substances also contributes to the chemical barrier — for instance, lysozyme (an enzyme) from apocrine sweat glands breaks down bacterial cell walls.5–7 In addition, melanin protects cells from ultraviolet radiation. It forms a protective cap over the nuclei of viable skin cells, absorbing the ultraviolet light and shielding DNA from damage.8
Biological barrier
A number of cells in the skin provide a biological barrier to prevent invasion by foreign substances such as bacteria. Langerhans’ cells located in the epidermis process and present antigens to helper T cells to stimulate antibody production (see Chapter 12). In addition, virus particles are presented to cytotoxic T cells which trigger immune responses. Memory T cells in the skin also provide local immunity against pathogens. If foreign substances penetrate the epidermis, they may come into contact with this line of defence cells, the dermal macrophages. Furthermore, eccrine sweat glands contain secretory IgA that is believed to have a role in cutaneous immunity.
Regulation of body temperature
The integumentary system plays an important role in thermoregulation. Structures of the integumentary system that function in the regulation of body temperature are the peripheral thermoreceptors, sweat glands and cutaneous blood vessels. The thermoreceptors in the skin are stimulated by hot or cold conditions. After these afferent nerve signals have been interpreted and processed by the hypothalamus, efferent nerve signals are sent to the blood vessels and sweat glands in the skin. When body temperatures are elevated, sweat glands are activated and sweat is evaporated from the surface of the skin, thus cooling the body. The cutaneous blood vessels dilate, thereby allowing more warm blood to be brought to the surface for heat dissipation. In cold conditions, the cutaneous blood vessels constrict, causing warm blood to be retained in the body core. In addition, shivering in skeletal muscles increases heat production, thereby raising body temperature. Thermoregulation is discussed fully in Chapter 13.
Cutaneous sensation
The skin contains a number of sensory receptors that enable the body to detect and respond to changes in the environment. For instance, thermoreceptors and nociceptors
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(stimulated by pain) are located in the dermis. Merkel cells, located in the basal layer of the epidermis, are involved in the sensation of light touch. Other receptors involved in touch include Meissner’s corpuscles located in the dermal papillae (which assist with two-point discrimination), Ruffini’s end organs (which detect continuous touch or pressure) and pacinian corpuscles (which detect deep pressure and vibration). Hair follicle receptors respond to bending of hairs and detect light touch. A dermatome refers to the region of the skin which is innervated by specific spinal nerves. These have important clinical significance, as pain felt to the skin within one dermatome can indicate some dysfunction of that particular spinal nerve (see Fig. 18.9). For example, pain in the region down the posterior of the leg and into the heel associated with S1 can indicate damage to spinal nerve 1. This also provides part of the reason why pain from the heart is referred to regions such as down the left arm, due to the dermatome provided by the T2 spinal nerve (thoracic nerve 2).
Production of vitamin D
The major source of vitamin D in the body is the exposure to sunlight which provides an important step in activating our vitamin D. When the body is exposed to ultraviolet radiation, a cholesterol-related steroid located in the skin is converted into a form of vitamin D (vitamin D3), which, when passing through the liver and kidneys, is converted to the active form of vitamin D (calcitriol). Vitamin D is required by the small intestine for absorption of calcium and phosphorus.
Excretion
The skin has only a small role in excretion. Small amounts of ammonia, urea and uric acid are excreted in the sweat.
C2
C2
C3
C3
C2 C2
C7 8 6 C3
C6 C5 Th2 Th1
8 C7 6
C4 C5 C6
C4
C4
Th2
Th2/3 Th4 Th5
C5 Th2
Th2
C5
Th1
Th1
Th12 L1
Th1 Th12 L1 Th10
L2 S5 S3 L3
L1
C5 C6 C7 C8
C6 7 C6
Th12
C4
Th1 Th2
Th12 L L1 2
Th12 L1
7 L2
L5 S1 S2
L5 S1 S2 S3
C6
C8
C7
S4/5
L3 C8 6 C7
L3
L4
L2 S2
S2
L4 L3 S2
L4
S2
L5
S1
L5 S1 L5
L4 S1
L5 S1
FIGURE 18.9
Dermatomes of the skin. Dermatomes refer to regions of the skin which are innervated by specific spinal nerves. For example, cervical nerve 3 (C3) innervates the front and back of the neck.
FOCU S ON L EA RN IN G
1 Relate the structural features of the skin to its function of protection. 2 List the receptors found in the skin and state the sensation detected by each. 3 Discuss the role of the integumentary system in the regulation of body temperature.
The skin undergoes a number of changes from birth through to old age. The newborn infant has soft, velvety skin covered with an oily substance, vernix caseosa — a mixture of desquamating cells and sebum. Skin surface lipids are low in cholesterol and high in wax esters in the first 2 weeks after birth. Shortly after birth the sebaceous glands begin a period of inactivity until puberty. As a result of low melanocyte function the skin of the newborn is less pigmented. The nerve network and cutaneous receptors, with the exception of Meissner’s corpuscles, are completely developed by birth. At birth the skin’s acid mantle develops and within the first hours of life colonisation by skin microorganisms, which are part of the skin flora, occurs. During childhood the skin
remains smooth and flexible. There are fewer sweat glands and the sebaceous glands remain inactive throughout childhood. With the secretion of sex hormones at puberty, the apocrine sweat glands and sebaceous glands are activated. Increased production of sebum causes the skin to be oilier. With secretion of apocrine sweat body odour develops. Also, evaporation of sweat plays a greater role in thermoregulation than in childhood. These glands remain active during adolescence and adulthood with activity decreasing after middle-age. At puberty there is a change in the skin flora with greater numbers of Propionibacterium acne present on the skin surface.
PAEDIATRICS
Paediatrics and the integumentary system
CHAPTER 18 The structure and function of the integumentary system
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Ageing and the integumentary system
F O CUS O N L E A R N IN G
1 Compare the structure of young and aged skin. 2 Discuss the role of intrinsic and extrinsic factors in skin ageing. 3 List the structural changes in aged skin and discuss the consequences of these changes.
the dermal papillae and rete ridges so that the epidermal layer can separate from the dermis more easily. In the dermis there are age-related changes to the fibres, cells and appendages. The dermis atrophies with a 20% reduction in dermal thickness. Decreased numbers of collagen and elastin fibres and increased linkage of the fibres cause the skin to become thin, fragile and inelastic. As a result, after stretching the skin fails to recover its shape and wrinkles develop. Dermal cells such as fibroblasts are decreased in number. Reduced numbers and increased fragility of the dermal capillaries cause the skin to be more easily bruised. With reduced numbers of nerve endings sensory perception is affected and there may be difficulty in discriminating between heat, pain and itching. Structural modifications and an overall decline in numbers of Meissner’s corpuscles and pacinian corpuscles have been associated with diminished vibration perception and two-point discrimination. It has been suggested that these changes to perception could contribute to a higher number of falls in the aged. In addition, a reduction in the number and function of the sebaceous and sweat glands causes the skin to become drier and thermoregulation is less efficient. The hair follicles are reduced in number and so the hair thins, and with the reduction in melanocyte function the hair also becomes grey. The subcutaneous layer, which consists primarily of adipose tissue and provides protection and insulation to the body, also atrophies with age. The changes to the integumentary system resulting from the ageing process lead to an increased risk of injury to the skin, slower wound healing, increased risk of skin infections (e.g. dermatophytosis, cellulitis, zoster) and age-associated skin diseases (e.g. benign or malignant tumours, unspecified pruritus). In addition to these effects, older skin may not respond as efficiently to topical medications.
AGEING
Ageing of the skin is a complex process consisting of both an intrinsic component that is genetically determined and an extrinsic component that is related to environmental factors (these concepts are elaborated on in Chapter 38). It is now believed that ageing is not ‘coded’ in the genome but modifications in gene functions are involved. Researchers have shown that regulation of genes involved in cell cycle control, manufacture of elastin and collagen and manufacture of the extracellular matrix are altered in ageing. Extrinsic factors that cause ageing include exposure to sunlight, cigarette smoking and health status. Exposure to sunlight is the most significant extrinsic factor causing skin ageing. Ultraviolet radiation is absorbed by skin molecules, generating reactive oxygen species that damage cellular components (refer to Chapter 4), interfere with enzymes that are required for DNA repair and interfere with Langerhans’ cells. Ultraviolet radiation also initiates damage to genetic material resulting in mutations. Thus photoageing (the effects of chronic ultraviolet light exposure on the skin) causes ageing by both directly damaging cellular components and amplifying the effects associated with normal intrinsic ageing. Nicotine damages skin by decreasing blood flow and thus oxygen and nutrients to the skin. Ageing causes changes to both the epidermis and the dermis of the skin, as well as the subcutaneous layer and skin appendages. Epidermal cell production slows, causing the skin surface to become thinner and more easily damaged. The number of melanocytes and Langerhans’ cells in the epidermis decreases, resulting in less protection from microbiological invasion and ultraviolet radiation. In addition, the mechanisms required to produce vitamin D in epidermal cells become less efficient, leading to lower levels of vitamin D in the elderly. Finally, the dermal–epidermal junction flattens with destruction of
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chapter SUMMARY The structure of the skin • The skin consists of an outer layer, the epidermis, and an inner layer, the dermis. • The epidermis is a stratified squamous epithelium composed of the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum and stratum corneum. • Types of cells found in the epidermis are keratinocytes, melanocytes, Langerhans’ cells and Merkel cells. • Keratinocytes are formed by mitosis of stem cells in the stratum basale. As they are pushed up towards the surface they lose their nuclei and organelles and become filled with keratin. Dead cells desquamate from the stratum corneum. • The dermis is composed of connective tissue and is divided into two layers, the papillary and reticular layers. Extending through the dermis are hair follicles, sweat glands, sebaceous glands, blood and lymphatic vessels, and nerves. Receptors that receive sensory stimuli are also located in the dermis. • At the junction of the epidermis and dermis, downward finger-like projections of the epidermis called rete ridges fit into upward projections of the papillary layer of the dermis, anchoring the two layers together. • Skin colour is due to a combination of the pigments melanin, carotene and haemoglobin, and dermal circulation.
Appendages of the skin • Hair is composed of dead keratinised cells. Each hair has three parts: (1) the bulb that produces hair; (2) the root; and (3) the shaft. • Nails contain keratinised epidermal cells. They consist of the nail body, the visible section of the nail, and the nail root, the section concealed under the skin. Nails grow by mitosis of cells in the stratum basale of the matrix. Nails protect the distal ends of the fingers and toes. • There are two types of sweat glands: eccrine sweat glands and apocrine sweat glands. Eccrine sweat glands are the more numerous being distributed over most of the body. They are small, simple coiled tubular glands that open onto the skin surface. They secrete sweat, excrete wastes and help regulate body temperature.
Apocrine sweat glands are distributed in the axilla, areolar of the breast and pubic area. They are large, simple branched tubular glands and empty into hair follicles. They begin to function at puberty. • Sebaceous glands are simple branched glands whose ducts open into hair follicles. They secrete sebum, an oily substance that lubricates the hair and skin.
The function of the integumentary system • The skin protects the body from invasion of harmful substances, damage by environmental factors, and loss of fluids and electrolytes. It protects the body by physical barriers (continuous layer of keratinised cells), chemical barriers (acid pH, antimicrobial substances, melanin) and biological barriers (Langerhans’ cells, dermal macrophages). • Peripheral thermoreceptors, sweat glands and cutaneous blood vessels play an important role in the regulation of body temperature. • Sensory receptors located in the skin enable the body to respond to temperature, touch, pressure and pain. • When the skin is exposed to ultraviolet light, several precursor conversions lead to active vitamin D manufacture. • Small amounts of ammonia, urea and ureic acid are excreted through the skin.
Paediatrics and the integumentary system • In childhood the skin is smooth and flexible. There are fewer sweat glands and sebaceous glands are quiescent. • At puberty the apocrine sweat glands and sebaceous glands are activated.
Ageing and the integumentary system • Ageing of the skin involves both intrinsic (genetically determined) and extrinsic (environmental) factors. Changes to the skin include thinning of the skin surface, reduced numbers of melanocytes and Langerhans’ cells, atrophy of the dermis, decreased numbers of elastin and collagen fibres, increased fragility of dermal capillaries, reduced numbers of sebaceous and sweat glands, reduced number of hair follicles and atrophy of the subcutaneous layer.
CHAPTER 18 The structure and function of the integumentary system
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CASE STUDY
ADU LT Rhianna is a 26-year-old female who spends time taking care of her skin. She believes that she is making good choices for keeping her skin looking good by using natural body washes; moisturising her face, neck and arms every morning and evening; and avoiding exposure to the sun. Although her mother has quite pale skin, her father has dark skin and Rhianna has an olive–brown skin, with very little body hair. 1 Discuss the layers of Rhianna’s epidermis, including the names of the layers and their functions. 2 Discuss the components of pigmentation of Rhianna’s skin.
3
Discuss cutaneous sensation. Rhianna is embarrassed when she sweats under her arms, even though she lives in Queensland and knows that it is normal to sweat in summer. Discuss the type of sweating that occurs in the armpits, including reference to the link to body odour. 5 Rhianna has recently discovered a new facial moisturiser; this product claims to be alkaline and it is meant to prevent ageing. Discuss the usage of an alkaline product in terms of the skin’s function as a chemical barrier. 4
CASE STUDY
AGEING Marge is 85 years old and is a resident in an aged-care facility. She has a history of coronary artery disease and has a Transiderm-nitro® (glyceryl trinitrate) patch applied each day and removed at night. Marge walks with the aid of a walking frame, and although she prefers to remain in her room, the nurses encourage her to sit outside for about 10 minutes each day. Recently, when undressing, Marge sustained a skin tear to her arm. The epidermis separated from the dermis and epidermal tissue was lost. The wound was cleaned with normal saline and a non-adherent dressing was secured with a bandage. 1 Marge has the drug glyceryl trinitrate administered by the transdermal route. Explain by what process the drug enters the body using this route of administration and
2
3
4 5
what features the drug requires to enable it to penetrate the skin. The nurses encourage Marge to sit outside each day. Describe the function of the skin that is activated by sunlight. Marge has sustained a skin tear that has separated the dermis and epidermis. Describe how the epidermis and dermis are anchored together. How does this structure change in aged skin? Outline the age-related changes that cause Marge’s skin to be more prone to injury. With the loss of skin integrity due to the skin tear, predict a potential complication that may occur for Marge and explain the reasons.
REVIEW QUESTIONS 1 Name and describe the layers of the epidermis from deep to superficial. 2 Without a blood supply, explain how the epidermis receives oxygen and nutrients. 3 Discuss the life of a keratinocyte from when it is produced to when it is shed. 4 Explain where the melanocytes are located and their function. 5 Outline the differences between eccrine and apocrine sweat glands.
6 Explain how the integumentary system helps maintain normal body temperature on a very hot day. 7 List the features of the skin that prevent bacteria that come into contact with the body surface from causing an infection. 8 Explain why sunlight is necessary for bone growth. 9 Describe the function of sebum. 10 Explain what causes the differences in skin colour between light and dark skin.
Key terms
CHAPTER
19
Alterations of the integumentary system across the life span Adriana Tiziani
Chapter outline Introduction, 453 Skin lesions, 453 Skin cancer, 453 Basal cell carcinoma, 457 Squamous cell carcinoma, 459 Melanoma, 460 Inflammatory disorders of the skin, 462 Dermatitis, 462 Acne vulgaris, 465 Acne rosacea, 465 Cutaneous lupus erythematosus, 466 Papulosquamous disorders, 467 Infections of the integumentary system, 468 Bacterial infections, 468
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Viral infections, 470 Fungal infections, 471 Parasitic infestations, 473 Traumatic conditions of the integumentary system, 475 Pressure injuries, 475 Skin tears, 477 Burns, 478 Vascular disorders, 481 Cutaneous vasculitis, 481 Scleroderma, 481 Port-wine stain, 482
acne rosacea, 465 acne vulgaris, 465 allergic contact dermatitis, 463 atopic dermatitis, 463 basal cell carcinoma, 457 body lice, 474 burns, 478 candidiasis, 472 carbuncles, 468 cellulitis, 468 cutaneous lupus erythematosus, 466 cutaneous vasculitis, 481 dermatitis, 462 folliculitis, 468 furuncles, 468 haemangiomas, 482 head lice, 473 herpes simplex virus, 470 herpes zoster, 470 impetigo, 469 irritant contact dermatitis, 462 melanoma, 460 molluscum contagiosum, 471 papulosquamous disorders, 467 paronychia, 470 pediculosis, 473 port-wine stain, 482 postherpetic neuralgia, 471 pressure injury, 475 psoriasis, 467 pubic lice, 474 rule of nines, 479 scabies, 473 scleroderma, 481 seborrhoeic dermatitis, 465 skin tears, 477 squamous cell carcinoma, 459 staphylococcal scalded skin syndrome, 469 tinea, 472 varicella, 470 warts, 471
CHAPTER 19 Alterations of the integumentary system across the life span
Introduction The integumentary system is the most visible organ system and so alterations to the skin are usually noticeable. Disorders and diseases of the integumentary system are common across the life span, such as nappy rash and acne in the younger population and skin tears in the elderly. In addition, skin alterations are particularly relevant to clinicians in Australia and New Zealand, as we have the highest rates of skin cancer in the world. The skin is the largest organ in the body and is exposed to many potentially damaging agents including ultraviolet radiation, chemicals and physical trauma. Alterations of the integument include inflammatory conditions due to infections, allergies or unknown causes; benign and malignant neoplasms; traumatic conditions; and vascular disorders. Although the number of disorders affecting the integumentary system is vast, in the following sections we discuss only the commonly encountered conditions.
Skin lesions Physical description of the skin when diagnosing a skin disorder includes detail about the skin lesion which is defined as being a pathological or traumatic breach of the normal skin. Skin lesions are either primary (original appearance) or secondary (the appearance has been changed by normal progress over time). Identification of the morphological structure and physical appearance of skin lesions is important to understand the underlying pathophysiology. Descriptions and examples of primary and secondary lesions are listed in Table 19.1. This list can be used as a reference tool when
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referring to the pathophysiological conditions throughout the rest of the chapter.
Skin cancer Skin cancer is the most common form of cancer, accounting for about 80% of all newly diagnosed cancers in Australia. In 2014, over 2000 Australians died of skin cancer.1 Interestingly, clinicians are not required to report the incidence of some types of skin cancers (non-melanoma skin cancers (NMSC): the commonly seen squamous cell and basal cell carcinoma) to health authorities, so skin cancers are actually much more common than suggested by publications that list the incidence of diseases. The mortality rate of NMSC is currently estimated to be 1.9 deaths /100 000 people, accounting for approximately 560 deaths annually.2 This high rate is attributed primarily to the high ambient solar ultraviolet (UV) radiation with levels higher in the Southern Hemisphere than in the Northern Hemisphere. Fair-skinned people are the most susceptible to developing skin cancer — skin cancer is rare in Aboriginal and Torres Strait Islander peoples and the Māori population. UV radiation can be divided into UV-B (280–320 nanometres (nm)) which is absorbed by the epidermis, and UV-A (320–400 nm) which penetrates the dermis and is capable of altering structural and matrix proteins contributing to the photoageing process (discussed in Chapter 18). A person’s ability to tolerate sunlight is inversely proportional to the degree of melanin pigmentation. Sunburn is the result of exposure to UV radiation, especially UV-B. Vasodilation of dermal blood vessels occurs 4–12 hours later. Chronic effects of sun exposure can be non-malignant (e.g. wrinkling,
TABLE 19.1 Primary and secondary skin lesions PRIMARY SKIN LESIONS
EXAMPLES
Macule A flat, circumscribed area that is a change in the colour of the skin; less than 1 cm in diameter
Freckles, flat moles (naevi), petechiae, measles, scarlet fever
a
Papule An elevated circumscribed area less than 1 cm in diameter
Wart (verruca), elevated moles, lichen planus
a Continued
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TABLE 19.1 Primary and secondary skin lesions—cont’d PRIMARY SKIN LESIONS
EXAMPLES
Patch A flat, non-palpable, irregularshaped macule more than 1 cm in diameter
Vitiligo, port-wine stains, Mongolian spots, café-au-lait spots
b
Plaque Elevated, firm and rough lesion with flat top surface greater than 1 cm in diameter
Psoriasis, seborrhoeic and actinic keratoses
f
Wheal Elevated, irregular-shaped area of cutaneous oedema; solid, transient; variable diameter
Insect bites, urticaria, allergic reaction
a
Nodule Elevated, firm, circumscribed lesion; deeper in dermis than a papule; 1–2 cm in diameter
Erythema nodosum, lipomas
c
Tumour Elevated, solid lesion; may be clearly demarcated; deeper in dermis; greater than 2 cm in diameter
Neoplasms, benign tumour, lipoma, haemangioma
b
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TABLE 19.1 Primary and secondary skin lesions—cont’d PRIMARY SKIN LESIONS
EXAMPLES
Vesicle Elevated, circumscribed, superficial, does not extend into dermis; filled with serous fluid; less than 1 cm in diameter
Varicella (chickenpox), herpes zoster (shingles)
a
Bulla Vesicle greater than 1 cm in diameter
Blister, pemphigus vulgaris
a
Pustule Elevated, superficial lesion; similar to a vesicle but filled with purulent fluid
Impetigo, acne
b
Cyst Elevated, circumscribed, encapsulated lesion; in dermis or subcutaneous layer; filled with liquid or semisolid material
Sebaceous cyst, cystic acne
b
Telangiectasia Fine, irregular red lines produced by capillary dilation
Telangiectasia in rosacea
c Continued
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TABLE 19.1 Primary and secondary skin lesions—cont’d PRIMARY SKIN LESIONS
EXAMPLES
SECONDARY SKIN LESIONS
EXAMPLES
Scale Heaped-up, keratinised cells; flaky-skin; irregular shape; thick or thin; dry or oily; variation in size
Flaking of skin with seborrhoeic dermatitis following scarlet fever, or flaking of skin following a drug reaction; dry skin
d
Lichenification Rough, thickened epidermis secondary to persistent rubbing, itching or skin irritation; often involves flexor surface of extremity
Chronic dermatitis
e
Keloid Irregular-shaped, elevated, Keloid formation following progressively enlarging scar; surgery grows beyond the boundaries of the wound; caused by excessive collagen formation during healing
b
Scar Thin to thick fibrous tissue that replaces normal skin following injury or laceration to the dermis
Healed wound or surgical incision
c
Excoriation Loss of the epidermis; linear, hollowed-out, crusted area
Abrasion or scratch, scabies
b
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TABLE 19.1 Primary and secondary skin lesions—cont’d PRIMARY SKIN LESIONS SECONDARY SKIN LESIONS
EXAMPLES
Fissure Linear crack or break from the epidermis to the dermis; may be moist or dry
Athlete’s foot, cracks at the corner of the mouth
c
Erosion Loss of part of the epidermis; depressed, moist, glistening; follows rupture of a vesicle or bulla
Varicella, variole after the rupture
g
Ulcer Loss of epidermis and dermis; concave; varies in size
Pressure injury, venous ulcer
f
Atrophy Thinning of the skin surface and loss of skin markings
Aged skin, striae
h
blotchiness, telangiectasia) or malignant (e.g. basal cell carcinoma, squamous cell carcinoma, melanoma). It is therefore important to protect the skin from UV radiation by using clothing (e.g. wide-brimmed hats, long sleeves), sunscreens (sun protection factor (SPF) >30+) and limiting exposure to the sun.
Basal cell carcinoma
Basal cell carcinoma is a malignant tumour of the integument that arises from cells in the basal layer of the epidermis. It is the most common form of skin cancer in
Australia and New Zealand and is estimated to account for at least two-thirds of non-melanoma skin cancers. Since neither Australian nor New Zealand registries record non-melanoma skin cancers, incidence rates have been determined from national population surveys. From a total of 430 000 cases of non-melanoma cases, it was estimated that about 69% were basal cell carcinoma, with the remaining 21% being squamous cell carcinoma.2 Data collected from general practices throughout Australia have shown that basal cell carcinoma accounted for 0.6% of all general practitioner–patient encounters between April 2005 and March 2007.3
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The predominant cause of basal cell carcinoma is repeated exposure to solar UV radiation, especially in the form of ultraviolet B (UVB) with wavelengths 280–320 nm.4 The sun emits several types of electromagnetic radiation: UV, visible and infrared which are emitted as waves and have different wavelengths. For instance, UV light has a wavelength that is shorter than visible light. The sun emits three types of ultraviolet light: UVA, UVB and UVC. UVA has the longest wavelength, followed by UVB and UVC. The highest energy rays are UVC, but fortunately UVC is filtered out by the earth’s atmosphere and does not reach the surface. However, UVB is particularly harmful to the skin and, with the destruction of the ozone layer, UVB radiation can penetrate the earth’s atmosphere, thereby increasing the risk for UV-induced photocarcinogenesis (cancer arising from light). Exposure to UV radiation during childhood and adolescence significantly increases the risk of developing basal cell carcinoma. A very small number of basal cell carcinomas can be attributed to other causes, such as ionising radiation therapy, and immunosuppression in some individuals.2 Basal cell carcinoma arises from stem cells located in the basal layer of hair follicles or the epidermis. The precise pathogenesis of basal cell carcinoma is not known. It probably begins with a gene mutation (concepts of cancer are discussed in Chapter 37). Both UVA and UVB can damage DNA. UVB is absorbed directly by DNA, causing changes in a number of genes. Also, UVA causes DNA damage by generating oxygen radicals (see Chapter 4), which causes breaks in the DNA molecule.5 Studies suggest that alterations in particular tumour suppressor genes may be related to the formation of basal cell carcinoma.6,7 Changes in genes may decrease repair of UV-induced DNA damage and induce cell cycle proliferation, leading to the formation of basal cell carcinoma. Basal cell carcinomas are slow-growing tumours that rarely spread (or metastasise) to other parts of the body. They occur most frequently on body areas that are exposed to the sun, such as the face, head, neck, shoulders and back. There are three common growth patterns (superficial, nodular and morphoeic), each with different clinical features: 1 Superficial basal cell carcinomas are common, particularly in younger individuals. Lesions are flat, erythematous, scaling macules (involving colour change to a small area of skin; also called blemishes). If untreated, they will enlarge, reaching 5–10 cm in diameter. 2 Nodular basal cell carcinomas are found more often in the elderly. These lesions begin as a small pink nodule that enlarges and becomes an ulcer surrounded by a raised, rolled pearly border (see Fig. 19.1). 3 Morphoeic basal cell carcinomas have a sclerosing (meaning causing to harden) growth pattern and have the appearance of a pale scar that feels hard on palpation and rarely ulcerates. This form of basal cell carcinoma tends to be longstanding and highly invasive, meaning that they grow into the tissues.
FIGURE 19.1
Basal cell carcinoma. Ulcerated lesion with raised pearly border.
The most common treatment of basal cell carcinomas is surgical excision. Complete excision with a 4–5 mm margin cures the majority of patients. For highly aggressive basal cell carcinomas Mohs surgery can be used. In this procedure all margins of the excised tumour are examined to ensure a high cure rate.8 Cryotherapy, the destruction of tissues by the application of a cryogenic agent such as liquid nitrogen, can be used to treat well-defined lesions of non-aggressive basal cell carcinomas on sites other than the head and neck but is not suitable for morphoeic or recurrent basal cell carcinomas. Imiquimod 5% cream can be used to treat superficial basal cell carcinoma. The cream is applied 5 times a week for 6 weeks to the tumour and a 5-mm margin of normal skin surrounding it. Imiquimod is a cytokine and interferon-inducer that stimulates an immune response. For superficial basal cell carcinomas on the trunk and limbs, curettage and diathermy/electrodesiccation can be used. Curettage is the medical term for surgical scraping — the tumour tissue is scraped away, and this is followed by the application of diathermy (local heat, which can stop bleeding or destroy tissue) to the base. Photodynamic therapy is an effective treatment for superficial and thin nodular basal cell carcinomas. Light is used to activate a photosensitiser such as methyl aminolevulinate (Metvix®), which is localised in tumour tissue to form cytotoxic reactive oxygen species, to cause destruction of the carcinoma. Radiation therapy is generally used only to treat basal cell carcinomas not suited to surgery or as an adjuvant to surgery for persistent or advanced basal cell carcinomas. Although basal cell carcinomas rarely metastasise (spread to other areas), they may destroy local healthy tissue. Basal cell carcinomas have a long recurrence period of 10 to more than 20 years. Therefore, follow-up monitoring is important. Since the main cause of basal cell carcinomas is exposure to sun, prevention is aimed at improving sun-protective behaviours. Both the Cancer Council of Australia and the Cancer Society of New Zealand have devised strategies to improve sun protection and reduce
CHAPTER 19 Alterations of the integumentary system across the life span
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FIGURE 19.3
Solar keratosis. The lesion appears as plaque with a hyperkeratotic surface.
FIGURE 19.2
Squamous cell carcinoma on the ear. The lesion has irregular borders.
the incidence of skin cancers. Such strategies include avoiding exposure in the middle of the day, staying in the shade, wearing clothing and hats that protect exposed skin, using sunscreen (with sun protection factor (SPF) >30+) and avoiding the use of solariums and sunbeds.9
Squamous cell carcinoma
Squamous cell carcinoma (see Fig. 19.2) is a cancer arising from keratinocytes in the outer layers of the epidermis. It may arise from skin or other sites lined by squamous epithelium, such as the oesophagus, mouth and vagina. Squamous cell carcinoma has precursor lesions, is invasive and may metastasise (spread to other body regions; refer to Chapter 37). The incidence of squamous cell carcinoma, the second most common of the non-melanoma skin cancers, continues to rise both in Australia and worldwide. In Australia it is estimated that squamous cell carcinoma makes up 29% of non-melanoma skin cancers.2 The predominant cause of squamous cell carcinomas and related squamous keratinocyte tumours is cumulative sun exposure. Other risk factors include age (> 50 years), being male, having fair skin (that burns easily without tanning), blue or green eyes, blond or red hair, being exposed to chemical pollution such as tar or arsenic or large numbers of x-rays, immune suppression, smoking, preexisting ulcers or scars and genetic syndromes such as xeroderma pigmentosum in which the mechanism for DNA repair is defective.8 In addition, a number of precancerous conditions including solar (acitinic) keratosis and squamous cell carcinoma in situ (Bowen’s disease) can develop into
squamous cell carcinoma. Those with > 15 solar (acitinic) keratosis are 10–15 times more at risk of developing squamous cell carcinoma than those with none.8 Treatment options for squamous cell carcinoma are similar to those for basal cell carcinoma.
Solar (acitinic) keratosis
The majority of squamous cell carcinomas arise from solar keratoses. Solar keratoses are lesions that have atypical nuclei in the epidermal basal layer and hyperkeratosis and are associated with chronic exposure to UV radiation.10 (See Fig. 19.3.) They appear as irregular plaques with a rough, hard, hyperkeratotic surface with a sandpaper-like texture if palpated.10 Plaques are usually less than 1 cm in size although lesions can join together and appear larger, Solar keratoses are associated mainly with middle age (> 40 years) and are found most commonly on the face, ears and back of hands and are usually the same colour as the surrounding skin although they can be pink, red or brown. The lesions can remit spontaneously, persist or progress into squamous cell carcinoma. Recommended therapy for solar keratoses include cryotherapy, topical medications including 5% 5-fluorouracil cream (an antimetabolite that stops the cell cycle, and is often used in combination with fluorinated steroid cream to reduce irritation), imiquimod 5% cream (which stimulates the immune response), 3% diclofenac gel (which induces apoptosis, inhibits cell proliferation and suppresses angiogenesis (blood vessel growth)) or photodynamic therapy.10
Squamous cell carcinoma in situ (Bowen’s disease)
Squamous cell carcinoma in situ (meaning remaining where it originated) consists of abnormal keratinocytes confined to the epidermis. The lesions involve the full thickness of the epidermis and are well-demarcated, erythematous scaly patches up to several centimetres in diameter. They are found most commonly on the ears, face, hands and lower
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legs. Squamous cell carcinoma in situ is more likely to progress to invasive disease than solar keratosis, with about 5% progressing into invasive squamous cell carcinoma.11 Development of a lump or bleeding may indicate that the lesion has progressed to invasive squamous cell carcinoma. Treatment includes cryotherapy, removal of the lesion and cauterisation to the base, 5-fluorouracil cream, imiquimod cream and photodynamic therapy. The events involved in the pathogenesis of squamous cell carcinoma (both in situ and invasive) are largely unknown. Damage to DNA results in monoclonal differentiation within a keratinocyte, meaning the cell line that produces keratinocytes is damaged. Excessive UV exposure overwhelms the mechanisms that repair DNA and mutations can occur in several tumour-suppressor genes including p53.12 Mutations lead to uncontrolled cell proliferation and loss of apoptosis. (See Chapter 37 for details of p53 and loss of apoptosis as related to cancer.) Inflammation is a major component of the neoplastic progression. Tumour cells co-opt signalling molecules of the innate immune system that maintain chronic levels of lymphocytes and mast cells promoting tumour growth, invasion and metastasis.12 Squamous cell carcinoma in situ begins as an erythematous papule (small, raised skin region) or nodule. Invasive squamous cell carcinomas are usually slow-growing nodules that may develop ulcers that do not heal. The borders are irregular and bleed easily. About 5% of squamous cell carcinomas metastasise. Since squamous cell carcinomas are aggressive, have potential for recurrence and may spread to lymph nodes and distant sites, treatment is usually surgical excision.
as those who have never had sunburn. The highest risk occurs if the sunburn occurs in childhood.15,16 People with fair skin and blond or red hair have a greater risk of melanoma that may be associated with genetic variation in the melanocortin receptor (a receptor involved in the production of melanin).15,16 Other risk factors include a previous history of skin cancer, the presence of multiple melanocytic naevi (a benign accumulation of melanocytes) or atypical naevi and a family history with the most common genetic abnormality being mutation of the p16 gene. More recently, the use of sunbeds has been associated with development of melanoma, especially in those under 35 and who had undergone multiple treatments. Sunbeds have consequently been banned for commercial use throughout Australia (except the Northern Territory, where there were no operators).9,17
Melanoma
CLINICAL MANIFESTATIONS
Melanoma is a malignant tumour that arises from melanocytes. It progresses rapidly and has a high rate of metastasis. Australia and New Zealand have the highest incidence rates of melanoma in the world, being 11 times higher than the estimated average worldwide rate.13 Melanoma is the fourth most common malignant cancer in Australia with it being the most common cancer in Australians aged 15 to 44 years. Between 1982 and 2014, the incidence of melanoma in Australia increased from 27 to 49 per 100 000 people.13 The incidence of melanoma is lower in non-Caucasians when compared to Australian-born population with Indigenous Australians developing melanoma at a rate of only 9 cases per 100 000 compared with 33 cases per 100 000 for non-Indigenous Australians.2 The clinical outcomes for non-Caucasians are poorer because diagnosis is often later with people presenting with more advanced and thicker tumours (commonly on the soles or palms considered ‘sun protected’ areas).14 The cause of melanoma involves both environmental and genetic factors. The primary environmental factor is intermittent exposure to UV radiation in sunlight. This link is very evident, as individuals who have had sunburn (with blistering) are twice as likely to develop melanoma
PATHOPHYSIOLOGY
Although the exact pathogenesis of the transformation of a melanocyte into melanoma is not fully known, it is believed to be a multistep process of progressive genetic mutations.18–20 Abnormalities of the genetic pathways within the melanocyte promote melanocyte proliferation and apoptosis leading to the development of melanoma (see Fig. 19.4). The different genetic components include changes to the melanocortin 1 receptor (MC1R), mutations of the CDKN2A, CDK4 and N-ras genes, with a loss of the phosphatase and tensin (PTEN) homologue on chromosome 10. (Homologue refers to chromosomes with the same genes.) Enzymes such as cathepsin then mediate degradation of matrix proteins allowing spread via the lymphatic system and metastasis.20 Melanomas differ in size, shape and colour. They range in size from a few millimetres in diameter to a few centimetres. They have irregular borders and may be dark brown, black, blue or red in colour. During the horizontal growth phase they are flat and during the vertical growth phase they become raised. Some melanomas may be itchy or bleed. There are four main types of melanomas: • Superficial spreading melanomas (see Fig. 19.5) are the most common, accounting for about 70% of melanomas. They occur most frequently on sun-exposed areas such as the back and legs. They may arise from an existing naevus (singular of naevi — skin lesions) that shows change in size, shape or colour. The mean age for superficial spreading melanomas is 40 years old. • Nodular melanomas account for about 15% of melanomas and usually occur during the fifth or sixth decade of life. They are raised dome-shaped lesions often with a uniform blue-black colour and tend to bleed. • Lentigo melanomas account for 10–15% of melanomas and are more common in the elderly. They are slow-growing and appear as a pigmented macule that is undergoing change. They can invade the dermis and become a lentigo malignant melanoma (see Fig. 19.6).
CHAPTER 19 Alterations of the integumentary system across the life span
Change to melanocyte
Genetic alteration
Clinical appearance
Melanocyte
CDKN2A CDK4 mutation of UV radiation
causes
Genetic alterations
however If minor, DNA is corrected
mutation of
mutation of
it is possible that
N-ras
loss of cell cycle control leads to
abnormal cell growth
inflammatory chemicals degrade matrix proteins Loss of PTEN on chromosome 10
Cell returns to normal
undergoes Proliferation of Melanocyte results in melanocytes proliferation in epidermis leads to Dysplasia
results in
leads to
Melanoma results in
Atypical melanocytes with large irregular nuclei
CONCEPT MAP
Environmental factor
461
results in Lesion varying in colour with irregular borders
Invasion and metastasis
FIGURE 19.4
Proposed pathogenesis of melanoma. The development of melanoma is believed to be a multistep process resulting from complex interactions between UV light and genes. Genetic alterations include melanocortin 1 receptor (MC1R) variants, mutations of CDKN2A and CDK4 genes (involved in controlling cell division), mutations of N-ras genes that can promote resistance to apoptosis and loss of the phosphatase and tensin (PTEN) homologue gene on chromosome 10. Enzymes such as cathepsin then mediate degradation of the matrix proteins, allowing invasion and metastasis.
FIGURE 19.6 FIGURE 19.5
Superficial spreading melanoma. The lesion is raised and coloured brown and black.
• Acral lentiginous melanomas account for 1–3% of melanomas in Australia. They are a flat light-coloured or pink lesion occurring on the palms of the hands or soles of the feet. This type of melanoma is equally common in both fair-skinned and dark-skinned people and is thought to have no relationship with UV exposure.
Lentigo malignant melanoma. A spreading lesion with variable colours of brown and an irregular border.
EVALUATION AND TREATMENT
Diagnosis of melanoma is based on biopsy results. Melanomas are classified and staged using the classification and staging system for melanoma published in 2002 by the American Joint Committee on Cancer and the International Union against Cancer. The TNM (tumour, lymph node,
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metastases) staging includes melanoma thickness and ulceration, the number of metastatic lymph nodes and the site of distant metastases.14 (A general description of the TNM system is in Chapter 37.) Early diagnosis and treatment are essential, as invasion of melanoma into deeper skin tissue and ulceration result in a poor prognosis. Therefore, the standard treatment for primary melanoma is wide local surgical excision of the skin and subcutaneous tissue.14 If the melanoma invades deeper tissue, there is a risk of spread to the regional lymph nodes. The risk of metastasis is linked to the Breslow thickness of the primary melanoma (a standardised method to determine the thickness of melanomas). The risk of metastasis is related to the thickness of the melanoma. Patients with a melanoma greater than 1 mm in thickness are given the opportunity to discuss sentinel lymph node (the node receiving lymphatic drainage from the tumour) biopsy. If the biopsy is positive, treatment may include lymph node dissection and adjuvant therapy (other cancer therapies, such as chemotherapy, radiotherapy or more targeted biological therapies).
RESEARCH IN F
CUS
Using modified herpes virus therapy to treat melanoma lesions Researchers have found that oncolytic viruses are able to recognise, infect and destroy malignant cells with minimal impact on normal human cells. Using this information, the herpes simplex virus type 1 (HSV-1) has been genetically modified (talimogene laherparepvec) to treat inoperable melanoma lesions. Treatment involves a series of intralesional injections. While this therapy showed good results in clinical studies (decrease in skin and lymph node lesion size), the treatment may not improve overall survival rate or have an effect on metastatic spread to brain, bone, liver, lungs or other internal organs. Current research is investigating the combination of this modified virus therapy with other immunotherapies or other targeted therapy. If the results of these studies are significant, it may be that this virus therapy becomes an important component in the future management of patients with metastatic melanoma.
F OC US O N L E ARN IN G
1 Name the 3 main types of skin cancer and the cells affected in each. 2 Discuss the relationship between sun exposure and skin cancer. 3 Describe the appearance of basal cell carcinoma, squamous cell carcinoma and melanoma. 4 Compare and contrast the treatments of basal cell carcinoma, squamous cell carcinoma and melanoma.
Inflammatory disorders of the skin Dermatitis
Dermatitis, also called eczema, is the most common inflammatory condition of the skin and is caused by both exogenous and endogenous agents. Exogenous dermatitis includes irritant contact dermatitis and allergic contact dermatitis. Endogenous dermatitis includes atopic dermatitis and seborrhoeic dermatitis. Acute dermatitis is associated with pruritus, erythema, vesicles and scales. The manifestations of chronic dermatitis include pruritus, dryness of the skin, skin thickening, hyperpigmentation and sometimes fissures.
Irritant contact dermatitis
Irritant contact dermatitis is a non-allergic inflammatory response to chemical or physical agents. The inflammatory response may occur after the first exposure or it may result from chronic cumulative exposures. Common substances causing irritant contact dermatitis include water, soap, detergents, oils, acids, alkalis and rubber. As well as exposure to the irritant, environmental factors such as heat, low humidity and UV radiation and mechanical factors such as friction, occlusion and pressure may also contribute to the development of contact dermatitis. Heat, for example, causes sweating, which facilitates the penetration of irritants. Occlusive gloves enhance irritation from heat and sweating. Low humidity decreases the level of ceramide, a major lipid in the stratum corneum, essential for maintaining the water permeability barrier of the skin. Irritant contact dermatitis is the most common occupational skin disorder, usually affecting the hands. People in occupations that involve frequent hand cleansing, wearing occlusive gloves for more than 2 hours per day or exposing skin to liquid for more than 2 hours per day have a high risk of developing irritant contact dermatitis. Occupational irritant contact dermatitis caused by wet work is particularly common in nurses. The pathogenesis of irritant contact dermatitis consists of exposure to the irritant, which triggers a cascade of skin barrier disruptions, cellular damage and release of chemical mediators resulting in an inflammatory response (refer to Chapter 13).21 Irritants damage the skin by a number of mechanisms, including direct cytotoxicity, lipid-barrier removal, cell membrane damage and the breakdown of proteins. Once the irritant penetrates the damaged stratum corneum, keratinocytes release cytokines and stimulate MHC class II antigens.21 Although a number of cytokines are released, it has been suggested that tumour necrosis factor-alpha (TNF-α) is the major mediator of inflammation (see Fig. 19.7). The clinical manifestations of irritant contact dermatitis are a result of the inflammatory response. Acute irritant contact dermatitis develops rapidly after exposure to highly irritating substances and manifests with pruritus, burning, pain, erythema, blistering and swelling. The rash
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CONCEPT MAP
Irritant damages Stratum corneum irritant penetrates damaged stratum corneum Irritant damages Keratinocytes release
stimulate
stimulate
Cytokines cell adhesion molecules
MHC-antigens Inflammatory disease acute irritant contact dermatitis • • • • •
Pruritis Blistering Burning Swelling Erythema
cumulative irritant contact dermatitis • • • • •
Thickened lesions Fissuring Hyperkeratosis Excoriations Scaling
FIGURE 19.7
The pathogenesis of irritant contact dermatitis. Irritant contact dermatitis is a pathophysiological cascade of skin barrier disruptions, cellular damage and release of chemical mediators following exposure to an irritant.
is contained to the area of exposure. Cumulative irritant dermatitis following repeated exposure to mild irritants results in thickened lesions with fissuring, hyperkeratosis, excoriations and scaling. Treatment includes avoiding contact with the irritant, short-term use of topical corticosteroids (having antiinflammatory and immunosuppressive effects) and emollients that, by providing a surface film of lipids, restore some of the barrier function.
Allergic contact dermatitis
Allergic contact dermatitis is a type IV delayed T-cell mediated hypersensitivity reaction. The inflammatory reaction occurs in sensitised individuals when they are later exposed to the antigen. The development of allergic contact dermatitis occurs in two phases. During the initial phase sensitisation is acquired. This is followed by a subcutaneous inflammatory reaction when subsequently exposed to the same antigen.
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Allergens including metals, chemicals, microorganisms, drugs and latex can form sensitising antigens. For the immune response to be induced, the allergen must penetrate the epidermis. A number of risk factors that damage the skin’s barrier function, enhancing penetration of allergens, have been associated with the development of allergic contact dermatitis. These include friction, heat exposure, humidity and frequent handwashing. Once the allergen has penetrated the epidermis it binds to a protein. Langerhans’ cells transport the antigen to lymph nodes and present it to T lymphocytes, which become sensitised to the antigen. When the chemical allergen is encountered again a rapid, more aggressive immune response occurs.22,23 The sensitised T lymphocytes secrete cytokines that elicit the inflammatory response causing a rash with pruritus, erythema, oedema and vesicular lesions. The lesions may weep, increasing the risk of secondary infections. Patch testing is used to diagnose allergic contact dermatitis. Management includes removal of the irritant and topical corticosteroids. If the reaction is severe, oral corticosteroids may be required.
Latex allergy
As use of latex gloves has increased over recent decades, so latex sensitivity has increased. Latex consists of a protein-based structure to which individuals may become sensitised. It can be found in a number of products including some catheters and condoms. As a result of high exposure to powdered latex gloves, healthcare workers have a high risk of becoming sensitised. The latex allergen leaches out of the gloves and into the powder, which carries the latex into the environment. Exposure to latex may result in two types of responses: • a type IV delayed T-cell mediated hypersensitivity (allergic contact dermatitis) • a type I hypersensitivity reaction that causes anaphylaxis; this response is mediated by immunoglobulin E. Repeated exposure to latex causes rupture of mast cells with release of histamine. The histamine increases capillary permeability resulting in tissue swelling and a fall in blood pressure. Histamine release from the mast cells in the airways causes oedema in the airways, increased resistance to airflow and wheezing.24 For more details on hypersensitivity reactions, see Chapter 15. Sensitised individuals should not be exposed to latex. In the workplace, for example, non-latex gloves should be worn. People with latex allergy are advised to wear a MedicAlert bracelet and, if necessary, carry an adrenaline auto-injector (Epipen®, so named as the name used for adrenaline in the US is epinephrine). They should also be aware that cross-reactivity exists between latex and a number of plant-derived foods such as nuts, avocados, potatoes, tomatoes and bananas.25
Atopic dermatitis
Atopic dermatitis is an inherited chronic inflammatory skin disorder. Together with asthma and allergic rhinitis it
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PAEDIATRICS
Paediatrics and nappy rash Nappy rash is the most common dermatitis of infancy and early childhood. Nappy dermatitis is confined to areas covered by the nappy — that is, the lower aspect of the abdomen, genitalia, buttocks and upper portion of the thighs. It is a contact dermatitis caused by a combination of factors including maceration by wet nappies; irritants such as ammonia (produced from urine), faeces, chemical agents present in nappy wipes and nappy soaking solutions; Candida albicans; and friction between the nappy and skin. The lesions caused by nappy rash vary from mild erythema to blistering and ulcers (see Fig. 19.8). Treatment includes frequent changing of the nappy to keep the skin clean and dry, using disposable nappies that absorb the urine, applying a barrier cream at each change and exposing the area to air. If there is Candida infection, topical antifungal medication such as imidazole or nystatin should be applied. Low-potency topical steroids can be used in the short term when the condition has failed to respond to other approaches.
is a condition of the atopic state. It occurs mainly in children, with at least 60% of cases arising within the first year of life. Although atopic dermatitis can persist into adulthood, symptoms usually diminish in puberty. However, the prevalence in adolescence can be as high as 10% with girls being more likely to experience it than boys. Furthermore 1 in 4 teenagers with atopic eczema at 16 years will have developed it in adolescence rather than in childhood. It is currently unclear if the risk factors for developing atopic eczema in adolescence are the same as those for childhood.26 The cause of atopic dermatitis involves a complex interplay between environmental triggers and genetic factors including altered innate and adaptive immune responses.27 Although genetically determined, factors such as stress may exacerbate the disease. Interestingly, the prevalence varies from less than 2% in China and Iran to 20% in northern and western Europe, Australia and the US.28 PATHOPHYSIOLOGY
Although the exact pathogenesis of atopic dermatitis remains unclear, it is believed that epidermal barrier dysfunction has a primary role. Genetic alterations in constituents of the epidermal barrier including mutations in the filaggrin gene have been recently identified.29 The filaggrin gene encodes for filaggrin, a protein necessary for the formation and hydration of the skin barrier. Defects in the epidermal barrier may also result from changed lipid composition such as a decrease in ceramides, a major water-retaining molecule. The resulting damage to the epidermal barrier causes increased transdermal water loss and allows the
FIGURE 19.8
Nappy rash with Candida albicans as a secondary infection. This is an erythematous rash over the area covered by the nappy. It has spread to the groin folds, which usually occurs with a secondary infection.
entrance of antigens, pathogens and nonspecific irritants that cause activation of the inflammatory response.29 The resulting dermatitis involves complex actions of Langerhans’ cells, natural killer cells and eosinophils and IgE production by B cells. CLINICAL MANIFESTATIONS
Clinical manifestations result from both epidermal barrier dysfunction and the inflammatory response. The most commonly affected sites in infants with atopic dermatitis are the face, scalp and extensor surfaces. In older children and adults flexural surfaces such as the antecubital and popliteal fossae are more commonly affected.28 Skin dryness is a consequence of transepidermal water loss. Mild cases are associated with erythema in localised areas of the skin (see Fig. 19.9). Acute lesions are erythematous, itchy and scaling. Weeping and crusted lesions may develop. Chronic lesions are thickened plaques, papules or nodules.24 Dermal fibrosis is a feature of chronic atopic dermatitis. Due to disturbance of the antimicrobial barrier, recurrent bacterial, viral and fungal infections occur. More than 90% of people with atopic dermatitis chronically carry Staphylococcus aureus on their skin. Signs and symptoms of infection include pustule formation, crusting and weeping exudate.24 EVALUATION AND TREATMENT
The standard treatment for acute exacerbations of atopic dermatitis includes avoidance of allergic trigger (with about 50% of children with moderate to severe atopic dermatitis also having an IgE-mediated food allergy) and the use of
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FIGURE 19.10 FIGURE 19.9
Atopic dermatitis. An erythematous rash on the antecubital fossae of both arms.
topical corticosteroids. Topical corticosteroids should be used at lowest potency (and therefore least systemically absorbed) in order to control symptoms. Immunomodulators or systemic therapy such as tacrolimus, oral corticosteroids and cyclosporin may also be prescribed in severe cases.24 Management with antiseptics and emollients in the bath may reduce critical colonisation and antibiotics may be required if infection occurs. Other management strategies include the use of mild, non-alkali soaps and emollients and phototherapy for severe conditions.24
Seborrhoeic dermatitis
Seborrhoeic dermatitis is a chronic inflammatory skin disorder affecting areas of the body where sebaceous glands are most prominent, such as the scalp, eyebrows, nasolabial folds, behind the ears, axillae and chest. Although the cause is unknown, the trigger appears to be from the Malassezia yeasts. When affecting the scalp in infants it manifests as cradle cap and in adults as dandruff. The lesions are scaly, white or yellow plaques. It is treated with shampoos containing sulfur, salicylic acid, zinc pyrithione or tar.
Acne vulgaris
Acne vulgaris is an inflammatory disorder of the pilosebaceous follicle that mainly affects adolescents: 85% of teenagers and young adults develop acne vulgaris. It affects both males and females, but the most intense and severe clinical cases occur in males. Spontaneous regression usually occurs by the age of 20, but in some people it may persist during adult life. Acne vulgaris causes polymorph cutaneous lesions including comedones, papules, cysts, pustules and abscesses that may leave scars (see Fig. 19.10). The areas of the body most affected are the face, anterior trunk and upper back, where there are greater concentrations of sebaceous glands.
Acne vulgaris with comedones and inflammatory pustules.
Factors causing acne include overactivity of the pilosebaceous ducts, blockage of the ducts, excessive sebum production and proliferation of Propionibacterium acnes. The initial trigger is thought to be the increased hormonal influences of androgens at puberty.30 Several factors are involved in the pathogenesis of acne vulgaris. Androgens stimulate the sebaceous glands. Although the androgens are in normal quantity, the pilosebaceous unit overreacts to them. The increase of sebaceous secretion is the initial alteration. Retention of sebum due to hyperkeratosis leads to the formation of comedones. With overgrowth of bacteria and release of free fatty acids, a papula-pustule is formed.31 When the follicular wall of a closed comedone ruptures, inflammation is initiated. Pustules form when the inflammation is close to the surface; papules and cystic nodules when the inflammation is deeper. After regression of the lesions scars may be left. While some of the commonly associated causes of acne including diet (e.g. chocolate, fatty foods) and cleanliness have no evidence base, stress and hormones (e.g. females noticing a worsening in acne 2–7 days before menstruation begins) do have some basis. Topical treatments including benzoyl peroxide, salicylic acid and tretinoin are used as the first line of therapy. In severe and topical-resistant cases, oral medications may be used, including antibiotics, isotretinoin and hormones. Severe or persistent acne can be controlled and scarring avoided with oral isotretinoin. However, the most serious adverse effects associated with this drug include its teratogenic effect with a high incidence of miscarriage and depression and suicidal thoughts, therefore prescribing is limited to dermatologists.
Acne rosacea
Acne rosacea is a chronic inflammatory skin disease that affects adults and is characterised by central facial erythema, telangiectasia (small dilated blood vessels on the skin),
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cosmetics) and appropriate skin care to help repair and maintain skin barrier integrity including the use of sunscreen (SPF > 30+). In patients with inflammatory rosacea, topical agents such as metronidazole, ivermectin and azelaic acid are used or oral treatment can include antibiotics (e.g. doxycycline) or isotretinoin (in severe resistant rosacea).33 Laser therapy can be used to treat telangiectasia while surgical procedures such as decortication and sculpting may be used in severe cases of rhinophyma. It should also be noted that patient with rosacea report depression and anxiety therefore early detection and treatment is essential in improving quality of life.32,33
FIGURE 19.11
Acne rosacea. Erythema and pustules on the forehead, nose and cheeks.
lesions, oedema and flushing (see Fig. 19.11). There are periods of exacerbation and remission. It occurs more commonly in women (with symptoms more severe in males), those over 30 years and with Celtic or Scandinavian ancestry with fair skin, blond hair and blue eyes.32 Both genetic and environmental factors seem to be involved in the pathogenesis of acne rosacea although the exact cause is unknown. Environmental factors including sunlight, heat, cold, alcohol and emotional stress trigger exacerbation of acne rosacea in people with a genetic predisposition to the condition. Chronic photodamage caused by light exposure causes degradation of the dermal collagen and elastic tissue. This is due to production of reactive oxygen species and an increase in enzymes that degrade the dermal layer.32 In addition, there is damage to the superficial cutaneous vasculature. Peptides are abnormal in the skin of people with rosacea and have a role in the skin’s inflammatory responses.32 The clinical manifestations of acne rosacea result from the damage to the dermis and the inflammatory response. Increased loss of water from the epidermis causes skin dryness and scaling with patients complaining of skin swelling and roughness, as well as stinging or burning. Erythema occurs on the nose, forehead, chin and cheeks and telangiectasia develops. After a prolonged period acne rosacea may develop into bullous hyperplasia of the nose, known as rhinophyma which can cause a reduced quality of life due to this disfigurement.32 Rosacea can be mistaken for other conditions such as acne vulgaris, seborrheic dermatitis, systemic or discoid lupus erythematous and folliculitis. Differentiation is based on presentation (e.g. acne vulgaris presents with comedones and cysts; seborrheic dermatitis is scaly and itchy) and location (e.g. seborrheic dermatitis affects eyebrows, ears and nasolabial folds; folliculitis affects hair follicles and not the face).32 There is no cure for rosacea. Management aims to reduce or alleviate symptoms and includes avoiding UV exposure, avoiding known triggers (e.g. sun, cold, heat, alcohol, stress,
Cutaneous lupus erythematosus
Cutaneous lupus erythematosus (commonly known as lupus) is an inflammatory autoimmune disease. Lupus may be limited to the skin (cutaneous lupus erythematosus) or have multi-organ involvement (systemic lupus erythematosus (SLE)) including kidneys, skin, mucous membranes, joints, central nervous system, lungs, heart, gut, haemotological system and eyes.34 In a small percentage of cases, patients with cutaneous lupus erythematosus can develop SLE. Mucocutaneous manifestations such as malar (cheek) rash, alopecia and oral ulcers are common in patients with systemic lupus erythematosus. Cutaneous lupus erythematosus is subdivided into chronic cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus and acute cutaneous lupus erythematosus.35,36 The cause of lupus erythematosus is related to both genetic and environmental factors (see Chapter 15 for more details). The pathogenesis is still not well understood. It is believed that predisposition to the different subsets of cutaneous lupus erythematosus is related to different genes.36 A major environmental factor triggering cutaneous lupus erythematosus is UV light with photosensitivity occurring in about 75% of patients with SLE. Other triggering factors include medications, hormones, stress, viruses and skin trauma.36 The initiation of the autoimmune reaction cascade has been attributed to UV-induced keratinocyte apoptosis (programmed cell death).36 Complex mechanisms involving apoptosis, autoantibodies, T cells, B cells and vascular changes induce the lesions of cutaneous lupus erythematosus.36 Rashes vary with the type of cutaneous lupus erythematosus. In acute cutaneous lupus erythematosus there is an erythematous rash on both cheeks and across the nose in a butterfly pattern. Subacute cutaneous lupus erythematosus has a maculopapular rash that may occur on any part of the body. The lesions of chronic cutaneous lupus erythematosus are usually located on areas of the skin exposed to light. They are erythematous, raised lesions with scaling. As the lesion progresses the centre becomes hypopigmented and the border hyperpigmented. The lesions spread and may merge. As the lesions resolve, scarring may occur. The management of cutaneous lupus erythematosus includes protection from sunlight and avoidance of
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photosensitising drugs. Lesions may be treated with topical corticosteroids. For patients with widespread lesions antimalarial drugs are used. Treatment of severe cutaneous lupus erythematosus includes immunosuppressive drugs (e.g. methotrexate, azathioprine), retinoids and thalidomide.
F O CUS O N L E A R N IN G
1 Relate the pathophysiological mechanisms of irritant contact dermatitis and allergic contact dermatitis to the clinical manifestations. 2 Explain the 2 types of allergic responses that may be caused by latex. 3 Relate the clinical manifestations of atopic dermatitis to the pathogenesis. 4 Discuss the causes and clinical manifestations of acne vulgaris. 5 Discuss the causes and triggering factors of cutaneous lupus erythematosus.
Papulosquamous disorders
Papulosquamous disorders are a group of skin disorders that present with scaly papules and plaques and include psoriasis, lichen planus and pityriasis rosea. Psoriasis is a chronic immune-mediated inflammatory disorder of the skin characterised by hyperproliferation of keratinocytes, infiltration by T lymphocytes and vascular changes in the dermal layer. There is hyperplasia (increase in cell numbers) of the epidermal spinosum layer and incomplete differentiation of the granular and cornified layers. It affects both males and females and commonly presents by the age of 20 years. The aetiology consists of both genetic and environmental changes. At least 10 genes have been found to be associated with psoriasis, three of which are involved in the interleukin pathway.37 Environmental factors that can trigger the condition include stress, alcohol, trauma, infections and some medications such as ACE inhibitors and β-adrenergic receptor blocking drugs. T lymphocytes and the cytokines that they release are involved in the pathogenesis of psoriasis. Antigens are presented to the T lymphocyte receptors to begin activation of the T lymphocytes. The activated T lymphocytes migrate into the skin and when they encounter the initiating antigen they release cytokines. TNF-α, interleukin-23 and interferon are considered key cytokines in causing keratinocyte activation, hyperproliferation and abnormal growth of dermal blood vessels.37,38 Psoriasis is characterised by increased epidermal cell turnover, with the time for epidermal shedding reduced to 3 days. Increased cell proliferation causes the epidermis to thicken and plaque to form. As a result of the loosely cohesive keratin the lesions have a silvery appearance. The blood vessels in the dermal papillae become tortuous and
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dilated with increased permeability, causing erythema. The scales are loosely adherent and when removed minute bleeding points are revealed. There are several forms of psoriasis. Plaque-type psoriasis (psoriasis vulgaris) is the most common type. In this form, lesions are red plaque with silver scale. The lesions have well-defined edges and vary in size and shape. The lesions most commonly occur on the knees, elbows and scalp (see Fig. 19.12). Guttate psoriasis is characterised by small pink papules occurring on the trunk and limbs. This form of psoriasis usually occurs a few weeks after a streptococcal respiratory infection and may resolve spontaneously in weeks or months, but may return with recurrent streptococcal infections. In milder forms of psoriasis topical treatments alone can be used. Creams or ointments that contain vitamin D and corticosteroids have been found to be the most effective in treating psoriasis.38,39 Corticosteroids inhibit epidermal proliferation, enhance normal differentiation and inhibit inflammation. Vitamin D inhibits keratinocyte proliferation and enhances differentiation. Other topical treatments include tazarotene (retinoid) and tacrolimus (calcineurin inhibitor). Sun exposure may also be beneficial to supplement topical treatment. Moderate-to-severe psoriasis can be treated with topical therapy in combination with oral systemic agents or UV light (narrow band, broad band or in combination with psoralen).37 Systemic agents include immunosuppressants such as methotrexate and cyclosporin. Biological therapies (bioactive substances that act at the cellular level) are also used to treat moderate-to-severe psoriasis or psoriatic arthritis. These drugs target specific immune responses associated with psoriasis. Biological therapies currently used for the treatment of psoriasis are alefacept (blocks T cell activation), etanercept (binds to TNF-α thus lowering the amount available), adalimumab (binds to and blocks the action of TNF-α) and infliximab (blocks the effects of TNF-α). In some studies (especially
FIGURE 19.12
Psoraisis. Lesions have well-defined edges and silver scale, and vary in size and shape.
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in those aged > 65 years with moderate to severe psoriasis), these biological therapies have produced fewer adverse effects than the more conventional systemic immunosuppressant therapies39,40
F OC US O N L E ARN IN G
1 State the cause of psoriasis. 2 Discuss the pathogenesis of psoriasis. 3 Describe the lesions of psoriasis.
Infections of the integumentary system Infections of the integument may present alone or as a complication of underlying conditions such as psoriasis or atopic dermatitis. Integumentary infections may be caused by bacteria, viruses, fungi or parasites. Although most infections occur superficially, systemic signs and symptoms may develop. The host-pathogen interaction is explored in detail in Chapter 12 on immunity. Continuity of epidermal keratinocytes, normal skin flora, sebum and immune responses often provides protection against pathogens that cause skin infections. There is a high prevalence of skin infections in the Indigenous population in Australia, particularly those living in remote communities with 3.3% of Indigenous children aged 0–14 years having some form of skin and subcutaneous tissue disease.41 The most common skin infections affecting Indigenous population are scabies and streptococcal pyoderma. In some remote communities up to 50% of children may be infected with scabies.42 Although skin infections do not usually directly cause death, they are a cause of serious complications such as acute post-streptococcal glomerulonephritis and acute rheumatic fever. The rates of hospitalisation for infectious skin disease are twice as high in the Indigenous population as in the non-Indigenous population.42 The high incidence of infectious skin diseases in the Indigenous population has been attributed to overcrowding and poor housing, inadequate water supply, heat and humidity, poor education and poor hygiene.41–43
the follicle and release chemotactic factors and enzymes that cause inflammation. The superficial lesions consist of small pustules with a surrounding area of erythema. The pustules develop in clusters and form crusts. Topical antibiotics are used to treat the condition. Although the pustules usually heal in a few days, they may develop into furuncles.
Furuncles and carbuncles
Furuncles (or boils) result from the spread of bacterial infection through the follicular wall into the surrounding dermis. The most common infecting organism is Staphylococcus aureus. Furuncles most commonly affect young adult males and are usually located on hair-bearing sites such as the face, back of the neck, chest, axillae, buttocks and thighs. The lesions are small, painful red nodules that become pustular and develop central necrosis (see Fig. 19.13). Scarring may occur following discharge of necrotic tissue and pus. Carbuncles are collections of infected hair follicles that most commonly occur on the back of the neck, shoulders or thighs. A carbuncle extends into the lower dermis and subcutaneous tissue and forms an erythematous, painful swollen nodule that drains pus through multiple openings of the skin. Fever and malaise often occur during lesion development. Abscesses may form which require incision and drainage. Recurrent infections are treated with antibiotics such as beta lactams.
Cellulitis
Cellulitis is a spreading infection of the dermis and subcutaneous tissues. It is usually caused by group A streptococci (Streptococcus pyogenes) and Staphylococcus aureus. It often occurs on the lower limbs and is most commonly seen in the elderly. It is also common in children as periorbital cellulitis. People who have leg ulcers or wounds and those with lymphoedema or venous disease are at risk of developing cellulitis. Cellulitis usually affects one leg only. The infected area is red, hot, swollen and painful.
Bacterial infections
When pathogenic bacteria invade the skin, superficial or systemic infections may develop.
Folliculitis
Folliculitis is an inflammation of the hair follicle, occurring most prominently on the scalp and extremities, but can also occur on the eyelid. It usually occurs in children and adults with a predisposing factor that increases the number of bacteria on the skin surface. The most common bacterium causing folliculitis is Staphylococcus aureus. Bacteria invade
FIGURE 19.13
Furuncle. The lesion is a red pustular nodule.
CHAPTER 19 Alterations of the integumentary system across the life span
There may be demarcation between the affected skin and normal skin. A lesion that has allowed entry of the bacteria is often present. Systemic manifestations such as fever, malaise and vomiting may also be present. Systemic antibiotics, such as flucloxacillin, are used to treat the disorder. In milder conditions antibiotics are administered orally and in more severe cases they are given intravenously. Further treatment options use a combination of high stretch bandaging to aid lymphatic drainage and oedema control, and an intravenous antibiotic regimen that can be managed as an outpatient. Cellulitis can recur with between 22–49% of patients presenting with cellulitis having experienced at least one previous episode.44
Staphylococcal scalded skin syndrome
Staphylococcal scalded skin syndrome is a toxin-mediated condition caused by Staphylococcus aureus that causes red, blistering and desquamation of the skin which resembles a scald or burn. It occurs mainly in children under 5 years who have not yet developed antibodies against the staphylococcal toxins or in adults who are immunosuppressed. Neonates have the highest risk because of their lack of immunity, not having prior exposure to the toxin.
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The strains of Staphylococcus aureus that cause staphylococcal syndrome produce toxins that cause epidermolysis (destruction of the epidermis) by interfering with the cell-to-cell adhesion of keratinocytes.46 As a result there is separation of the skin just below the granular layer of the epidermis. Clinical manifestations begin with fever, irritability and malaise often associated with a respiratory tract infection. Discrete erythematous areas develop that spread from the face and trunk to cover the entire body except the palms, soles and mucous membranes. Large fragile bullae form within 24–48 hours on the erythematous area and the pain is severe. The bullae rupture causing large areas of epidermis to slough off and resemble a burn. Loss of skin leads to hypothermia, fluid loss causing dehydration and secondary infection. Before treatment is commenced, culture and histology are undertaken to differentiate staphylococcal scalded skin syndrome from toxic epidermal necrolysis. Once confirmed, the infection is treated with oral or intravenous antibiotics. The aseptic technique should be used for dressings. Regular analgesia is needed for fever and pain relief. Healing usually occurs in 10–14 days without scarring.
PAEDIATRICS
Paediatrics and impetigo Impetigo is a contagious superficial skin infection that occurs mainly in children but may occur at any age. It frequently occurs in childcare centres and schools and hence is referred to as ‘school sores’. The main causative organisms are Staphylococcus aureus, Streptococcus pyogenes and group A beta-haemolytic streptococci. The organisms enter through damaged skin and are transmitted through direct contact. The incubation period is 1–3 days for Streptococcus pyogenes and 4–10 days for Staphylococcus aureus.45 Clinical manifestations usually appear 4–10 days after infection. The infection begins with small blisters (containing a clear yellow/honey-coloured fluid) which burst within 1–2 days leaving a yellow crust. The skin underneath is red and inflamed (see Fig. 19.14). If left untreated the lesions can develop into skin ulcers that penetrate the dermis, called ecthyma. These lesions are painful and can leave scars. Management of impetigo (‘school sores’) involves removal of crusts using saline, soap and water by soaking for 20–30 minutes and then wiping crust off with wet towel. Antibiotic treatment consists of penicillin where Streptococcus pyogenes is the infecting pathogen and mupirocin ointment where Staphylococcus aureus is the infecting pathogen. For severe or longstanding infections, flucloxacillin, cephalexin or roxithromycin can be used. Impetigo is very contagious; however, most cases of impetigo are no longer infectious after
FIGURE 19.14
Impetigo. Lesions consist of pustules that burst, leaving a yellow crust.
24 hours of appropriate antibiotic therapy. Lesions on exposed surfaces must be covered with a watertight dressing and children with impetigo are excluded from school or childcare until antibiotic treatment has commenced. Covering the lesions, as well as cutting fingernails will reduce the risk of scratching and spreading pathogens to another area. Consideration should also be given to using antibacterial soap for bathing for 2–3 weeks.
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Paronychia
Paronychia is an infection of the nail fold. Acute paronychia is usually caused by the bacteria staphylococci or streptococci. Damage to the nail fold allows bacteria to enter, causing a painful inflammation. Pus may accumulate in the nail fold and under the nail, forming an abscess that may need to be incised and drained. Chronic paronychia develops slowly and is most commonly caused by Candida albicans. It often follows damage to the cuticle by water and detergents. The space between the nail fold and nail plate opens, allowing a warm, moist environment for growth of the microorganism. The skin around the nail becomes red, swollen and painful. Pus may be expressed from the nail fold. Although the nail plate is usually not infected, it may become discoloured. Treatment involves keeping the hands dry.
FIGURE 19.15
Herpes simplex. Lesions consist of vesicles that ulcerate and crust.
Viral infections
Herpes simplex virus
There are two types of herpes simplex virus (HSV): type 1 and type 2. HSV-1 generally infects the oral and respiratory mucosa and HSV-2 the genitalia, although infections can occur anywhere on the skin.47 HSV-1 is transmitted by respiratory droplets or direct contact with infected saliva, whereas HSV-2 is spread by sexual contact. Neonates are at high risk of herpes infection if delivered vaginally, if cervical herpes infection is present or if there has been a prolonged rupture of the membranes in a mother with a primary genital herpes infection. After entering the mucous membranes or abraded skin, the virus enters the epithelial cells and replicates within them. The virus moves along sensory nerve pathways to the dorsal root ganglia where latent infection is established.47 The primary infection may be relatively severe with systemic manifestations such as fever and malaise. Antibodies are produced so that recurrent infections are less severe. A burning, tingling or stinging sensation at the site of the lesion often precedes recurrent infection with HSV-1. This is followed by the appearance of small, inflamed painful vesicles that ulcerate and crust (see Fig. 19.15). The lesions most commonly occur on the lips, in the mouth and around the nose. UV exposure, stress, fatigue or skin irritation may trigger reactivation of the virus. Treatment is symptomatic and the lesions usually resolve within 2 weeks. Over-the-counter topical aciclovir (an antiviral agent) creams can be used, which may reduce the duration of the infection. Prodromal manifestations (symptoms that occur early before specific symptoms appear) such as pain, tingling or itching may also precede reactivation of HSV-2. In females vesicles occur on the vulva, perianal skin, vagina and cervix. In the male the vesicles occur on the penile shaft, prepuce and glans and the perianal area. Between 24 and 72 hours after appearing the vesicles rupture forming painful, weeping ulcers. Regional lymph nodes may enlarge. Antiviral medications including aciclovir, valaciclovir and famciclovir may reduce the severity and duration of symptoms. There
does appear to be an emergence of viral resistance to acyclovir.47
Herpes zoster and varicella
Herpes zoster and varicella are both caused by the varicella-zoster virus.47,48 Varicella (chickenpox) occurs as the primary infection. Following the infection the virus remains dormant in trigeminal and dorsal root ganglia and may be reactivated many years later to cause herpes zoster (commonly referred to as shingles).47 Varicella occurs most commonly in children, with the peak incidence being in 5–9-year-olds. In adults the infection tends to be more severe. Chickenpox is highly contagious and is transmitted by direct contact with fluid from the vesicles or airborne respiratory droplets.47,48 The person is infectious from up to 4 days prior to the appearance of the rash until 5–6 days after the appearance of the rash. The rash can be preceded by systemic manifestations such as fever, headache, sore throat and malaise. The rash begins as maculopapular lesions (containing both macules and papules) that become vesicles. The vesicles progress to pustules that crust and are very itchy. Lesions are most numerous on the trunk and less so on the face, scalp and limbs. It is recommended in Australia that children be immunised against chickenpox when they are 18 months old or when they are between 10 and 14 years old if they have not had chickenpox or been immunised against it (see Chapter 14 for immunisation schedules). Children with chickenpox should be excluded from school for at least 5 days after rash appears.49 Herpes zoster results from reactivation of the varicella virus that entered the cutaneous nerves from an episode of chickenpox. Although it can affect anyone who has had chickenpox, it is more prevalent in older people whose immune responses have declined with age or those who are immunosuppressed.47,48 Trigger factors include stress and illness. Individuals with shingles are potentially contagious to people who have not had chickenpox and it is possible to develop chickenpox from contact with shingles.
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FIGURE 19.16
Herpes zoster. A rash of vesicles on the skin of a thoracic dermatome of the affected nerve.
The rash usually occurs on the skin of a single dermatome (an area of skin innervated by a single nerve), but one or two adjacent dermatomes may also be involved. Thoracic dermatomes are most commonly affected, but cervical and lumbosacral dermatomes may also be affected. If the ophthalmic branch of the trigeminal nerve is infected, severe and permanent eye damage can occur.48 The first sign of shingles is tingling, itching or pain in the area of the affected nerve. A rash of vesicles with an erythematous base occurs, following the line of the affected nerve (see Fig. 19.16). New lesions continue to form over 3–5 days, with pustulation over 4–6 days and scabbing over 7–10 days.47 In 2–4 weeks healing occurs and the crusts fall off. However, pain termed postherpetic neuralgia can persist for 3–6 months. Children with shingles can attend school if the lesions are adequately covered; however, they should be excluded from swimming and contact sports for 7 days after the rash appears.48 Treatment includes antiviral medications such as famciclovir, valaciclovir or aciclovir. If antiviral medications are started within 72 hours, the rash appearance and pain can be reduced and healing accelerated. Topical creams and lotions can be used to help relieve the discomfort. Analgesics such as paracetamol should be given for pain relief. In cases of severe pain or postherpetic pain, more potent analgesics (e.g. opioids) or low dose anti-epileptics (e.g. gabapentin) or tricyclic antidepressant (e.g. amitryptilline) may be required. The vaccine, Zostavax®, is available for people over 50 years. It decreases the incidence of herpes zoster, and although its efficacy is only 50%, it reduces the incidence or postherpetic neuralgia by more than 60% and its duration of protection beyond 4 years is currently not known.48
Warts
Warts (verrucae) are benign epidermal lesions caused by the human papillomavirus. Warts most commonly occur in children and are transmitted by direct contact. Different
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types of warts are caused by different types of the human papillomavirus and vary in size, shape and location. Common warts (verruca vulgaris) occur most commonly on the hands and are raised lesions with rough surfaces. Flat warts (verruca plana) occur most commonly on the face, hands and lower legs, and are flat smooth lesions. Plantar warts occur on the soles of the feet. Most wart infections resolve without medical intervention. They may be treated with topical agents such as salicylic acid or by cryotherapy using liquid nitrogen. Genital warts (condylomata acuminata) are generally a sign of genital human papillomavirus infection and are one of the most commonly sexually transmitted infections; however incidental spread from cutaneous warts can occur, particularly in children. More than 40 types of papillomaviruses can infect the anogenital tract of men and women causing genital warts. The warts are soft, raised lesions that may appear in clusters with a cauliflower-like appearance. They occur on the external genitalia including the penis, scrotum, vulva, perineum and perianal area. They may also appear in the vagina, on the cervix or in the anus. Treatment involves removal of the warts by cryotherapy or topical preparations such as imiquimod cream or podophyllotoxin solution. Human papillomavirus vaccine (Gardasil®) prevents cervical cancer, precancerous lesions and genital warts due to the human papillomavirus.
Molluscum contagiosum
Molluscum contagiosum is a contagious infection of the skin caused by the poxvirus. It occurs most commonly in children and is transmitted by direct skin-to-skin contact or indirect contact with contaminated towels, bedclothes or clothing. After attaching to the surface of the epithelial cells the viral DNA is engulfed by the host cell and becomes incorporated into the host cell DNA. The virus uses the host cell DNA to replicate itself. When the host cell dies it ruptures, releasing the virus particles, which infect new epidermal cells. The infected cells form pearly, umbilicated dome-shaped papules 1–5 mm in diameter. The central plug, consisting of dead epithelial cells and virus particles, is highly contagious. The lesions are mainly found on the trunk, face and extremities. The individual lesions form a crust after 6–12 weeks and gradually disappear leaving a small pitted scar.50 All lesions usually disappear in 6–9 months in immunocompetent patients. No specific treatment has been developed. Imiqimod cream can be used to treat the lesions although it can be painful and scarring is a possibility.
Fungal infections
Fungal infections of the skin, hair and nails are caused by dermatophytes (meaning ‘skin plant’ in Greek), a group of fungi that invade keratin. The three most common species infecting the skin are the Epidermophyton, Microsporum and Trchophyton genera. When caused by dermatophytes the superficial fungal or mycotic infections of the skin are termed tinea or dermaphytosis.
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Tinea infections
Tinea is a superficial skin infection caused by dermatophytes. The infection may be transmitted from person to person, animal to person or soil to person. The fungi infect the dead, keratinised cells of the epidermis. They emit enzymes that digest the keratin causing scaling and hair breakage. They may also produce an immune response. Tinea infections are classified according to the body region infected: • Tinea corporis (ringworm of the body) in Australia is caused mainly by the Microsporum species. The lesions are flat, red and circular. They may be either dry and scaly or moist and crusted (see Fig. 19.17). • Tinea capitis (scalp) occurs most frequently in children. The lesions are small papules that spread leaving scaly patches of temporary baldness. The infected hairs become brittle and break easily. • Tinea pedis (‘athlete’s foot’) occurs in both adults and children. It is often spread by using communal showers. The lesions are found between the toes and plantar surfaces where the skin is scaly, itchy and painful with fissures or blisters filled with a watery fluid. • Tinea manus (hand) occurs on the palms and finger webs. The lesions are dry, scaly, erythematous lesions or moist vesicles. • Tinea cruris (groin) is an infection of the groin and pubic area. The lesions are small, erythematous scaling vesicular patches with well-defined borders. • Tinea unguium (onchomycosis) is a fungal infection of the nails. It affects both the toenails and fingernails. It is characterised by nail plate separation from the nail bed and yellow–brown accumulations of brittle keratin over the nail (see Fig. 19.18). Diagnosis consists of microscopy and culture of skin scrapings, or observation of the skin with UV light — the spores and filaments (hyphae) of fungi fluoresce blue–green when exposed to ultraviolet light. Treatment depends on
the type of fungi causing the infection. Most fungal skin infections are treated with topical antifungal drugs; for example, clotrimazole (Canesten®), ketoconazole (Nizoral®) and miconazole (Daktarin®). Topical antifungal therapy may be used for chronic fungal infections or infections of the nails. For resistant tinea capitis infection other topical and oral antifungal treatments are given.
Candidiasis
Candidiasis infections are caused by the yeast-like fungus, Candida albicans. This fungus inhabits the skin and mucous membranes as part of the normal flora. However, an opportunistic infection caused by Candida albicans can occur when an individual is immunosuppressed, having depleted numbers of normal resident skin bacteria to keep the candidal organisms in check. Factors that predispose to infection are occluded moist skin surfaces that rub together (e.g. dentures, occluded wound dressings), systemic administration of antibiotics, pregnancy, diabetes mellitus, Cushing’s syndrome, debilitated states including generalised malnutrition, immunosuppression and infants younger than 6 months of age because of decreased immune activity. Candidiasis occurs in skin folds, the mouth, vagina and penis: • Skin candidiasis is most common in infants, debilitated adults and obese patients. It occurs when occluded moist areas of skin rub together and become macerated.51 Common sites include under the breasts, the axillae,
FIGURE 19.18 FIGURE 19.17
Tinea corporis. The lesions are flat, red and circular.
Onychomycosis. A fungal infection of the nails. The nail plate has separated from the nail bed and there are accumulations of yellow–brown keratin over the nail.
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groin and webs of fingers and toes. The rash appears red, inflamed and pustular and sometimes has a white exudate. The area is painful. • Oral candidiasis is the most common form of candidiasis and appears as white patches on the tongue and oral mucosa. Under the white plaque the tongue is red, swollen and painful. Ulceration may occur in severe cases. • Vaginal candidiasis appears as red, swollen vaginal and labial membranes with a non-offensive whitish vaginal discharge and may be associated with burning, itching and pain as well as dysuria or dyspareunia at times. In more severe cases the rash can extend to the perianal and groin areas. • Candidal balanitis causes red, tender papules and pustules on the glans and shaft of the penis. Treatment of candidiasis depends on the site and severity of the infection. Candidiasis of the skin is treated with antifungal creams. Oral candidiasis is treated with oral gels, suspensions or lozenges such as nystatin or fluconazole. To treat vaginal candidiasis, antifungal vaginal pessaries or cream are used.
Parasitic infestations Scabies
Scabies is a contagious parasitic infestation caused by the microscopic mite Sarcoptes scabiei. It is transmitted either by direct skin-to-skin contact or indirectly from contaminated items such as bedclothes and towels. Scabies often spreads in conditions where there is close contact between people such as childcare centres, schools and aged-care facilities or in underdeveloped countries. Other high-risk groups include Indigenous communities in Australia and New Zealand.41,43 The female mite burrows into the stratum corneum and lays 2–3 eggs per day during her life span of 30 days. The eggs hatch 10 days later into larvae and travel back up to the surface of the skin to mature. The signs and symptoms of scabies are the result of an adaptive immune response.52 The predominant manifestation is intense pruritus (itching) which usually starts 4–6 weeks after infestation, being more severe at night and occurring over most of the body. Pruritus is the result of a hypersensitive reaction to components of saliva, eggs and faecal material of the mites. The diagnostic sign of scabies is the burrow, the track made by the female. The burrows occur mainly between the fingers, wrists, elbows, axillae, lower abdomen, penis, breasts and shoulder blades and appear as short, grey, wavy lines. The scabies rash consists of papules, vesicles and erythema (see Fig. 19.19). Scratching may lead to secondary infections. Crusted scabies (‘Norwegian scabies’) is a very contagious variant of scabies in which there is hyperinfestation with thousands of mites present in exfoliating scales. This form of scabies often occurs in immunocompromised people, institutionalised elderly people and Aboriginal Australians. It appears to occur when the immune system is unable to adequately attack the mites via the T helper-2 cell response
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FIGURE 19.19
Scabies. The burrows of the scabies mite between the fingers.
resulting in very large numbers of mites.52 It presents as a scaly, erythematous rash with crusts and hyperkeratinisation but minimal pruritus, making it difficult to differentiate from psoriasis or eczema. Treatment includes topical permethrin preparations (e.g. Lyclear® cream or Quellada scabies treatment® lotion) or benzyl benzoate 25% preparations (e.g. Ascabiol® or Benzemul® 25%). For moderate to severe infections the treatment may be repeated 14 days after the first treatment. Prior to treatment all bed linen, towels and clothing should be machine washed in hot water and dried at high heat (e.g. clothes dryer) as otherwise the mite can survive on these items. All family members and close contacts should be treated simultaneously. It should be noted that many of these recommended treatments have potential side effects including secondary dermatitis, oedema and ulceration. Furthermore, resistance to permethrin is widespread. Oral ivermectin may be prescribed in those where topical agents were contraindicated or ineffective. It is also not recommended in those under 5 years of age, making it unavailable for management of scabies in this most vulnerable group.52
Pediculosis
Pediculosis is an infestation of blood-sucking lice. The lice have three pairs of legs with powerful claws. The female louse lays up to 300 eggs, called nits, during her lifetime. The nits hatch in 7–10 days giving rise to nymphs that become adults in 10 days. Three species of lice infest humans: Pediculus humanus capitis (head lice), Pediculus humanus corporis/ humanus (body lice) and Phthirus pubis (pubic lice). Head lice are the most common type of louse occurring commonly in schoolchildren. Transmission is through direct head-to-head contact with a person with head lice. Head lice grip the shaft of the hair with their claws. The female lays eggs, usually at night, at the base of the hair shaft. The eggs adhere to the hair shaft and hatch about 8 days later (see Fig. 19.20). Itching is the primary manifestation and
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FIGURE 19.20
Eggs of the pediculosis adhering to the hair shaft.
is caused by a reaction to louse saliva. Scratching can cause crusted lesions to form. Lice, which are about 3 mm in length, can be identified on the hair. Unhatched eggs are dark-coloured and are found close to the scalp. Hatched eggs are white and are found further away from the scalp and are therefore easier to see. Head infestation is diagnosed by the presence of lice or viable eggs. Treatment consists of physical methods using a fine-tooth comb to remove nits and lice and application of topical antiparasitics. A number of antiparasitic agents such as permethrin (e.g. Quellada® head lice treatment) and benzyl benzoate may be applied topically. Two applications (7 days apart) are usually required. Pubic lice are oval and white to grey in colour. Transmission is by direct contact. Infestation can involve axillary hair, chest hair, facial hair, eyebrows and eyelashes but commonly, pubic and perianal hair. The most common manifestation is pruritus. Lice and nits are visible. Treatment involves application of a topical antiparasitic agent and washing all bed linen, towels and clothing in hot water. Sexual partners should also be treated because of the close body contact. Body lice range in size from 2 mm to 4 mm and live in clothing, coming onto the skin to feed. Body lice tend to be associated with poverty and poor hygiene. Treatment consists of topical antiparasitic agents and washing clothes and bedding in hot water and dried on high heat.
Ticks
Ticks are bloodsucking external parasites causing dermatological disease both directly by their bite and indirectly as vectors of bacterial, rickettsial, protozoal and viral diseases. There are two main families of ticks: soft ticks with a wrinkled, soft appearance; and hard ticks with a hard dorsal plate. In Australia, there are approximately
75 species of tick, with the most medically important one being the paralysis tick, Ixodes holocylus. This tick has four stages of development in its life cycle: egg, larva, nymph and adult. Before dying, the female deposits a large number of eggs in moist leaf litter which hatch into larvae after 40–60 days. The larvae, nymphs and adults all need to feed on blood to survive, with the hosts being either animal or human. Ticks use their mouthparts to penetrate the skin and attach to the host, breaking through dermal blood vessels to obtain blood and increasing their body weight by more than one hundred times. From their saliva they secrete a number of substances including anticoagulants and prostaglandins that modulate the flow of blood and suppress the immune response of the host.53 The manifestations of tick bite are caused by the physical trauma to the skin, salivary secretions, toxins and excretions.53 The lesions are itchy, painful, erythematous macules, papules or nodules. Granuloma, lichenification and secondary infections may occur. Allergic reactions are the most serious condition associated with ticks.54 They are caused by allergens secreted by the tick. The allergic reaction can vary from localised itching and swelling to severe widespread reactions including anaphylaxis. Tick paralysis in humans is rare but is most likely to occur in children. It is caused by neurotoxins secreted by the tick. Clinical manifestations include unsteady gait, weakness of the limbs, rashes, flu-like symptoms and ascending flaccid paralysis. Even after removing the tick, the condition may continue to deteriorate for a time and recovery is slow.55 Ticks can transmit infectious diseases through salivary secretions. The main tick-borne infectious disease in Australia is spotted fever caused by bacteria belonging to the Rickettsia family. The Rickettsiae species most commonly found in Australia
FOCU S ON L EA RN IN G
1 Name 6 infections of the integument caused by bacteria. 2 State the cause and describe the clinical manifestations of folliculitis, furuncles, cellulitis, impetigo, staphylococcal scalded skin syndrome and paronychia. 3 Compare and contrast infections caused by herpes simplex type 1 virus and herpes simplex type 2 virus. 4 Compare and contrast the cause, pathogenesis and clinical manifestations of herpes zoster and varicella. 5 Discuss the causes and clinical manifestations of warts and molluscum contagiosum. 6 Describe the lesions of tinea corporis, tinea capitis, tinea pedis, tinea manus, tinea cruris and onchomycosis. 7 Discuss the cause and clinical manifestations of scabies. 8 Relate the life cycle of the louse to the clinical manifestations of pediculosis. 9 Describe the life cycle of the tick and relate it to the clinical manifestations of tick bite.
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include R. australis (Queensland tick typhus, spotted fever), R. tsutsugamushi (Scrub typhus), R. honei (Flinders Island spotted fever) and R. typhi (murine typhus). Although treatment involves removing the tick as soon as possible, evidence is lacking in relation to tick removal.53 The whole tick should be removed using fine-tipped forceps, firmly gripping the mouth part and lifting gently to detach the tick. The body should not be squeezed. In people with a history of allergic reactions ticks should be removed by a doctor and where resuscitation facilities are available.56
Traumatic conditions of the integumentary system Pressure injuries
In the past, pressure injuries were known by a variety of terms including bed sores, decubitus ulcers, pressure sores and pressure ulcers. New Zealand and Australia have both adopted the term pressure injury. A pressure injury is an area of localised injury to the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure or pressure in combination with shear and/or friction.57 Most pressure injuries occur over bony prominences such as the sacrum, heels and ischial tuberosities. In neonates and children, the occiput (back of the skull) is the most common area affected by pressure injuries. In adults, pressure injuries to the foot are common, particularly in the context of diabetes mellitus. A number of factors including immobility, poor nutritional status, incontinence and debilitation increase the risk of a person developing a pressure injury. Medical device-related pressure injuries are thought to account for up to one-third of pressure injuries in hospitalised adult patients and more than half of hospitalised children and are pressure injuries occurring on tissue (including both skin and mucous membranes) beneath a medical device (e.g. catheter, oxygen tubing, nasal prongs).58 PATHOPHYSIOLOGY
A growing body of evidence suggests that some pressure injuries result from deep tissue injury near a bony prominence and then extend upwards towards the skin’s surface. Other pressure injuries occur when friction and shear occur at the skin’s surface or there is other superficial skin damages leading to changes in the skin’s physical characteristics thereby increasing pressure and damage in deeper tissue.58,59 Muscle is less resistant than skin to pressure changes and therefore may necrose prior to skin breakdown. The most significant extrinsic factors causing pressure injuries are the duration and amount of pressure applied to skin and soft tissues over bony prominences. Pressure is defined as the force (patient’s body weight) exerted on a unit of area (skin contact area). When applied over a bony prominence the pressure will compress all the tissues lying between the skin and underlying skeleton. As a result blood
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vessels will be occluded. If pressure is relieved within a few hours there is a brief period of reactive hyperaemia (redness) and blood recirculates to the area, delivering oxygen and nutrients and thus preventing tissue damage. However, sustained pressure leads to decreased capillary blood flow, occlusion of blood vessels and tissue ischaemia. Capillary pressure over 32 mmHg (normal range 12–32 mmHg) compromises oxygenation and microcirculation,59 leading to tissue necrosis and ulceration. Another extrinsic factor implicated in the pathogenesis of pressure injuries is shear. Shear refers to the mechanical force acting in parallel to a plane. This can occur when a patient slides down a chair or bed. As the patient slides, shear force is created by the motion of the deep fascia and skeletal muscle relative to the skin, which is restrained from moving as a result of frictional forces. The resulting distortion of capillaries and soft tissue causes ischaemia. Friction opposes the movement of one surface against another such as the skin against a bed sheet. Frictional forces may lead to superficial skin erosions that initiate pressure injury. Moisture, especially if prolonged, is another extrinsic factor which decreases tissue tolerance making it less resilient to external forces such shear and friction thereby increasing the risk of pressure injury. Moisture can be due to sweating, incontinence or wound exudate. Because faecal incontinence can both change the pH of the skin and expose the skin to bacteria and enzymes, it poses a further risk to tissue tolerance.60,61 There are also a number of intrinsic factors that impact on tissue tolerance and include age, chronic illness or conditions (particularly if they affect tissue perfusion (e.g. peripheral vascular disease, smoking), the lymphatic system (e.g. lymphoedema) and sensation [e.g. diabetic neuropathy]), poor nutrition and dehydration, and elevation of skin temperature.60,61 (See Chapter 13 for wound healing.) CLINICAL MANIFESTATIONS
The clinical manifestations of pressure injuries result from tissue ischaemia and the inflammatory response. However, there is still a lack of knowledge about the complex biochemical, cellular and genetic changes that occur.58 Ischaemia leads to necrosis and ulcer formation. Pressure injury ranges from discoloured areas of skin to large necrotic areas of tissue involving muscle, tendon and bone. Pressure injuries are generally classified by six stages, as defined by the European Pressure Ulcer Advisory Panel (EPUAP) and National Pressure Ulcer Advisory Panel (NPUAP; see Table 19.2) and these six stages are recognised by Australia, New Zealand and the USA, while Europe currently uses the first four stages only.57,61 The inflammatory response causes hyperaemia, pain, fever and leucocytosis (see Chapter 13). If the ulceration is large, toxicity and pain lead to loss of appetite, debility and renal insufficiency. Proteolytic enzymes from bacteria that colonise the dead tissue and from the macrophages dissolve the necrotic tissue, causing a foul-smelling discharge. Infection and inflammation of surrounding tissue may
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TABLE 19.2 EPUAP/NPUAP pressure injury classification system Category/ Stage I
Non-blanchable erythema of intact skin
Intact skin with a localised area of non-blanchable erythema, which may appear differently in darkly pigmented skin. Presence of blanchable erythema or changes in sensation, temperature, or firmness may precede visual changes. Colour changes do not include purple or maroon discolouration; these may indicate deep tissue pressure injury.
Category/ Stage II
Partial-thickness skin loss with exposed dermis
Partial-thickness loss of skin with exposed dermis. The wound bed is viable, pink or red, moist, and may also present as an intact or ruptured serum-filled blister. Adipose (fat) is not visible and deeper tissues are not visible. Granulation tissue, slough and eschar are not present. These injuries commonly result from adverse microclimate and shear in the skin over the pelvis and shear in the heel. This stage should not be used to describe moisture associated skin damage (MASD) including incontinence associated dermatitis (IAD), intertriginous dermatitis (ITD), medical adhesive related skin injury (MARSI), or traumatic wounds (skin tears, burns, abrasions).
Category/ Stage III
Full-thickness skin loss
Full-thickness loss of skin, in which adipose (fat) is visible in the ulcer and granulation tissue and epibole (rolled wound edges) are often present. Slough and/or eschar may be visible. The depth of tissue damage varies by anatomical location; areas of significant adiposity can develop deep wounds. Undermining and tunnelling may occur. Fascia, muscle, tendon, ligament, cartilage and/or bone are not exposed. If slough or eschar obscures the extent of tissue loss this is an Unstageable Pressure Injury.
Category/ Stage IV
Pressure Injury: Full-thickness skin and tissue loss
Full-thickness skin and tissue loss with exposed or directly palpable fascia, muscle, tendon, ligament, cartilage or bone in the ulcer. Slough and/or eschar may be visible. Epibole (rolled edges), undermining and/or tunnelling often occur. Depth varies by anatomical location. If slough or eschar obscures the extent of tissue loss this is an Unstageable Pressure Injury.
Unstageable Obscured fullpressure thickness skin injury and tissue loss
Full-thickness skin and tissue loss in which the extent of tissue damage within the ulcer cannot be confirmed because it is obscured by slough or eschar. If slough or eschar is removed, a Stage 3 or Stage 4 pressure injury will be revealed. Stable eschar (i.e. dry, adherent, intact without erythema or fluctuance) on the heel or ischaemic limb should not be softened or removed.
Suspected deep tissue injury
Intact or non-intact skin with localised area of persistent non-blanchable deep red, maroon, purple discolouration or epidermal separation revealing a dark wound bed or blood filled blister. Pain and temperature change often precede skin colour changes. Discolouration may appear differently in darkly pigmented skin. This injury results from intense and/or prolonged pressure and shear forces at the bone-muscle interface. The wound may evolve rapidly to reveal the actual extent of tissue injury, or may resolve without tissue loss. If necrotic tissue, subcutaneous tissue, granulation tissue, fascia, muscle or other underlying structures are visible, this indicates a full thickness pressure injury (Unstageable, Stage 3 or Stage 4). Do not use DTPI to describe vascular, traumatic, neuropathic, or dermatologic conditions.
Persistent nonblanchable deep red, maroon or purple discolouration
develop, particularly if the individual is immunosuppressed or has diabetes mellitus. EVALUATION AND TREATMENT
An estimated 95 000 pressure injuries develop annually in Australia,61 which adds significantly to the cost of healthcare. The first step in preventing pressure injury is to identify patients at risk. A number of risk assessment scales such as the Norton scale, Braden scale and Waterlow scale have been developed and are validated and reliable to use for assessing pressure injury risk in adults. Paediatric pressure injury risk assessment scales include Neonatal Skin Risk Assessment Scale for Predicting Skin Break down (NSRAS), Braden Q (modified Braden scale), Starkid Skin Scale, Garvin scale and Glamorgan scale.61,62 Pressure injuries can be prevented by protecting the patient’s skin by managing the intrinsic and extrinsic risk factors such as reducing or eliminating shear, friction and moisture.61 One of the most effective methods of preventing pressure injuries is repositioning to reduce the duration of pressure on an area
of the body. Support surfaces that redistribute pressure or relieve pressure such as alternating pressure mattresses are also used to reduce shear, friction and the amount or duration of pressure between the individual and the support surface. Other important prevention issues include reducing friction and shear by providing transfer assistance devices (such as overhead handles) to encourage independent transfer, not massaging or vigorously rubbing the patient’s skin, using water-based skin emollients to maintain skin hydration, as well as implementing continence management plans.57,60,61 Before deciding on a management strategy, the pressure injury and surrounding area should be assessed (including size, depth, type and quantity of exudate, presence of malodour, wound bed tissue including type and amount, pain, presence/absence of undermining or tracking, state of wound edges and surrounding skin) and documented so that the effectiveness of any management strategy can be evaluated. Furthermore, any clinical infection should be identified and treated using antimicrobial therapies such
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as topical agents (e.g. cadexomer iodine, silver, honey) and systemic antibiotics may also be required.57,60,61 When treating a pressure injury a moist environment should be maintained on the wound bed. Selection of dressing products is generally based on characteristics such as wound size and location, ease of application and removal, management of exudate, odour, pain and infection, accessibility, cost, comfort and patient preference.61 There are currently many dressing products available which can create an optimal healing environment and can be used in pressure injury management including hydrocolloids, hydrogels, hydrofibres, foams, films, alginates and soft silicones. There is no evidence to suggest that any one of these products is more effective than another.61 It should be noted, however, that regardless of the dressing product used, if pressure is not offloaded from the area, no healing will occur.
RESEARCH IN F
CUS
What is the evidence to support therapies in wound care? When searching for robust evidence (e.g. systematic reviews) to support the use of particular therapies in wound care, the conclusions will often contain comments such as ‘small trial’, ‘heterogenous patient group’, ‘trial of short duration’, ‘unclear outcomes’, or ‘at high or unclear risk of bias’ with final conclusions including ‘quality of evidence ranges from moderate to very low’ and ‘more research is required’. When looking at evidence based medicine, the gold standards are randomised controlled trials (RCTs) and meta-analysis of these RCTs. A robust RCT is one that is adequately powered (i.e. sufficient patients enrolled in the study to do statistical analysis of the results), has clear definitions, blinding and randomisation. In wound care, much of the research that has been done does not meet this criteria for an RCT and are therefore excluded from any analysis. How does a healthcare professional determine ‘best practice’ in order to achieve optimal wound healing? Best practice guidelines and consensus documents based on current and scientifically produced and evaluated data available (usually by a team of experts in the field) have been produced by a number of reputable organisations and these can be used to guide wound care. For example, in the prevention and management of pressure injuries, such documents include World Union of Wound Healing Societies (WUWHS) Consensus Document: Role of dressings in pressure ulcer prevention, National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel, Pan Pacific Pressure Injury Alliance (NPUAP/EPUAP/PPPIA) Prevention and treatment of pressure ulcers and Wounds UK Best Practice Statement: eliminating pressure ulcers. It is therefore important for the nurse to be aware and source these documents to guide wound care practice to deliver what is considered as best practice.
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Surgical management of large cavity pressure injuries such as stage III or IV (especially in those with spinal injuries) may consist of debridement with simple closure by primary intention or repaired using skin flaps or grafting. If the wound is infected or heavily colonised, the procedure is generally recommended in two stages to reduce the bacterial count before the flap reconstruction. Flap failure is most likely to occur in spinal injured patients who have poor nutrition and/or poorly controlled diabetes.63
Skin tears
Skin tears are wounds caused as a result of shearing, friction or blunt trauma to the skin. Payne and Martin have defined a skin tear as ‘a traumatic wound occurring principally on the extremities of older adults, as a result of friction alone or shearing and friction forces, which separate the epidermis from the dermis (partial thickness wound) or which separate both the epidermis and dermis from underlying structures (full thickness wound).’ Neonates are also prone to skin tears because of their fragile skin.64 Skin tears occur most frequently in the elderly because the ageing process causes epidermal thinning, loss of dermal and subcutaneous tissue, flattening of the dermal–epidermal ridge, decreased collagen and elastin, decreased number of sweat glands and reduced sebum production. These changes cause the skin to be fragile and dry, making it more prone to tear when subjected to trauma, shearing or frictional forces. Risk factors associated with skin tears include impaired mobility or vision, dependence for activities of daily living, a history of previous skin tears, predisposition for falls, cognitive deficit, poor nutritional or hydration status, fluid volume deficit, vascular-related comorbidities (e.g. clotting disorders, chronic heart failure) decreased sensation, ecchymosis or senile purpura, and medications including corticosteroid or anticoagulant therapy.64 A recent study found that race may also be a risk factor with the incidence of skin tears amongst Japanese elderly being lower than that for people with fair skin in the West.63 The reduced cohesion between the epidermis and dermis resulting from the flattening of the rete ridges and the dermis and subcutaneous tissue is a major contributing factor in the pathogenesis of skin tears. Loss of cohesion enables skin layers to slide across each other, breaking blood vessels when subjected to tractional forces. This results in a traumatic wound that usually bleeds and is painful. Skin tears can occur on any part of the body but are most common on extremities, with upper and lower limbs or dorsal aspect of hands in the elderly or device-related trauma or use of adhesives on head, face or extremities in neonates.64 Skin tears can present from a simple linear laceration to extensive tissue loss and necrosis. The most widely used classification of skin tears (Payne-Martin Classification) grades the wound on a scale of I to III (see Table 19.3). Although other classification systems such as STAR and
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TABLE 19.3 The Payne-Martin classification for skin tears Category I Skin tears without tissue loss
Linear type (full- Epidermis and dermis thickness) are pulled in one layer from supporting structures. The wound is incision-like in appearance Flap type (partial thickness)
Category II Skin tears with partial tissue loss Category III Skin tears with complete tissue loss
Epidermis and dermis are separated. Flap can be completely approximated or approximated to expose no more than 1 mm of the dermis
Scant tissue loss 25% or less of the type epidermis flap is lost Moderate-tolarge tissue loss type
More than 25% of the epidermis flap is lost
Complete tissue loss
The epidermal flap is absent
ISTAP (International Skin Tear Advisory Panel) have been devised,63,65,66 they have had variable uptake. A number of strategies are used to prevent the occurrence of skin tears. These include assessment of risk factors, careful handling of at-risk patients, padding leg supports on wheelchairs and bed rails, providing a safe environment to prevent trauma, protecting fragile skin by wearing long sleeves and pants, keeping the skin well hydrated, avoiding the use of soaps and using emollients, keeping the skin clean and free of urine and faeces, and not placing adhesives directly onto the skin.64 Although there is no universal consensus for the management of skin tears, generally accepted principles include: assess the skin trauma and control the bleeding, clean the wound with 0.9% normal saline or sterile water to remove blood clot, pat dry carefully, approximate the skin tear flap as closely as possible (if viable) using a non-adherent dressing applied without tension and minimise the risk of infection or development of complications such as delayed wound healing or necrosis. The dressing should be left in place for 5–6 days to allow the flap to stick to the underlying tissue. If exudate levels are high or infection is present, dressing should be changed more frequently. Furthermore, it is recommended that the dressing is marked with an arrow to indicate direction of removal to decrease risk of damaging the healing area. The peri-wound area should also be protected using a skin barrier product.64
Burns
Bushfires are a common occurrence during the Australian summer and have resulted in more than 250 deaths due to
burn-related injuries in the last 40 years. During 2012–13, there were approximately 5857 injuries in Australia due to thermal causes which include exposure to smoke, fire, heat and hot substances, accounting for 1% of all injuries. One-third of those sustaining a thermal burn were aged 14 years and under.67 However, existing databases do not count the low severity injuries that are not admitted to hospital nor do these figures represent those injury survivors who are left with some sort of disability. A burn injury occurs when heat damages the body’s tissues including the skin, muscle, bone and subcutaneous structures. Burns can be caused by thermal, electrical, chemical or radiation sources: • Thermal burns include scald injuries, flame burns and contact burns. • Scald burns are caused by hot liquids or steam. They are a common burn injury in children, especially in those aged 0–4 years accounting for 51% of all hospitalised burn injuries in children.67 • Flame burns are often deep burns. Heat from the flame causes denaturation of proteins in the skin. • Contact burns are caused by touching a hot object such as an iron or a hot plate on the stove. • Electrical burns can cause injuries from direct contact with the electrical source or from the source’s arc. As the electricity passes through the body, the current is converted to heat, which damages the tissue between the points of entry and exit. Low-voltage injuries tend to cause burns at the sites of entry and exit, whereas high-voltage injuries cause extensive tissue damage with soft tissue and bone necrosis. • Chemical burns occur when the skin is exposed to acids, alkalis or other corrosive chemicals. When in contact with the skin, chemical energy is converted into thermal energy, causing tissue damage. Chemical burns cause necrosis and continue to cause damage until completely removed. • Radiation burns commonly occur due to exposure to UV radiation from sunlight, as discussed earlier. Also, radiotherapy treatments for cancer may cause radiation burns to the skin. PATHOPHYSIOLOGY
The pathogenesis of burns involves both local and systemic responses. A burn has three zones of injury: 1 The zone of coagulative necrosis is the area closest to the source of the burn. In this area there is coagulation of cellular proteins and destruction of the microcirculation, resulting in rapid cell death and necrosis (see Chapter 4). 2 The middle zone, the zone of stasis (slowed blood flow), is characterised by decreased tissue perfusion. Increased capillary permeability results in leakage of fluid into the extravascular space. 3 The outermost area, the zone of hyperaemia, is an area with increased tissue perfusion.68
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In addition to the local effects of the burn there are systemic effects. The extent of the systemic effects depends on the total body surface area of the burn and the depth of the burn. Burns exceeding 20% of total body surface area are considered to be major burns and are associated with massive fluid shifts, oedema and release of inflammatory mediators. Immediately after the burn injury, the systemic microcirculation loses its vessel wall integrity and plasma leaks out of the damaged capillaries into the surrounding tissues. There is also a systemic inflammatory response resulting from cytokine and inflammatory mediator release from the damaged cells. This further increases vascular permeability, causing additional fluid loss from the bloodstream. With the loss of plasma from the bloodstream, the blood becomes more viscous, impairing the microcirculation, and the haematocrit rises. Intravascular hypovolaemia (low blood volume) and burn shock result from the massive fluid losses from the circulating fluid volume. With the loss of plasma proteins from the vascular space, hypoproteinaemia (low protein levels) may result. Damage to the cells causes a shift of electrolytes, with sodium moving into the injured cells and potassium moving out, leading to hyperkalaemia. There is also a decrease in transmembrane potential involving non-thermally damaged cells, which contributes to the fluid and electrolyte shifts. As a result of the systemic inflammatory response and hypovolaemia, most organ systems of the body are affected. Reduced cardiac output results from decreased plasma volume, increased afterload and decreased contractility (refer to Chapter 22 for a detailed description). Cardiac contractility is decreased in the first 24 hours after injury and is thought to be caused by circulating mediators such as TNF-α as well as impaired calcium.69 With reduced cardiac contractility, the blood flow to the liver, gastrointestinal organs and kidneys is reduced, resulting in slowed peristalsis and gastric emptying and reduced urine output. A burn injury is followed by a hypermetabolic state that is mediated by elevated levels of catecholamines (adrenaline or noradrenaline) and cortisol. The hypermetabolic state with increased oxygen consumption is related to an increase in and resetting of the thermal regulatory set point, resulting in a higher body temperature. Immune function is suppressed with impaired phagocytosis and impaired cellular and humoral immunity, thereby increasing susceptibility to systemic wound sepsis. As a result of the loss of skin integrity, the skin’s functions of protection from invasion of harmful substances, loss of fluids and electrolytes and regulation of body temperature are altered. Following a burn the normal protective defence mechanisms, including defensins derived from the keratinocytes and acidic secretions from the sweat and sebaceous glands, are lost, resulting in the wound becoming colonised and invaded by microorganisms.69 Two key factors when assessing the burn wound are (1) the total body surface area that has been burnt and (2) the depth of the burn. A number of tools are used to determine the surface area burned. One of these is the Wallace’s rule
A
4½%
B
4½%
18%
4½%
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4½%
18% 4½%
4½%
1% 9%
9%
9%
9%
FIGURE 19.21
Estimation of burn injury: rule of nines. The total surface area burned is often assessed using the rule of nines, whereby the body is divided into sections with each section representing 9% of the total surface area. A Adults (anterior view). B Adults (posterior view).
of nines, in which the adult body is divided into 11 sections with each section representing 9% of the total body surface area (see Fig. 19.21). A more accurate assessment that considers the varying rate of growth in the head, thighs and lower legs of different age groups is the Lund and Browder chart. Burns are also classified according to depth of injury (see Fig. 19.22). Burn depth may be described in terms of degree (first, second, third or fourth degree) or in term of thickness (superficial, partial thickness or full-thickness). In Australia and New Zealand burn depth is most frequently described as: • epidermal • superficial dermal partial thickness • mid-dermal partial thickness • deep dermal partial thickness • full-thickness (see Table 19.4).70 CLINICAL MANIFESTATIONS
Due to the complexity of a burn injury, the clinical manifestations and complications are widespread. As a result of the shock, the patient’s heart rate will increase to circulate the remaining blood in an effort to maintain cardiac output. Loss of skin integrity leads to a loss of body temperature, which leads to increased metabolism. With loss of skin integrity, sensations perceived by the skin are affected. Irritation of nerves causes pain. Although in a full-thickness burn nerves are destroyed and the burned tissue itself is often insensate, the patient will still suffer pain. The modalities of touch, two-point discrimination,
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Hair follicle Degree of burn Superficial partial thickness Deep partial thickness
Sweat gland
CLASSIFICATION
DESCRIPTION
Epidermis
Superficial epidermal
Dry and red, blanches with pressure, no blisters or blisters may appear after some days. Sensation present and may be painful. Heals with no scarring
Dermis
Superficial dermal partial thickness
Pale pink with fine blistering, blanches with pressure. Usually extremely painful. Can have colour-match defect. Low risk of hypertrophic scarring
Structure
Fat Fullthickness
TABLE 19.4 Depth assessment of burns
Muscle Bone
B
Mid-dermal partial Dark pink with large blisters. Capillary thickness refill sluggish. May be painful. Moderate risk of hypertrophic scarring Deep dermal partial thickness
Blotchy red, may blister, no capillary refill. In child may be dark lobster red with mottling. Healing time is longer than 2–3 weeks. High risk of hypertrophic scarring
Full-thickness
White, waxy or charred. No blisters. No capillary refill. No sensation or pain. Will scar. Healing can only be achieved by grafting
warming and vibration are significantly reduced because of damage to the sensory receptors.68 Another sensation patients often suffer is pruritus (itch). Loss of the protective barrier function, together with immunosuppression, places the patient at risk of developing localised and systemic infection.69 EVALUATION AND TREATMENT
C
FIGURE 19.22
Degree of burns. A A cross-section of skin indicating the degree of burn and structures involved. B A superficial partial-thickness injury following a scald. C A full-thickness burn destroys all layers of the skin. The area is waxy white and insensate.
The immediate management of a burn injury involves airway maintenance and fluid resuscitation. The goal of fluid therapy is to maintain tissue perfusion without causing fluid overload. Calculation of fluid replacement is commonly based on the Parkland formula (4 mL of intravenous solution (Ringer’s lactate solution) × percentage of total body surface area burned) and modified according to clinical variables such as urine output. Large quantities of protein are lost as a result of a burn injury, increasing nutritional requirements.70,71 Pain management is also an important aspect of treatment, and a number of different medications and pain management modalities are used (refer to Chapter 7). Another problem that may arise is compartment syndrome of the extremities or trunk associated with circumferential burns. As a result of constricting eschar forming around a limb or trunk, blood flow can be restricted and, in the case of the chest, ventilation can be compromised. Escharotomy (surgical division of the necrotic tissue) may be required to allow for muscle movement and return of blood flow (see Fig. 19.23). Necrotic tissue provides an environment for the growth of microorganisms, placing the patient at the risk of infection. Infections are mostly caused by staphylococci, streptococci and pseudomonas, thus meticulous wound management is required. For the patient with deep partial thickness and full-thickness burns, surgery to remove the burn eschar and provide wound
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• indirect injury through activation of the complement system (see Chapter 13).74 Causes of the inflammation include bacterial or viral infections or a toxic response to drugs. Vasculitis can have a varied appearance and it usually presents on the lower limbs. Skin lesions may include petechiae, ecchymoses, purpura, haemorrhagic bullae and chronic or recurrent urticaria. In severe cases the vasculitis may impair the blood supply causing necrosis and ulceration. Generally, the rash spontaneously resolves but it may recur at variable intervals after the initial episode. Treatment includes resting and elevating the affected limb, and finding and removing the cause. If the symptoms are severe, prednisone may be used.74
Scleroderma FIGURE 19.23
Escharotomy. Necrotic tissue has been surgically divided to allow for muscle movement.
coverage is undertaken as soon as the patient’s condition has stabilised. Wounds are covered with an autograft, split skin grafts or skin substitute material such as TransCyte® or Integra®.72 Cultured cellular epithelial autografts can also be used to cover the wounds. More recently, a cellular epithelial autograft suspension (CellSpray®) has been developed that takes only 5 days to culture and can be sprayed onto the wound.73 This technique has been found to improve scar quality. F O CUS O N L E A R N IN G
1 Describe the process by which pressure injuries develop. 2 Describe how pressure injuries are classified. 3 Discuss how age-related changes to the skin contribute to the pathogenesis of skin tears. 4 Relate the clinical manifestations of burns to both local and systemic responses to the injury. 5 Explain how burns are classified.
Vascular disorders Vascular disorders may be associated with skin diseases, may be congenital or may involve responses to local or systemic vasoactive substances.
Cutaneous vasculitis
Cutaneous vasculitis is an inflammation of the blood vessels in the skin; however, is not one specific disease. It can affect the capillaries, venules, arterioles and lymphatics. The inflammation is thought to arise through: • direct injury to the vessel wall by bacteria or viruses • indirect injury by activation of antibodies, which then generate inflammation within the vessel wall
Scleroderma is a rare, chronic autoimmune disease of the connective tissue characterised by fibrosis in the skin and organs of the body. Large amounts of collagen are deposited in the organs, and this is accompanied by inflammatory reactions and narrowing of blood vessels. Scleroderma is more prominent in women and although it is found in every age group, the age of onset is most frequently between 25 and 55 years. Although the cause of the disease is not known, it is believed that both genetic and environmental factors (including silica dust, industrial solvents and some chemotherapy medications) are involved in activation of the immune system causing injury and formation of scar tissue.75 There are two main types of scleroderma: (1) localised scleroderma, which affects only the skin, related tissues and the muscles below the tissues; and (2) systemic scleroderma (also called systemic sclerosis), which affects the skin and organs including heart, lungs, kidneys and digestive tract. The clinical manifestations depend on the type of scleroderma and the extent of involvement. Redness and swelling lead to the skin becoming hard, shiny, taut and tightly connected to the underlying tissue. Skin changes most often occur in the fingers, feet, face and neck. Skin tightness can lead to a decreased range of movement of the fingers, face and toes. Raynaud’s phenomenon with episodes of vasoconstriction can cause ulcers on the fingers. Calcium deposits develop in the subcutaneous tissue and erupt through the skin, appearing as hard nodules. Serious complications of systemic scleroderma include lung fibrosis, raised blood pressure and kidney failure, heart scarring leading to arrhythmias, digestive problems including acid reflux and swallowing issues and erectile dysfunction.75 There is no cure for scleroderma and treatment depends on the type of scleroderma and the symptoms. Drug treatment aims to inhibit tissue fibrosis, vascular changes and immune system changes. Drugs used include topical corticosteroids, immunosuppressive agents, vasodilator drugs and antifibrotic agents. Other management strategies include avoiding exposure to cold, not smoking, stress management, controlling heartburn and gentle, regular exercise to improve joint mobilisation and circulation.75
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Haemangiomas are benign lesions of capillary endothelium. They are not usually present at birth but emerge in the first few months of life. The incidence of haemangiomas is three times higher in female infants than in male infants, and higher in premature infants. Haemangiomas are classified as superficial or deep, or a combination of the two. Most common are the superficial haemangiomas, historically called strawberry haemangiomas. These are raised and bright red in colour. Deep haemangiomas are slightly raised and bluish in colour. Most haemangiomas occur on the face and neck, with fewer occurring on the trunk or extremities.76 Haemangiomas proliferate rapidly, plateau and most spontaneously involute (shrink). Proliferation generally occurs in the first 6–8 months of life but deep lesions can grow from 12 to 24 months. By 5 years of age, 50%
Port-wine stain
A port-wine stain (naevus flammeus) is a congenital capillary malformation composed of dilated vessels in the papillary dermis. It presents as pink, red or purplish macules. Port-wine stains can occur on any surface of the body but are most common on the face and neck. In the adult the lesion often darkens and sometimes becomes nodular. The standard treatment for port-wine stains is pulsed dye laser. The pulsed dye laser emits yellow light at a
of haemangiomas will maximally regress and by 9 years of age 90% will have regressed.76 Doppler ultrasound, CT scanning, MRI (with contrast) or tissue biopsy can be used to diagnose haemangiomas and differentiate from other conditions such as vascular malformation, pyogenic granuloma or tufted angioma.76 Treatment of haemangiomas is controversial and is dependent on location and active or possible complications. Often they are not treated, as little scarring occurs when haemangiomas are allowed to spontaneously involute. Indications for treatment include life-threatening or function-threatening lesions, lesions in locations likely to permanently scar, large facial haemangiomas and peduncled haemangiomas. Treatments include corticosteroids, intralesional interferon alpha, imiquimod, vincristine, and laser and debulking surgery.76
wavelength that corresponds to the absorption peak of oxyhaemoglobin. The energy emitted is converted to heat that causes thermal coagulation of the vessel wall. FOCU S ON L EA RN IN G
Describe the cause, pathogenesis and clinical manifestations of cutaneous vasculitis, scleroderma and port-wine stain.
chapter SUMMARY Skin lesions • Skin lesions are either primary (original appearance) or secondary (appearance has been changed by normal progress over time).
Skin cancer • Basal cell carcinoma arises from stem cells in the basal layer of the epidermis. The predominant cause of basal cell carcinoma is repeated exposure to UV radiation, which damages the DNA. Basal cell carcinomas are slowgrowing tumours that rarely spread. Treatment includes surgical excision, cryotherapy and imiquimod 5% cream. • Squamous cell carcinoma arises from keratinocytes in the outer layers of the epidermis. The predominant cause of squamous cell carcinoma is repeated UV exposure,
which damages DNA, and mutations in the genes, which cause uncontrolled cell proliferation and loss of apoptosis. • Squamous cell carcinoma has precursor lesions such as solar keratosis and Bowen’s disease, is invasive and may metastasise. Treatment is surgical excision. • Melanoma arises from melanocytes. It progresses rapidly and has a high rate of metastasis. The cause of melanoma involves both environmental and genetic factors. Treatment is wide excision of the skin and subcutaneous tissue.
Inflammatory disorders of the skin • Irritant contact dermatitis develops from exposure to chemical or physical agents that cause an inflammatory
PAEDIATRICS
Paediatrics and haemangioma
• •
• •
•
•
•
•
CHAPTER 19 Alterations of the integumentary system across the life span
response. Manifestations include a rash over the exposed area, pruritus, burning, pain, erythema, blistering and swelling. Treatment of irritant contact dermatitis is avoidance of contact with the irritant, topical corticosteroids and emollients. Nappy rash is a contact dermatitis confined to areas covered by the nappy. Allergic contact dermatitis is a type IV delayed T-cell mediated hypersensitivity reaction occurring in two stages: (1) initial sensitisation to an allergen; and (2) inflammatory reaction when subsequently exposed to the same antigen. Latex allergy may cause two types of responses: (1) a type IV delayed T-cell mediated hypersensitivity; or (2) a type I hypersensitivity reaction. Atopic dermatitis is associated with a family history of atopic conditions such as asthma and allergic rhinitis. The cause involves both genetic and environmental factors. Damage to the epidermal layer of the skin results in water loss and entry of antigens that activate the inflammatory response. Acne vulgaris is an inflammation of the pilosebaceous follicle. The initial trigger causing overactivity of the pilosebaceous ducts, blockage of the ducts and excessive sebum production is thought to be hormonal. Acne rosacea, an inflammatory condition affecting the face, is caused by both genetic and environmental factors. The clinical manifestations of skin dryness, erythema on the nose and cheeks, and telangiectasia result from damage to the dermis and an inflammatory response. Lupus erythematosus can affect only the skin (cutaneous lupus erythematosus) or have multi-organ involvement (systemic lupus erythematosus). The cause involves both genetic and environmental factors with triggers including sunlight, medications, hormones, stress, viruses and skin trauma. The lesions vary depending on the type of lupus erythematosus. Psoriasis is a chronic, inflammatory skin disorder characterised by increased epidermal cell turnover, causing the epidermis to thicken and plaque to form.
Infections of the integumentary system • Folliculitis is a bacterial infection of the hair follicle. • A furuncle is a bacterial infection that spreads from the hair follicle into surrounding tissue. • A carbuncle is a collection of infected hair follicles. • Cellulitis is a spreading infection of the dermis and subcutaneous tissues. Local manifestations include redness, heat, swelling and pain in the infected area. Systemic manifestations such as fever, malaise and vomiting may also be present. • Staphylococcal scalded skin syndrome is a toxinmediated condition caused by Staphylococcus aureus. Toxins produced by the bacteria cause separation of the skin just below the granular layer of the epidermis. It occurs mainly in young children who have not developed antibodies against the toxins or adults who are immunosuppressed. It is treated with antibiotics.
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• Paronychia is an infection of the nail fold. Skin around the nail is red, swollen and painful. • Herpes simplex type I is a viral infection that affects the oral and respiratory mucosa, and herpes simplex type 2 affects the genitalia. Lesions are small, inflamed painful vesicles that ulcerate and crust. Latent infection is established in dorsal root ganglia. • Herpes zoster (shingles) and varicella (chickenpox) are both caused by the same herpes virus. Varicella occurs most commonly in children and causes a vesicular rash on the trunk, limbs, face and scalp. Herpes zoster occurs mainly in adults and results from reactivation of the varicella virus. It causes a painful vesicular rash, usually on the skin of a single dermatome. • Warts are benign epidermal lesions caused by the human papillomavirus. Condylomata acuminata are genital warts transmitted by sexual contact. • Molluscum contagiosum is a contagious condition of the skin caused by the poxvirus. Lesions are pearly papules with a central plug consisting of dead epithelial cells and virus particles found on the trunk, face and extremities. • Tinea infections are superficial skin infections caused by dermatophytes. They are classified by location: tinea corporis (body), tinea capitis (scalp), tinea pedis (feet), tinea manus (hands), tinea cruris (groin) and tinea unguium (nails). They are treated with antifungal drugs. • Candidiasis is an infection caused by the yeast-like fungus, Candida albicans. It occurs on the skin and mucous membranes. • Scabies is a contagious parasitic infection caused by Sarcoptes scabiei. The characteristic feature of scabies is the burrow, a track made by the female where she lays her eggs. • Pediculosis is an infestation of blood-sucking lice that infest the head, body or pubic area. • Ticks are blood-sucking parasites that secrete a number of substances including anticoagulants and prostaglandins into the host. The manifestations of the tick bite include itchy, painful, erythematous lesions. Allergic reactions are caused by both the physical trauma to the skin and the salivary secretions, toxins and excretions of the tick.
Paediatrics and impetigo • Impetigo is a contagious superficial skin infection caused by Staphylococcus aureus and Streptococcus pyogenes. Lesions begin as small blisters that become pustular, rupture and form crusts.
Traumatic conditions of the integumentary system • Pressure injuries are areas of localised injury to the skin resulting from pressure or pressure in combination with shear and/or friction. As a result of pressure, underlying blood vessels are occluded, leading to ischaemia, tissue necrosis and ulceration. • Skin tears caused by shearing, friction or blunt trauma result in separation of the epidermis from the dermis or the epidermis and dermis from the underlying Continued
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structures. They may present from a simple linear tear to extensive tissue loss and necrosis. • Burns can be caused by thermal, electrical, chemical or radiation sources. There are both local and systemic responses to a burn injury. Burns exceeding 20% of the total body surface area are associated with fluid shifts, oedema and release of inflammatory mediators. As a result of the loss of skin integrity, the normal protective functions of the skin are lost. The two key factors when assessing a burn are the total body surface area burnt and the depth of the burn.
• Scleroderma is an autoimmune disease of the connective tissue characterised by fibrosis in the skin and organs of the body. • Port-wine stains are congenital malformations of capillaries in the papillary layer of the dermis.
Paediatrics and haemangioma • Haemangiomas are benign lesions of capillary endothelium. Superficial haemangiomas are raised and bright red. Deep haemangiomas are bluish in colour. Most haemangiomas spontaneously regress.
Vascular disorders • Cutaneous vasculitis is an inflammation of the blood vessels of the skin caused by bacterial or viral infections or a toxic response to drugs.
CASE STUDY
A DULT Mark is 39 years old and was referred to a dermatologist for a suspicious-looking mole on the back of his lower left leg. Mark is a sales manager who lives with his wife and two children. He has lived near the beach all his life and when younger spent most weekends surfing. He is fit and still enjoys surfing and jogging along the beach. Although he now wears sunscreen when outdoors, he admits that when he was younger he just smeared zinc across his nose. The dermatologist noted that Mark has light skin and blond hair. Mark explained that the mole at the back of his leg had become itchy, and that it had become slightly raised and changed colour over the past 4–6 weeks. Although he has a number of moles he has no previous history of melanoma and no known family history of melanoma. On examination the dermatologist noted that the lesion was 6 mm × 8 mm, raised and consisted of light brown, dark brown and black colours. It had irregular borders and was not ulcerated. On palpation of
Mark’s groin he noted there was no lymphadenopathy. The lesion was excised and a full-thickness biopsy was performed. Histopathology showed proliferation of atypical melanocytes that extended into the papillary layer of the dermis. It also showed lymphocytes present surrounding the malignant cells in the dermis. The Breslow thickness was 0.35 mm and the TNM stage was given as T1a. The diagnosis of malignant melanoma was confirmed. 1 Name 2 factors that placed Mark at risk of developing melanoma. 2 Explain how a melanocyte may be transformed into a melanoma. 3 Detail the features of Mark’s lesion that were suggestive of a melanoma. 4 Explain why the doctor examined Mark’s lymph nodes in his left groin. 5 Discuss the importance of excising Mark’s lesion and performing a biopsy.
CASE STUDY
A GEING Elsie is an 83-year-old woman who has lived in a nursing home for the past 8 years since the death of her husband. Elsie was diagnosed with Alzheimer’s disease 10 years ago. In the last 12 months, Elsie has become less and less mobile spending long periods in bed, often not eating meals unless prompted to do so or only eating very small amounts. Furthermore, Elsie has had many instances of incontinence (both urine and faeces) because she has not been able to tell staff that she wants to use the toilet — the nurses are finding it difficult to communicate with her. Three weeks ago while Elsie was
being bathed, the nurse noticed a reddened area on Elsie’s left hip. Within a few days, the area had become a purplish colour, ‘boggy’ in texture and cool to touch compared to the surrounding tissue. 1 List at least 4 factors which may have contributed to Elsie’s injury. 2 What stage was Elsie’s injury when it was first noticed? 3 What other areas are at risk of pressure injury? 4 Discuss management strategies for preventing this type of injury from occurring? 5 Describe the mechanism that led to this injury occurring?
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REVIEW QUESTIONS 1 Explain from what cells basal cell and squamous cell carcinoma arise. 2 Outline how UV radiation may promote the development of malignant skin cancers. 3 Explain how the pathogenesis of irritant contact dermatitis causes the clinical manifestations of the condition. 4 Describe the characteristics of psoriasis. 5 Describe the causes and clinical manifestations of impetigo.
6 7 8 9
Compare and contrast herpes zoster and varicella. Describe the lesions of scabies. Explain the mechanism of pressure injury development. Describe both the local and systemic responses to a burn injury. 10 Outline the problems that can arise as a result of the loss of skin integrity caused by a burn injury.
Key terms
CHAPTER
20
The structure and function of the musculoskeletal system Derek Nash
Chapter outline Introduction, 487 The structure and function of bones, 487 Elements of bone tissue, 487 Types of bone tissue, 489 Characteristics of bone, 491 Maintenance of bone integrity, 492 The structure and function of joints, 493 Fibrous joints, 494 Cartilaginous joints, 494 Synovial joints, 494
486
The structure and function of skeletal muscles, 498 Whole muscle, 498 Components of muscle function, 504 The clinical relevance of skeletal muscle, 509 Ageing and the musculoskeletal system, 510 Ageing of bones, 510 Ageing of joints, 510 Ageing of muscles, 510
amphiarthroses, 493 appendicular skeleton, 491 articular cartilage, 496 axial skeleton, 491 bone matrix, 487 calcification, 487 cartilaginous joints, 494 compact bone (cortical bone), 489 contraction, 504 coupling, 504 diarthroses, 493 endomysium, 498 epimysium, 498 excitation, 504 fascia, 498 fibrous joint, 494 fusiform muscles, 498 Golgi tendon organs, 500 gomphosis, 494 ground substance, 487 haversian system, 489 intraarticular menisci, 496 isometric contraction, 507 isotonic contraction, 507 joint, 493 joint capsule, 495 joint cavity, 496 lacuna, 488 mineralisation, 489 myofibrils, 501 neuromuscular junction, 504 osteoblast, 488 osteoclasts, 488 osteocyte, 488 osteoid, 488 pennate muscles, 498 perimysium, 498 periosteum, 490 relaxation, 505 remodelling, 492 ruffled border, 488 sarcopenia, 510 spindles, 500 spongy bone (trabecular or cancellous bone), 489 suture, 494 symphysis, 494 synaptic cleft, 504 synarthroses, 493 synchondrosis, 494 syndesmosis, 494 synovial fluid, 496 synovial joints, 494 synovial membrane, 496 tendon, 498 tetanus, 506
CHAPTER 20 The structure and function of the musculoskeletal system
Introduction Our knowledge of the musculoskeletal system dates back to the ancient Greeks. The Greek word for bone is osteum and so we have osteology as the study of bones. Many of the terms used to describe bone incorporate the Greek word — for example, bone-destroying cells are known as osteoclasts and bone-building cells are known as osteoblasts. The Greek word for muscle is mysium and this word can be found in the term for the tough outer wrapping of a muscle, the epimysium, while individual muscle cells are called myocytes. The musculoskeletal system provides shape, support and movement to the body. The bones provide the structure and the joints between them determine the movements possible. Bones are also central to mineral homeostasis. The attachment of muscles on the bones provides a series of levers about the joints, which control the strength or speed of movement. Muscles, as the only contractile tissue within the body, drive the movement. The energy consumed by the muscles also serves to maintain body temperature. We start with an exploration of the skeletal system.
The structure and function of bones Bones give form to the body, support tissues and permit movement by providing points of attachment for muscles. Many bones meet in moveable joints that determine the type and extent of movement possible. Bones also protect many of the body’s vital organs. For example, the bones of the skull, thorax and pelvis are hard exterior shields that protect the brain, heart, lungs and reproductive and urinary organs. The hollow centres of bones are filled with marrow. There are two types of marrow, known as red marrow and yellow marrow, named because of their colour. Red marrow fills the gaps between the trabeculae of spongy bone (the structure of bone is explained later in this chapter) and is the site of blood cell formation. The bones of a newborn infant have only red marrow. As we age, some of the red marrow is replaced by yellow marrow, which forms part of our fat reserve. If required, the yellow marrow can once again become red marrow. In the adult, red marrow normally exists only in the flat bones (the skull, scapulae, sternum and pelvis), the bodies of the vertebrae, the ribs and the proximal ends (closest ends to the body) of the humerus and femur. Bones also have a crucial role in mineral homeostasis, storing the minerals calcium, phosphate and magnesium, which are essential for cellular and bodily function. Most importantly, calcium is needed for neuron synaptic transmission (see Chapter 6), as well as for haemostasis (blood clotting) and muscle contraction.
487
Elements of bone tissue
Mature bone is a rigid connective tissue consisting of cells, fibres, a gelatinous (jelly-like) material termed ground substance and large amounts of crystallised minerals, mainly calcium, which give bone its rigidity. Ground substance consists of proteins secreted by chondroblasts (cartilageforming cells). The structural elements of bone are summarised in Table 20.1. Bone is a very dynamic tissue responding to the stresses that it experiences. The cells within bone enable bone to grow, repair itself and change shape in response to stress. Even mature bone is undergoing a continuous process of production and removal. The fibres in bone are collagen, which gives bone its tensile strength (the ability to resist stretch). The crystallised minerals provide the compressive strength of bone (its hardness). Ground substance acts as a medium for the diffusion of nutrients, oxygen, metabolic wastes and minerals between bone tissue and blood vessels. Bone formation begins during fetal life with the growth of cartilage or membranes in the shape of each of the required bones. In mature bone, the repair or remodelling of bone begins with the production of an organic matrix by the bone cells. This bone matrix consists of ground substances, collagen and other proteins that take part in bone formation and maintenance. The next step in bone formation is calcification, in which minerals are deposited and then crystallise. Minerals bind tightly to collagen fibres, producing a composite material with high tensile and compressional strength, allowing bone to withstand pressure and weight-bearing. If the pressure or weight increases, the bone will respond by increasing in size and strength.
TABLE 20.1 The structural elements of bone STRUCTURAL ELEMENTS
FUNCTION
Bone cells Osteoblasts
Produce collagen and proteoglycans (polysaccharide and protein substances): stimulate osteoclast resorptive activity
Osteocytes
Maintain bone matrix
Osteoclasts
Resorb bone; assist with mineral homeostasis
Bone matrix Collagen fibres
Lend support and tensile strength
Proteoglycans
Control transport of ionised materials through matrix
Minerals (elements) Calcium
Crystallises to lend rigidity and compressive strength
Phosphate
Regulates vitamin D and thereby promotes mineralisation
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Bone cells
Bone contains three types of cells: osteoblasts, osteoclasts and osteocytes (see Fig. 20.1). Osteoblasts are the bone-forming cells. Their primary function is to lay down new bone. In the process of calcifying bone the osteoblasts imprison themselves in the newly formed bone and mature to become osteocytes. They help maintain bone by producing (synthesising) new bone matrix molecules. Osteoclasts function primarily to resorb (remove) bone. OSTEOBLASTS
An osteoblast is a specialised fibroblast cell derived from stem cells, which produces type I collagen and is the major bone-forming cell. Osteoblasts are responsive to parathyroid hormone and produce osteocalcin (the major non-collagenous protein of the bone matrix) when stimulated by the activated form of vitamin D. Osteoblasts are active on the outer
A Oc
Ob
B
surfaces of bones, where they form a single layer of cells. Osteoblasts bring about new bone formation by their production of osteoid (non-mineralised bone matrix; see Fig. 20.1A). Osteoblasts also add minerals to newly formed bone matrix. Stimulation of bone formation and the orderly mineralisation of bone matrix occur by concentrating some of the plasma proteins (growth factors) found in the bone matrix and by facilitating the deposit and exchange of calcium and other ions at the site. Various growth factors (proteins and peptides) are critical components of bone formation, maintenance and remodelling. OSTEOCLASTS
Osteoclasts are large (typically 20–100 micrometres in diameter; 1 micrometre = 0.001 millimetre) multinucleated cells that develop from the same cells as monocytes and macrophages (see Chapter 12). Osteoclasts are the major resorptive (removal) cells of bone.1 They migrate over bone surfaces to areas that have been prepared and stripped of osteoid by enzymes produced by osteoblasts in the presence of parathyroid hormone (see Chapter 10). Osteoclasts travel over the prepared bone surfaces, creating irregular scalloped cavities known as Howship’s lacunae or resorption bays (see Fig. 20.1A) as they resorb bone areas and then dissolve the bone minerals using acid. A specific area of the osteoclast cell membrane forms next to the bone surface and forms multiple infoldings to permit intimate contact with the resorption bay. These infoldings, known as the ruffled border, greatly increase the cells’ surfaces under their scalloped or ruffled borders. Osteoclasts resorb bone by secreting enzymes and hydrochloric acid. Osteoclasts also resorb bone through the action of lysosomes (vacuoles containing digestive enzymes) in their cytoplasm. Once resorption is complete, the osteoclasts loosen from the bone surface under the ruffled border through the action of calcitonin. The osteoclasts then disappear, either by degeneration to the form of their parent cells or through cell movements away from the site, in which the osteoclasts become inactive or resting osteoclasts. OSTEOCYTES
FIGURE 20.1
Cellular constituents of bone. A Bone-resorbing (osteoclasts) and bone-forming osteoblast cells. Note the multinucleate osteoclast cell (Oc) resorbing bone on the upper surface and smaller osteoblast cells (Ob) on the under surface secreting new osteoid. B Scanning electron micrograph showing an osteocyte within a lacuna. The cell is surrounded by collagen fibres and mineralised bone.
An osteocyte is a mature osteoblast that is trapped or surrounded in osteoid as it hardens as a result of minerals that enter during calcification (see Fig. 20.1B). The osteocyte is within a space in the hardened bone matrix called a lacuna (pool or cavity). Osteocytes are mostly nucleus with a thin layer of non-mineralised osteoid around it, like the egg white surrounding an egg yolk. The function of osteocytes is not fully understood, but it is known that they produce certain matrix molecules, thereby assisting bone calcification. Osteocytes are the most numerous bone cells. They also help concentrate nutrients in the matrix. Osteocytes have minute extensions called filopodia that extend into tiny canals in the bone matrix called canaliculi. The fluid found in the canaliculi around the filopodia is called the periosteocytic fluid. This fluid forms the only means of nutrient supply and waste removal for many of the osteocytes. Osteocytes help determine bone
CHAPTER 20 The structure and function of the musculoskeletal system
structure by acting as mechanosensory cells (these specialised cells are responsible for detecting stress and strain) that direct functional adaptation of bone.2 They sense the shape and structure of bone and determine where it is appropriate that bone be formed or resorbed. Osteocytes also prepare the bone for remodelling through the release of enzymes to dissolve the mineralised walls of the lacunae. Through exchanges among these cells, hormone catalysts and minerals, optimal levels of calcium, phosphorus and other minerals are maintained in blood plasma.
Bone matrix
Bone matrix is made of the extracellular elements of bone tissue, specifically collagen fibres, proteins, carbohydrate– protein complexes, ground substance and minerals. COLLAGEN FIBRES
Collagen fibres make up the bulk of bone matrix. They are formed as follows: 1 Osteoblasts produce and secrete type I collagen. 2 Collagen molecules assemble into three thin chains to form fibrils. 3 Fibrils organise into a staggered pattern, with each fibril overlapping its nearest neighbour by about one-quarter of its length. This arrangement creates gaps into which mineral crystals are deposited. 4 After mineral deposition, fibrils link together and twist to form rope-like fibres. 5 The fibres join to form the framework that gives bone its tensile and supportive strength.
Types of bone tissue
Bone is composed of two types of bony (osseous) tissue: compact bone (cortical bone) and spongy bone (trabecular or cancellous bone) (see Fig. 20.2). Compact bone comprises about 85% of the skeleton; spongy bone makes up the remaining 15%. Both types of bone tissue contain the same structural elements and, with a few exceptions, both compact tissue and spongy tissue are present in every bone. The major difference between the two types of tissue is the organisation of the elements (see Fig. 20.3). Compact bone is highly organised, solid and extremely strong. The basic structural unit in compact bone is the haversian system (also known as an osteon) (see Fig. 20.3). Each haversian system is made up of the following: • a central canal called the haversian canal • concentric layers of bone matrix called lamellae (singular, lamella) • tiny spaces (lacunae) between the lamellae
Epiphysis
Articular cartilage Spongy bone Epiphyseal plate Red marrow cavities
Compact bone Medullary cavity
PROTEOGLYCANS
Proteoglycans are large complexes of numerous polysaccharides (carbohydrates) attached to a common protein core. They strengthen bone by forming compressionresistant networks between the collagen fibres. Proteoglycans also control the transport and distribution of electrically charged particles (ions), particularly calcium, through the bone matrix, thereby playing a role in bone calcium deposition and calcification.
Endosteum
Diaphysis
Yellow marrow
Periosteum
GLYCOPROTEINS
Glycoproteins are carbohydrate–protein complexes that control the collagen interactions that lead to fibril formation. They may also function in calcification, resorption, transport of essential nutrients and maintenance of the osmotic pressure of bone fluid.
Bone minerals
Mineralisation (crystallisation) is the final step in bone formation, after collagen production and fibre formation. Mineralisation has two distinct phases: (1) initiation, where the initial mineral deposit is formed; and (2) growth, where mineral crystals are added to the initial mineral deposits. A series of complex chemical reactions transform calcium and phosphate from a fluid form into the solid hexagonal crystals of hydroxyapatite, which is essential to bone homeostasis.
489
Epiphysis
FIGURE 20.2
Cross-section of bone. Longitudinal section of long bone (tibia) showing spongy (cancellous) and compact bone.
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Part 3 Alterations to protection and movement
A
Osteons (haversian systems) Inner Periosteum layer
C
Endosteum
Outer layer
Trabeculae
Compact bone Haversian canals Cancellous (spongy) bone
Volkmann canals
Lacunae
Medullary marrow cavity
Central Mineralised matrix canal
Osteon (haversian system) Circumferential lamellae
B
Compact bone Cancellous (spongy) bone
Blood vessels within haversian or central canal
Trabeculae
Lacunae containing osteocytes Interstitial lamellae
Periosteum
Blood vessel within Volkmann or perforating canal
Concentric lamellae
FIGURE 20.3
The structure of compact and spongy bone. A Longitudinal section of a long bone showing both cancellous and compact bone. B A magnified view of compact bone. C Section of a flat bone. Outer layers of compact bone surround spongy bone. Fine structure of compact and spongy bone is shown in the middle.
• bone cells (osteocytes) within the lacunae (singular lacuna) • small channels or canals called canaliculi (singular canaliculus). Spongy bone is less complex and lacks haversian systems. In spongy bone, the lamellae are not arranged in concentric layers but in plates or bars termed trabeculae (hence the name trabecular bone), which branch and unite with one
another to form an irregular meshwork. The pattern of the network is determined by the direction of stress on the particular bone. The spaces between the trabeculae are filled with red bone marrow. The osteocyte-containing lacunae are distributed between the trabeculae and interconnected by canaliculi. Capillaries pass through the marrow to nourish the osteocytes. All bones are covered with a double-layered connective tissue called the periosteum. The outer layer of the
CHAPTER 20 The structure and function of the musculoskeletal system
periosteum contains blood vessels and nerves, some of which penetrate to the inner structures of the bone through channels called Volkmann canals (see Fig. 20.3). The inner layer of the periosteum is anchored to the bone by collagenous fibres that penetrate the bone.
Characteristics of bone
The 206 bones of the human skeleton are distributed between the axial skeleton and the appendicular skeleton: 80 bones are in the axial skeleton, making up the skull, vertebral column and thorax; the other 126 bones are in the appendicular
AA
Frontal bone
skeleton, making up the upper and lower extremities, the shoulder girdle (pectoral girdle) and the pelvic girdle (os coxae) (see Fig. 20.4). The skeleton contributes approximately 14% of an adult’s body weight. Bones can be classified by shape as long, flat, short (cuboidal) or irregular (see Fig. 20.5). Long bones are longer than they are wide and consist of a narrow tubular midportion (diaphysis) that merges into a broader neck (metaphysis) and a broad end (epiphysis) (see Fig. 20.2). The diaphysis consists of a shaft of thick, rigid compact bone that resists bending forces. Contained within the diaphysis is the elongated marrow (medullary) cavity. The
BB
Nasal bone
Parietal bone
Orbit
Zygomatic bone
Occipital bone
Maxilla Mandible
Cervical vertebrae (7) Clavicle
Manubrium Scapula
Sternum
Costal cartilage
Ribs
Xiphoid process Humerus
Vertebral column
Radius Ulna
Coxal (hip) bone Ilium Sacrum Coccyx
Clavicle Acromion Scapula Thoracic vertebrae (12)
Ribs Humerus
Lumbar vertebrae (5) Coxal (hip) bone
Ulna Radius
Carpal bones
Carpal bones Metacarpal bones Phalanges
Pubis Ischium Greater trochanter of femur
Coccyx Ischium Sacrum
Femur
Metacarpal bones Phalanges Femur
Patella
Tibia Axial skeleton Appendicular skeleton
491
Fibula
Tarsal bones Metatarsal bones Phalanges
FIGURE 20.4
Anterior and posterior skeleton. A Anterior view of skeleton. B Posterior view of the skeleton.
Tibia Fibula
Tarsal bones Phalanges Metatarsal bones Calcaneus
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Part 3 Alterations to protection and movement
FIGURE 20.5
Types of bones. A Long bones (humerus); B flat bones (scapula); C short bones (phalanx); and D irregular bones (vertebra).
marrow cavity of the diaphysis contains primarily fatty tissue, which is referred to as yellow marrow and contributes to the body’s energy reserve. During times of stress the yellow marrow assists red bone marrow in haematopoiesis (blood cell production). The yellow marrow cavity of the diaphysis is continuous with marrow cavities in the spongy bone of the metaphysis and diaphysis. The marrow contained within the epiphysis is red because it contains primarily blood-forming tissue (see Chapter 16). A layer of connective tissue, the endosteum, lines the outer surfaces of both types of marrow cavity. The broadness of the epiphysis allows weight-bearing to be distributed over a wide area. The epiphysis is made of spongy bone covered by a thin layer of compact bone. In a child, the epiphysis is separated from the metaphysis by a cartilaginous growth plate (epiphyseal plate). Chondroblasts (cartilage forming cells) continuously add to the centre of the growth plate as the edges are mineralised. Through this process the bone increases in length. At puberty hormonal stimulation of the chondroblasts causes them to accelerate cartilage production leading to a growth spurt. After puberty the chondroblasts divide less often, the epiphyseal plate calcifies and the epiphysis and metaphysis merge. Therefore, further elongation of bones during growth is no longer possible. By adulthood, the line
of demarcation between the epiphysis and metaphysis is undetectable. However, the epiphyseal plate can be clearly seen on x-rays and can be used to determine rates of bone growth. In flat bones, such as the ribs and scapulae, two plates of compact bone are roughly parallel to each other. Between the compact bone plates is a layer of spongy bone. Short bones, such as the bones of the wrist and ankle, are often cuboidal in shape. They consist of spongy bone covered by a thin layer of compact bone. Irregular bones, such as the vertebrae, mandibles and other facial bones, have various shapes that include thin and thick segments. The thin part of an irregular bone consists of two plates of compact bone with spongy bone in between. The thick part consists of spongy bone surrounded by a layer of compact bone.
Maintenance of bone integrity Remodelling
The structure of bone is maintained by remodelling, a continuing three-phase process in which existing bone is resorbed and new bone is laid down to replace it. • In phase 1 (activation), a stimulus (e.g. hormone, drug, vitamin, physical stressor) activates the production of osteoclasts.
CHAPTER 20 The structure and function of the musculoskeletal system
• In phase 2 (resorption), the osteoclasts gradually resorb bone, leaving behind an elongated cavity termed a resorption cavity. The resorption cavity in compact bone follows the longitudinal axis of the haversian system, whereas the resorption cavity in spongy bone parallels the surface of the trabeculae. • In phase 3 (formation), new bone (termed secondary bone) is laid down by osteoblasts lining the walls of the resorption cavity. Successive layers (lamellae) in compact bone are laid down, until the resorption cavity is reduced to a narrow haversian canal around a blood vessel. In this way, old haversian systems are destroyed and new haversian systems are formed. New trabeculae are formed in spongy bone. • The entire process of remodelling takes about 3–4 months. In this way bone is able to dynamically respond to the stresses it experiences. This ability of bone to adaptively respond to stress was recorded by Julius Wolff, a German anatomist. The process of remodelling in response to stress is also known as Wolff ’s law.
Repair
The remodelling process can repair microscopic bone injuries, but gross injuries such as fractures and surgical wounds (osteotomies) heal by the same stages as soft-tissue injuries, except that new bone, instead of scar tissue, is the final result (see Chapter 13). The stages of bone wound healing are listed here: 1 inflammation/haematoma formation — initial phase where inflammatory cells migrate to the site of injury and a haematoma (blood collection outside of blood vessel, due to injury) forms 2 procallus formation — soft callus occurs where connective tissue stem cells and blood vessels move to the fracture 3 callus formation — toughened area that arises due to woven components which will eventually become bone 4 replacement of the callus with true bone 5 remodelling of the periosteal and endosteal surfaces of the bone to the size and shape of the bone before injury (Fig. 20.6). The speed with which bone heals depends on the severity of the bone disruption; the type and amount of bone tissue that needs to be replaced (spongy bone heals faster); blood and oxygen supply to the site; the presence of growth and thyroid hormones, insulin, vitamins and other nutrients; the presence of systemic disease; the effects of ageing; and effective treatment, including immobilisation and the prevention of complications such as infection. In general, however, haematoma formation occurs within hours of fracture or surgery, formation of procallus by osteoblasts within days, callus formation within weeks, and replacement and contour modelling within years — up to 4 years in some cases.
A A
Osteoblasts
B B
C C
493
Osteoclasts
Osteoblasts forming new bone
Lining cells
New bone
Osteocytes FIGURE 20.6
Bone remodelling. In the remodelling sequence, bone sections are removed by boneresorbing cells (osteoclasts) and replaced with a new section laid down by the bone-forming cells, osteoblasts. The cells work in response to signals generated in that environment. Only osteoclasts mediate the first phase of remodelling. They are activated, scoop out bone, A, and resorb it; then the work of the osteoblasts begins, B. They form new bone that replaces bone removed by the resorption process, C.
FOCU S ON L EA RN IN G
1 List the functions of bone. 2 Describe the bone cells and briefly discuss the function of each cell. 3 List the non-living components of bone. 4 Discuss the importance of the process of remodelling.
The structure and function of joints The site where two or more bones are attached is called an articulation, or more commonly joint (see Fig. 20.7). The primary function of joints is to provide stability and mobility to the skeleton. Whether a joint provides stability or mobility depends on its location and its structure. Generally, joints that stabilise the skeleton have a simpler structure than those that enable the skeleton to move. Most joints provide both stability and mobility to some degree (see Fig. 20.8). Joints are classified based on the degree of movement they permit or on the connecting tissues that hold them together. Based on movement, joints are classified as synarthroses (immovable joints), amphiarthroses (slightly moveable joints) or diarthroses (freely moveable joints)
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Part 3 Alterations to protection and movement
Bone
Muscle fibre
Cartilage
Tendon
FIGURE 20.7
Main tissues of a joint. The joint is structured by a combination of bone which is covered by cartilage, and with muscles attached to the bones by tendons.
(see Fig. 20.8). On the basis of connective structures, joints are classified broadly as fibrous, cartilaginous or synovial. Each of these three structural classifications can be subdivided according to the shape and contour of the articulating surfaces (ends) of the bones and the type of motion the joint permits. Clinically, most problems occur with the cartilaginous intervertebral joints and the synovial joints. It will aid your understanding of joint problems to study the anatomy of each of these joints, as outlined below.
Fibrous joints
A joint in which bone is united directly to bone by fibrous connective tissue is called a fibrous joint. These joints have no joint cavity and allow little, if any, movement. Fibrous joints are subdivided into three types: • A suture has a thin layer of dense fibrous tissue that binds together interlocking flat bones in the skulls of young children. Sutures form an extremely tight union that permits no motion. By adulthood, the fibrous tissue has been replaced by bone. • A syndesmosis is a joint in which the two bony surfaces are united by a ligament or membrane. The fibres of ligaments are flexible and stretch, permitting a limited amount of movement. The paired bones of the lower arm (radius and ulna) and the lower leg (tibia and fibula) and their ligaments are syndesmotic joints. • A gomphosis is a special type of fibrous joint in which a conical projection fits into a complementary socket
and is held there by a ligament. The teeth held in the maxilla or mandible are gomphosis joints.
Cartilaginous joints
There are two types of cartilaginous joints: • A symphysis is a cartilaginous joint in which bones are united by a pad or disc of fibrocartilage. A thin layer of hyaline cartilage usually covers the articulating surfaces of these two bones and the thick pad of fibrocartilage acts as a shock absorber and stabiliser. Examples of symphyses are the symphysis pubis, which joins the two pubic bones in the pelvis, and the intervertebral discs, which join the bodies of the vertebrae. • A synchondrosis is a joint in which hyaline cartilage, rather than fibrocartilage, connects the two bones. The joints between the ribs and the sternum are synchondroses. The hyaline cartilage of these joints is called costal cartilage. Slight movement at the synchondroses between the ribs and the sternum allows the chest to move outwards and upwards during breathing.
Synovial joints
Synovial joints (diarthroses) are the most moveable and the most complex joints in the body (see Fig. 20.9). They incorporate a fluid-filled capsule (joint capsule) surrounding the articulating surfaces. Because injury of joints usually involves damage to some structure associated with the
CHAPTER 20 The structure and function of the musculoskeletal system
Costal cartilage
A
E
Fibrous connective tissue
495
E
Sternum A
B
F Scapula
Fibrocartilage disc
F
Articular cartilage
G B
H Vertebra
C
Humerus
C
G
Cartilage Pubic bone Ulna Fibula
D
Tibia Fibrous connective tissue
D
Lunate
Radius Scaphoid
Triquetrum Pisiform
H
Hamate Tibiofibular ligament
Capitate
Trapezium Trapezoid
FIGURE 20.8
Types of joints. Cartilaginous (amphiarthrodial) joints, which are slightly moveable, include a synchondrosis that attaches ribs to costal cartilage, A, a symphysis that connects vertebrae, B, and the symphysis that connects the two pubic bones, C. Fibrous (synarthrodial) joints, which are immovable, include the syndesmosis between the tibia and fibula, D, and sutures that connect the skull bones and the gomphosis (not shown), which holds teeth in their sockets, E. The synovial joints include the spheroid type at the shoulder, F, the hinge type at the elbow, G, and the gliding joints of the hand, H.
synovial joint, below we look more closely at the individual parts of these joints.
Joint capsule
The joint capsule comprises fibrous connective tissue that covers the ends of bones where they meet in a joint;
perforating fibres firmly attach the proximal and distal capsule to the periosteum, and ligaments and tendons may also reinforce the capsule. The capsule is composed of parallel, interlacing bundles of dense, white fibrous tissue richly supplied with nerves, blood vessels and lymphatic vessels. In addition, nerves in and around the joint capsule
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Part 3 Alterations to protection and movement
Tendon of vastus lateralis (fibrous capsule)
A
Synovial membrane (cut edge) Iliotibial tract (fibrous capsule) Lateral condyle Infrapatellar synovial fold Iliotibial tract (fibrous capsule) Infrapatellar fat body Patella Tendon of vastus lateralis (fibrous capsule) Quadriceps tendon (fibrous capsule)
Quadriceps tendon (fibrous capsule)
Tendon of vastus medialis (fibrous capsule)
B
Synovial membrane Medial condyle Medial meniscus Tibial collateral ligament (fibrous capsule) Lateral meniscus Synovial membrane Tendon of vastus lateralis (fibrous capsule)
Quadriceps femoris muscle Femur Quadriceps tendon Synovial membrane Suprapatellar bursa Subcutaneous prepatellar bursa Patella Articular cartilage Infrapatellar fat body Patellar ligament Subcutaneous infrapatellar bursa Deep infrapatellar bursa Epiphyseal line Tibia
FIGURE 20.9
Knee joint (synovial joint). A Frontal view. B Lateral view.
are sensitive to the rate and direction of motion, compression, tension, vibration and pain.
Synovial membrane
The synovial membrane is a smooth, delicate membrane that lines all the interior of the joint capsule except for the joint (articular) surfaces. The membrane is organised into folds around the joint that allow movement. Some cells within the membrane ingest and remove (phagocytose) bacteria (see Chapter 13) and particles of debris in the joint cavity; others secrete a substance that gives synovial fluid its viscous quality. The synovial membrane is richly supplied with blood and lymphatic vessels and is capable of rapid repair and regeneration.
Joint cavity
The joint cavity (also called joint space) is an enclosed, fluid-filled space between the articulating surfaces of two bones. It enables two bones to move ‘against’ one another and is surrounded by synovial membrane and filled with synovial fluid.
Synovial fluid
Synovial fluid is derived from the blood, as an ultrafiltrate of the plasma, and it also contains proteins secreted by the cells of the synovium. This fluid lubricates the joint surfaces, nourishes the pad of the articular cartilage and covers the ends of the bones. The fluid also contains free-floating synovial cells and various leucocytes (white blood cells;
see Chapter 16) that phagocytose joint debris and microorganisms. This is very important in maintaining an infection-free environment.
Articular cartilage
Articular cartilage is a layer of hyaline cartilage that covers the end of each bone; it may be thick or thin, depending on the size of the joint, the fit of the two bone ends, and the amount of weight and shearing force the joint normally withstands. The function of articular cartilage is to reduce friction in the joint and to distribute the forces of weight-bearing. Articular cartilage is composed of a few cartilage cells (chondrocytes) and a matrix of collagen and glycoprotein, but is mostly water. Individual water molecules rapidly enter or exit the articular cartilage to contribute to the resiliency of the tissue. It is important to note that the articular cartilage has no blood supply, and that the chondrocytes are widely spaced, making repair of cartilage difficult. Therefore, damage to the articular cartilage heals very slowly.
Intraarticular menisci
Intraarticular menisci are fibrocartilage structures found in some joints. In the knee the meniscus extends partway through the joint with free borders on the medial and lateral articular surfaces. The meniscus of the knee may be torn as a result of injury. The disrupted or detached portion of the meniscus may interfere with movement of the joint, causing pain, and may lock the joint or cause it to ‘give
CHAPTER 20 The structure and function of the musculoskeletal system Humerus
497
Axis of rotation Metacarpal
Plane of movement Transverse axis
Anterior/ posterior axis
Ulna Plane of movement Uniaxial (elbow)
Plane of movement Biaxial (finger)
Coxal bone
Anterior/ posterior axis
Transverse axis
Femur Plane of movement
Plane of movement Plane of movement
Longitudinal axis
Multiaxial (hip) FIGURE 20.10
Movements of the synovial joints. The synovial joints are uniaxial, biaxial or multiaxial to allow various types of movements.
way’. Injuries of this type are usually repaired by laparoscopic surgery and involve removing the torn or free cartilage. After surgery the meniscus may slowly grow back to the same shape as originally.
The movement of synovial joints
Synovial joints are described as uniaxial, biaxial or multiaxial according to the shape of the bone ends and the type of movement occurring at the joint (see Fig. 20.10). Usually, one of the bones is stable and serves as an axis for the motion of the other bone. The body movements made possible by various synovial joints are either circular or angular (see Fig. 20.11). The range of motion is a concept which applies to a joint, and refers to the extent to which the joint can undergo its full, normal range of motion. As an example, the shoulder joint should have an extensive ability to undergo abduction, as the arm is raised from by
the side, outwards and up to the head. A loss of the range of motion may occur in someone with shoulder injury, who has difficulty raising the arm that far; a decrease in the range of motion often accompanies abnormalities to the joint, and can be used clinically to indicate the extent and improvement in movements.
FOCU S ON L EA RN IN G
1 Relate the degree of movement to each of the three main types of joint. 2 Describe the structure of the synovial joint. 3 Discuss the function of synovial fluid. 4 Outline the structure and function of articular cartilage.
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Whole muscle
Arm/hand
Circumduction
Extension (elbow)
Hip/leg
Supination Pronation
Adduction
Knee Hip Abduction
Head
F
Flexion Hyperextension Extension H
Flexion/hyperflexion Rotation Foot
Dorsiflexion
Plantar flexion
Eversion/inversion
FIGURE 20.11
Body movements made possible by the synovial joints. A wide variety of movements are available at different joints. Many of these movements are found in opposite pairs; for example, adduction is the opposite movement to abduction.
The structure and function of skeletal muscles Life would not be possible without the contractile function of the skeletal muscles. They enable us to sit, walk, run, stand, speak and breathe. The total muscle mass makes up approximately 40% of an adult’s body weight and about 50% of a child’s body weight. Interestingly, muscle is mostly composed of water (accounting for about 75% of the weight), protein (20%), and organic and inorganic compounds (5%). One-third of all protein stores for energy and metabolism are contained in muscle. We begin by looking at some features of complete muscles, before examining how muscular function is organised. Then we discuss muscular function at the cellular level — an understanding of muscle function at this level will aid your comprehension of muscular dysfunction outlined in Chapter 21. Finally, we describe some of the clinical issues related to muscle.
There are more than 600 skeletal muscles in the human body (see Fig. 20.12). Of these, many have common names as well as scientific ones. For example, the muscles of the upper arm are known as the biceps (biceps brachii) and triceps (triceps brachii), and those of the thigh are the known as the quadriceps (a group of muscles, the rectus femoris, and the three vastus muscles, the medialis, intermedius and lateralis) and the hamstrings (biceps femoris, semimembranosus and semitendinosus). The abdominals or ‘abs’ (rectus abdominis) support the abdomen, and the ‘pecs’ (pectoralis major) enable movement of the arm back towards the body (adduction). The group of muscles that close the opening of the true pelvis are the pelvic floor muscles (bulbocavernosus, ischiocavernosus, transverse perineal, levator ani, and urethral and anal sphincters). These latter muscles become disturbed in the process of childbirth and after birth it is particularly important for mothers to perform pelvic floor exercises. In addition, many muscles are named according to the bone that they overlay. Thus the frontalis muscle is over the frontal bone, the temporalis muscle overlies the temporal bone and the occipitalis muscle is located over the occipital bone (note that the appropriate lobes of the brain also carry these names; see Chapter 6). The body’s muscles vary dramatically in size and shape. They range from 2 cm to 60 cm in length and are shaped according to function: • Fusiform muscles are elongated muscles shaped like straps and can run the length of a long bone. • Pennate muscles are broad, flat and slightly fan-shaped, with fibres running at an angle to the muscle’s long axis. The multipennate deltoid muscle, which flexes and extends the arm, is a good example of a muscle shaped according to its function. • Each skeletal muscle is a separate organ, encased in a three-part connective tissue framework called fascia. The layers of connective tissue protect the muscle fibres, attach the muscle to bones and provide a structure for a network of nerve fibres, blood vessels and lymphatic channels. The layers are as follows: 1 The endomysium forms the smallest unit of muscle visible without a microscope, as it surrounds the individual muscle fibres (muscle cells). 2 The perimysium organises groups of muscle fibres into bundles that are known as fascicles. 3 The epimysium, the outermost layer, is located on the surface of the muscle and wraps the fascicles into the unit that is the muscle (see Fig. 20.13). Each of these connective tissue layers extends beyond the individual muscle fibres and together they form the tendon (see Fig. 20.13). Thus each muscle fibre is ultimately attached to the origin (non-moving end) at one end of the muscle and to the insertion (the point the muscle is attached to that moves when the muscle contracts) at the other. Tendons allow short muscles to exert power on a distant
CHAPTER 20 The structure and function of the musculoskeletal system
A
499
B Sternocleidomastoid Trapezius Deltoid Serratus anterior Internal oblique
External oblique Transversus abdominis Tensor of fasciae latae Sartorius Adductor magnus Iliotibial tract Vastus lateralis Tendon of rectus femoris Patella Peroneus longus Tibialis anterior Extensor digitorum longus
Sternocleidomastoid
Trapezius Rhomboideus minor
Pectoralis major
Deltoid Latissimus dorsi
Biceps brachii
Brachioradialis Flexor carpi radialis Pectineus
Levator scapulae Supraspinatus Rhomboideus major Infraspinatus Teres minor Teres major Serratus anterior External oblique Anconeus
Triceps (long and short head)
Rectus abdominis
Iliopsoas
Splenius capitis
Brachioradialis Extensor carpi radialis longus
Flexor carpi ulnaris Extensor carpi ulnaris Abductor pollicis longus
Extensor digitorum communis Gluteus medius
Extensor pollicis brevis Adductor magnus
Gluteus maximus Adductor longus
Gracilis Rectus femoris Vastus lateralis
Gracilis Semitendinosus Biceps femoris (short head)
Iliotibial tract Semimembranosus Biceps femoris (long head) Semimembranosus
Patellar ligament Gastrocnemius
Peroneus longus Peroneus brevis
Gastrocnemius Soleus
FIGURE 20.12
Skeletal muscles of the body. A Anterior view. B Posterior view.
joint, whereas a thick muscle would interfere with the ability of the joint to move freely. The ligaments, tendons and fascia are made up of connective tissue that, because of its high tensile strength and elasticity, also buffers the limbs from the effects of sudden strains or changes in speed. The rapid recovery necessary for strenuous exercise is supported by the elastic property of muscle and its connective tissue. Skeletal muscle has been termed voluntary (controlled directly by the nervous system) or striated (having a striped pattern when viewed under a light microscope). Components that are visible on gross inspection of the whole muscle include the motor and sensory nerve fibres. These function together with the muscle, innervating portions of it supplying sensory information to the central nervous system and providing the electrical impulses needed for motor function.
Motor unit
The motor unit enables a variation in strength and precision of contraction for different muscles. A motor unit is defined as a single motor neuron and the muscle fibres that it
innervates (see Fig. 20.14). The cell body of the lower motor neuron is located in the anterior horn of the spinal cord; its axon runs through a peripheral nerve to synapse with the muscle fibres it excites. Thus the motor unit may be considered as the functional unit of skeletal muscle. The number of motor units per individual muscle varies greatly. In the calf, for example, one motor neuron innervates approximately 2000 muscle fibres, out of a total of 1 200 000 muscle fibres. This is a high innervation ratio of muscle fibres to neurons and it contrasts markedly with the low innervation ratio in the laryngeal muscles (involved in vocal production). There, 2 to 3 muscle fibres constitute each motor unit. The innervation ratio can be of great functional significance. The greater the innervation ratio of a particular muscle, the greater its endurance — thus, higher innervation ratios prevent fatigue. Lower innervation ratios allow for precision of movement.
Sensory receptors
Although muscles function as effector organs, they also contain sensory receptors and are involved in sending
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Tendon
Humerus
Fascia Muscle Epimysium Perimysium Endomysium
Blood vessel Axon of motor neuron Muscle fibre (muscle cell) Thick filaments Thin filaments
Myofibril
Muscle fibre (muscle cell) Sarcolemma Nucleus Sarcoplasmic reticulum
Fascicle
FIGURE 20.13
Cross-section of skeletal muscle showing muscle fibres and their coverings. Note that the connective tissue coverings, the epimysium, perimysium and endomysium, are continuous with each other and with the tendon. The muscle fibres are held together by the perimysium in groups called fascicles.
Motor unit 1
Muscle fibres
Motor unit 2
Neuromuscular Axon Motor Spinal junctions neurons cord
FIGURE 20.14
Motor units of a muscle. Each motor unit consists of a motor neuron and all the muscle fibres (cells) supplied by the neuron and its axon branches.
different signals to the central nervous system. Among these receptors are the muscle spindles and Golgi tendon organs. Spindles are mechanoreceptors that lie parallel to muscle fibres and respond to muscle stretching. They are the receptors involved with the muscle stretch reflex (the reflex
arc is described in Chapter 6) and the maintenance of normal muscle tone. Golgi tendon organs are dendrites that terminate and branch to tendons near the neuromuscular junction. They have an inhibitory effect on overexertion of muscle contraction. In this way the Golgi tendon organs
CHAPTER 20 The structure and function of the musculoskeletal system
protect the muscles from rupture. Together the muscle spindles, Golgi tendon organs and free nerve endings provide a means of reporting changes in muscle length, tension, velocity and tone.
501
A A Bone
Tendon
Muscle fibres
Each muscle fibre is a single muscle cell, cylindrical in structure and surrounded by a membrane capable of excitation and impulse propagation. The muscle fibre contains bundles of myofibrils, the fibre’s functional subunits, in a parallel arrangement along the longitudinal axis of the muscle (see Fig. 20.15). At birth, the muscle fibres have completed development from precursor cells called myoblasts. Myoblasts are the main cells responsible for muscle growth and regeneration. Myoblasts are termed satellite cells when in a dormant state.3 Different types of muscle fibres are named due to their appearance: red muscle (containing the oxygen-carrying protein myoglobin, which is a red colour) and white muscle (lacking myoglobin). They are also named according to their metabolic processes: slow-twitch fibres depend on aerobic metabolism, and fast-twitch fibres use the anaerobic pathway for rapid energy conversion (these pathways are discussed in Chapter 3). Muscle fibres are further grouped into type I (red, slow twitch) and type II (white, fast twitch). The motor neurons supplying the different muscle fibre types have different axon diameters and conduction velocities. Type I fibres are supplied by the smallest, slowest conducting neurons, whereas type II fibres are supplied by larger, faster conducting neurons. To highlight this difference, we can compare the composition of fibre types in different athletes: sprinters tend to have more fast-twitch fibres than slow-twitch fibres in their leg muscles, whereas endurance runners have more slow-twitch fibres than fast-twitch fibres in their leg muscles.4 Table 20.2 describes the specific characteristics of type I and type II fibres. In addition to the type of fibres, the diameter of the axon is directly related to the speed of conduction (see Chapter 6). Staining of muscle biopsy specimens cut transversely across the muscle provides a characteristic chequerboard appearance that shows an equal distribution of fibre types throughout the muscle. The existence of the different muscle fibre types in an individual muscle enables it to contract with a low force for a very long time (think how long you can walk) and also produce maximum force for a short time (how long can you maintain a sprint?). Nevertheless, some muscles contain proportionally more of one fibre type than another. The postural muscles have more type I fibres, allowing them the high resistance to fatigue that is necessary to maintain the same position for extended periods. The ocular muscles have more type II muscle fibres, allowing them to respond rapidly to visual changes. The number of muscle fibres varies according to location. Large muscles, such as the gastrocnemius in the calf, have more fibres (1 200 000) than smaller muscles, such as the lumbrical muscles in your hands (10 000). The diameter of muscle fibres also varies. The closely packed polygons
Bundles of muscle fibres MUSCLE FIBRE
Sarcomere
Thick myofilament (myosin) Thin myofilament (actin) Thick filaments
Thin filaments
Relaxed
Contracted Maximally contracted Sarcomere
B A
Myofibril
Myofibril Sarcomere FIGURE 20.15
Skeletal muscle structure. A Each muscle has many muscle fibres, each containing many bundles of thick and thin myofilaments. These are arranged to form adjacent segments called sarcomeres. During contraction, the thin filaments are pulled towards the centre of each sarcomere, thereby shortening the whole muscle. B This electron micrograph shows that the overlapping thick and thin filaments within each sarcomere create a pattern of dark striations in the muscle.
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TABLE 20.2 Characteristics of muscle fibres CHARACTERISTICS
TYPE I (RED)
TYPE II (WHITE)
Anatomical location
Deep axial portion of surface muscle
Surface portion of surface muscle
Contraction speed
Slow
Fast
Motor neuron type
Type I, α
Type II, A
Firing frequency
Low, long duration
Rapid, short duration
Resistance to fatigue
High
Low
Myoglobin
High
Low
Capillary supply
Profuse
Intermediate to sparse
Metabolism
Aerobic
Anaerobic
Mitochondria
Many
Few
Creatine kinase
Cardiac type
Fast, skeletal
Example (most Greater proportion Greater proportion muscles are mixed) of slow-contracting of fast-contracting fibres in laryngeal fibres in soleus and ocular muscles Glycogen content
Low
High
Intensity of contraction
Low
High
Aerobic metabolic capacity
High
Low
Fibre diameter
Small
Large
(muscle fibres) are small (10–20 micrometres) until puberty, when they attain the normal adult diameter of 40–80 micrometres. Females usually have smaller diameter fibres than males. Muscle fibres in small muscles, such as the ocular muscles, are approximately 15 micrometres in diameter; while in larger, more proximal muscles they are 40 micrometres. Only type II fibres are capable of hypertrophy (increasing cell size in response to increased functional demand; see Chapter 4). Thus body builders who train by doing few repetitions of near maximal force (5–8 repetitions using at least 80% of maximal force) over time develop large muscles (hypertrophied), while endurance athletes who train for long periods with less force do not develop hypertrophied muscles but instead develop enhanced capability of type I muscle. The major components of the muscle fibre include the cell membrane (sarcolemma and basement membrane), myofibrils, transverse tubules (T tubules), sarcoplasmic reticulum (called endoplasmic reticulum in other cells), sarcoplasm (cytoplasm) and mitochondria (see Fig. 20.16). Muscles receive inputs from neurons to initiate contraction, at the neuron–muscle synapse known as the neuromuscular junction. At the motor nerve end plate, where the nerve impulse is transmitted, the sarcolemma forms the highly convoluted synaptic cleft. The sarcolemma is made up of lipid molecules and proteins. The proteins perform normal cellular functions, such as transport of nutrients and protein synthesis (production). They also provide the sodium–potassium pump and, importantly, include the cell’s cholinergic receptors (so named because they bind acetylcholine). This allows acetylcholine to bind, when released from the neuron, to initiate muscle contraction.
Sarcomere Myofibril
Sarcolemma
Mitochondria T tubule
Sarcoplasmic reticulum
Triad
FIGURE 20.16
Skeletal muscle cell. The skeletal muscle cell is known as a muscle fibre. The cell membrane is the sarcolemma. Within the cell, the sarcomere contains the actin (coloured red in this image) and myosin (coloured blue) which are organised in parallel with the length of the cell.
CHAPTER 20 The structure and function of the musculoskeletal system
Contained within the sarcolemma is the sarcoplasm, the cytoplasm of the muscle cell containing the intracellular components that are common to all cells (see Chapter 3). The multiple nuclei of skeletal muscle fibres lie in the sarcoplasm, adjacent to the inside surface of the sarcolemma. The sarcoplasm provides a matrix that surrounds the myofibrils. It contains numerous enzymes and proteins that are responsible for the cell’s energy production, protein production and oxygen storage. The multiple mitochondria house enzyme systems for energy production. Many other structures are present in the sarcoplasm. The ribosomes are primarily composed of RNA and participate in the process of protein production. Glycogen granules (stores of glucose), myoglobin (a red pigment similar to haemoglobin that stores oxygen) and lipid droplets are suspended in the sarcoplasmic matrix. These are all important to muscle metabolism. Unique to the muscle is the sarcotubular system, a network that includes the transverse tubules and the sarcoplasmic reticulum, which crosses the interior of the cell. In the muscle cells, the sarcoplasmic reticulum is involved in calcium transport, which initiates muscle contraction at the sarcomere, a portion of the myofibril. The sarcoplasmic reticulum is composed of tubules that run parallel to the myofibrils. The longitudinal tubules are termed sarcotubules. The transverse tubules, which are closely associated with the sarcotubules, run across the sarcoplasm and communicate with the extracellular space. Together, the tubules of this membrane system allow for intracellular calcium uptake, regulation, release during muscle contraction and storage during muscle relaxation.
Myofibrils, sarcomeres and myofilaments
Myofibrils are the functional units of muscle contraction. They are the most abundant subcellular muscle component, equalling 85–90% of the total volume. On cross-section, they are seen to be irregular polygons with a mean diameter of between 1 and 2 micrometres. Myofibrils are densely packed — there are up to thousands in each muscle fibre. Within each myofibril are sarcomeres, the contractile units of the muscle cell. Sarcomeres are arranged in parallel and appear at regular intervals (see Fig. 20.15). They are normally between 1.6 and 2.2 micrometres long. Sarcomeres are made up of hundreds of rod-like structures called myofilaments. These are divided into thick and thin myofilaments, which contain the proteins actin, myosin, tropomyosin and troponin (see Table 20.3). The thick myofilament is made up of myosin, while the thin myofilament is composed mainly of actin, with tropomyosin and troponin attached. The reason why the thin myofilament is composed of three proteins and the thick myofilament of only one lies in the size of the proteins. Myosin has two subunits that resemble a golf club shaft bundled together and appears quick thick. In contrast, actin, tropomyosin and troponin strands twist around each other and appear thin. The importance of these proteins will become evident when we discuss muscle contraction later in the chapter. These proteins refract light differently, such that actin appears light and myosin
503
TABLE 20.3 Contractile proteins of skeletal muscle fibrils
NAME
APPROXIMATE PERCENTAGE OF MYOFIBRIL PROTEIN
Myosin Actin Troponin
Tropomyosin
50–55% 20% 7%
5–7%
FUNCTION
Contraction; breaks down ATP and develops tension Contraction; interacts with myosin Regulatory protein; in presence of calcium, promotes actin–myosin activation Regulatory and structural function; links filaments, controls filament length
appears dark. As a result, the muscle cells appear striped or striated.
Non-protein constituents of muscle
Substances such as nitrogen, creatine, creatinine (a breakdown product of creatine), phosphocreatine (an energy-storing compound), purines, uric acid and amino
RESEARCH IN F
CUS
Soft-tissue repair New scientific discoveries are showing promise in guiding our understanding of soft tissue repair. The importance of the extracellular matrix (ECM) in influencing differentiation, maintenance and remodelling of tissues has recently been described. The ECM interacts in a very dynamic way with cells. This interaction is orchestrated by various extracellular proteins that form signal transduction pathways. One of these extracellular proteins is matrillin-2 that is important in the timing of the beginning of differentiation of cells to replace dead or damaged tissue and regeneration of muscle, nervous and other tissues. Matrillin-2 seems also to be implicated in the development of tumours. To display such widespread effects matrillin-2 acts as a multiadhesion adaptor protein that interacts with other ECM proteins and integrins. In more specific terms matrillin-2 promotes axon and dendrite growth, Schwann cell migration, formation of neuromuscular junctions, regeneration of both skeletal muscle and hepatocytes and wound healing of the skin. Discoveries such as this present the real opportunity to engineer new tissues that can successfully treat conditions such as muscular dystrophy, severe traumatic injuries, burns and anatomical defects. The regeneration and formation of new tissue holds great promise for the fields of orthopaedics, plastic surgery, trauma and rehabilitation.
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acids all serve in the complex process of muscle metabolism. Energy is provided by glycogen and its derivatives. Creatine metabolism and creatinine metabolism have been used to measure muscle mass. Plasma creatine is taken up by muscle and converted into the high-energy phosphate compound phosphocreatine by the enzyme creatine kinase. Creatinine (a cyclic or circular molecule) is spontaneously formed in muscle from phosphocreatine (a linear form of the molecule). Plasma levels of creatinine are increased in muscle wasting diseases (because production of creatinine is increased) and kidney disease (because excretion of creatinine is reduced). (Tests for plasma creatinine are discussed in Chapter 28.)
Components of muscle function
The ultimate function of muscle is to contract. Muscle contraction occurs on the molecular level and leads to the observable phenomenon of muscle movement.
Neuromuscular junction
The area where the nerve fibre meets the muscle cell is referred to as the neuromuscular junction (see Fig. 20.17). The axon of the motor neuron (efferent neuron that innervates muscle) extends to the motor unit, where it connects to the sarcolemma of the muscle cell. It is important to understand that the end of the neuron, referred to as the presynaptic membrane, does not physically touch the sarcolemma of the muscle cell. Basically, there is a synapse between these two structures, which is a space called the synaptic cleft. The sarcolemma side is referred to as the postsynaptic membrane and when stimulated it causes muscle contraction. Muscle contraction occurs because the electrical signal (the action potential in the neuron; review using Chapter 6) is converted to a chemical signal, which travels across the synaptic cleft to interface with receptors on the postsynaptic membrane. This action triggers the generation of another electrical signal or action potential in the sarcolemma, resulting in muscle contraction. We now examine in detail how this arises.
Muscle contraction at the molecular level
The four steps of muscle contraction are (1) excitation, (2) coupling, (3) contraction and (4) relaxation. The process involves the movement of ions across the plasma membrane and through the sarcotubular system. The muscle fibre is an excitable tissue. At rest, an electric potential of –90 mV is continually maintained across the sarcolemma. This resting potential, generated by the presence of sodium ions outside the cell and potassium ions inside the cell against their respective concentration gradients, is created and maintained by the energy-requiring activity of the sodium–potassium pump (see Chapter 3). 1 Excitation is initiated by the binding of the neurotransmitter acetylcholine, released from the motor neuron, to the cholinergic receptors in the neuromuscular
junction (see Fig. 20.17). This process occurs in response to an action potential reaching the axon terminal (refer to Chapter 6). This causes vesicles in the axon terminal that contain acetylcholine to move to the presynaptic membrane, and by the process of exocytosis (‘cell splitting’; see Chapter 3), they release acetylcholine into the synaptic cleft. The gap of the synapse is microscopic and acetylcholine rapidly diffuses across this space to bind with acetylcholine receptors on the sarcolemma (the postsynaptic membrane). The membrane has folds, which increase the surface area, and there are millions of acetylcholine receptors, ready for the acetylcholine. When acetylcholine binds to the receptors, sodium channels in the sarcolemma open, allowing sodium to flux into the muscle cell and simultaneously potassium to move out. The inflow of sodium ions is, however, much greater than the outflow of potassium ions and results in a change in the distribution of charge, which causes the depolarisation of the membrane. The depolarisation simultaneously spreads to areas adjacent to the neuromuscular junction and through the transverse tubule system. The acetylcholine rapidly unbinds from the receptors and is broken down by the enzyme acetylcholinesterase in the synaptic cleft, which terminates the effects of acetylcholine. Ultimately, acetylcholine is reconstituted and stored in the synaptic vesicles ready for stimulation by future motor neuron action potentials. 2 Coupling follows the depolarisation of the transverse tubules. This depolarisation triggers the release of calcium ions from the sarcoplasmic reticulum, exposing binding sites on the actin molecule. The calcium binds to troponin on the thin myofilaments. However, in the resting state, troponin is bound to actin and the tropomyosin molecules spiral around the actin fibre, blocking the myosin-binding sites. Therefore, interaction between actin and myosin is prevented. After calcium binds, the calcium–troponin complex interaction facilitates the contraction process: calcium binding to troponin causes tropomyosin to move away, consequently exposing the binding sites to the myosin heads. 3 Contraction begins as the calcium ions combine with troponin, exposing the active sites on the actin. Myosin and actin can now form cross-bridges (see Fig. 20.18). The myosin heads undergo a conformational change, which pulls them along the actin filament.5 Under these circumstances, sliding of the thick and thin filaments occurs and the muscle contracts. Energy, in the form of adenosine triphosphate (ATP), is required to detach the myosin heads for the next cycle of the process. This is the sliding filament theory described by AF Huxley in the 1950s, but it is now called the cross-bridge theory because of the formation of the actin–myosin cross-bridges, the process of contraction. The process is so named because the actin actually slides along the myosin, causing the sarcomere to shorten. The useful distance of contraction of a skeletal muscle is approximately 25–35% of the muscle’s length.
CHAPTER 20 The structure and function of the musculoskeletal system
505
A A Spinal cord Motor nerve
Muscle
Axon of motor neuron
B A
1
Action potential
Neuromuscular junction (NMJ)
Motor neuron Vesicles
Muscle fibres (cells)
Neurotransmitter (ACh)
2
NMJ 3
Acetylcholinesterase
4
Muscle fibre membrane Receptor sites
Muscle
FIGURE 20.17
The arrangement of muscle fibres and the neuromuscular junction. A Muscle fibres and motor neurons. B The four steps in the transmission of the signal at the neuromuscular junction. (1) The action potential is transmitted to the end of the motor neuron. (2) The acetylcholine-filled vesicles move the presynaptic membrane. (3) The vesicles release acetylcholine into the synapse. (4) Acetylcholine binds to the postsynaptic membrane and causes depolarisation. As a result of this depolarisation, the processes of muscle contraction occur within the muscle cell.
4
Relaxation begins as calcium ions are actively transported back into the sarcoplasmic reticulum, removing ions from interaction with troponin. The cross-bridges detach and the sarcomere lengthens.
Muscle metabolism
As an energetic tissue, skeletal muscle requires a constant supply of ATP and phosphocreatine. These substances are necessary to fuel the complex processes of muscular function, driving the detachment of the myosin heads from the actin during contraction and transporting calcium ions back into
the sarcoplasmic reticulum to enable relaxation. Another internal process of the muscular system that requires ATP is protein production, which replenishes muscle constituents and accommodates growth and repair. The rate of protein production is related to hormone levels (particularly insulin), amino acid substrates and overall nutritional status. At rest, the rate of ATP formation from glucose is sufficient to maintain internal processes, given normal nutritional status. During activity, the need for ATP increases 100-fold. Activity lasting longer than 5 seconds expends the available stored ATP and phosphocreatine.
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A
Actin
Troponin
Tropomyosin
Thin filament A Thick filament
Ca2+
D
ATP
B
Ca2+
Myosin binding sites
C
Ca2+
FIGURE 20.18
The cross-bridge cycle of muscle contraction. The following steps occur after an action potential reaches the muscle cell. A The myosin head has a high affinity for actin but cannot bind because the actin-binding sites are not accessible. B When calcium enters the cell it binds to troponin, and the tropomyosin-blocking protein moves to allow myosin to bind actin, forming a cross-bridge. C The act of binding changes the shape of myosin and slides the actin along. D When a new molecule of ATP binds to the myosin, it changes and releases from the actin.
Stored glycogen and blood glucose are converted anaerobically to sustain brief, intense activity without increasing the demand for oxygen. Anaerobic metabolism (see Chapter 3) is much less efficient than aerobic metabolism, using six to eight times more glucose to produce the same amount of ATP. With increased activity, such as very intense exercise or with ischaemia, lactic acid concentrations increase, causing a decrease in muscle pH. This short-term mechanism buys time by allowing ATP formation in spite of inadequate energy stores or oxygen supply. When the anaerobic threshold is reached and more oxygen is required, physiological changes occur, including an increase in lactic acid and increases in oxygen consumption, heart rate, breath rate and muscle blood flow. Strenuous exercise requires oxygen, which activates aerobic metabolism to form ATP. Maximal exercise increases oxygen uptake by 15 to 20 times over the resting state. When these systems become exhausted or inadequate to respond to the need for ATP, fatigue and weakness finally force the muscle to reduce activity. One other factor that changes energy requirements is muscle fibre type. Type II fibres rely on anaerobic metabolism and fatigue readily. Type I fibres can resist fatigue
for longer periods because of their capacity for aerobic metabolism.
Muscle mechanics
The amount of tension a muscle fibre can develop depends on the number of cross-bridges formed. In addition, muscle fibres and motor units contract according to the all-ornone principle, meaning that they have two states, either contraction (on) or relaxation (off). The nervous system is able to control the force of contraction of a complete muscle by employing more (or fewer) motor units. As the requirement for force increases, more and more motor units are stimulated — this process is known as recruitment. The nervous system is also able to alter the frequency of stimulation of individual motor units, a process known as repetitive discharge. Recruitment and repetitive discharge of motor units allow the muscle to activate the number of motor units needed to generate the desired force. The total force developed is the sum of the forces generated by each motor unit. As the strength, speed and duration of stimuli increase, the summation of contractions reaches a critical frequency called tetanus, beyond which further contraction cannot occur.
CHAPTER 20 The structure and function of the musculoskeletal system
507
B B Muscle length
Tension
Sarcomere position
A
C Muscle length
A
Muscle length
Sarcomere
Sarcomere
C
Muscle length
FIGURE 20.19
The length–tension relationship. As this graph of muscle tension shows, the maximum strength that a muscle can develop is directly related to the initial length of its fibres. At a short initial length the sarcomeres are already compressed, and thus the muscle cannot develop much tension (position A). Conversely, the thick and thin myofilaments are too far apart in an overstretched muscle to generate much tension (position C). Maximum tension can be generated only when the muscle has been stretched to a moderate, optimal length (position B).
Other variables, such as fibre type, innervation ratio, muscle temperature and muscle shape, influence the efficiency of muscular contraction. The two muscle fibre types differ in their responses to electrical activity. Speed of contraction and tetanus are achieved more rapidly in type II (white fast-twitch) than in type I (red slow-twitch) muscle fibres. Low innervation ratios promote control and coordination, whereas high ratios promote strength and endurance. Muscles work best at normal body temperature, approximately 37°C. Finally, muscles with a large cross-sectional area, such as the fan-shaped pennate muscles, develop greater contractile forces than smaller diameter muscles. The initial length of a muscle and the range of shortening that occurs when the muscle contracts also determine the force it can generate. The maximal strength that a muscle can generate is directly related to the length of the muscle fibres before contraction. This is referred to as the length– tension relationship (see Fig. 20.19). This relationship is important to understand, because if the muscle is stretched too much, the myosin has nothing to bind to and muscle contraction will either not occur or be very weak. Conversely, if the muscle is shortened, the actin and myosin (sarcomere) are compressed and no tension can be developed. For instance, the long fusiform muscles (elongated muscles that are spindle shaped, such as the biceps) have a greater range
of shortening and can contract up to 57% of their resting length. Pre-stretching a muscle will increase the force and speed with which it can contract. If an athlete completes two vertical jumps, the first by crouching and holding the crouch for 5 seconds before jumping, and the second by crouching and immediately jumping, they will achieve a higher jump on the second attempt. The length–tension concept is particularly important in cardiac muscle contraction, which is explained in Chapter 22 (as the FrankStarling mechanism of the heart). This is crucial to your understanding of why the heart muscle cannot generate an adequate contraction during heart failure, which is discussed in detail in Chapter 23.
Types of muscle contraction
During isometric contraction (same length), the muscle maintains constant length as tension is increased (see Fig. 20.20). Isometric contraction occurs, for example, when the arm or leg is pushed against an immovable object. The muscle contracts, but the limb does not move. During isotonic contraction (same tension), the muscle maintains a constant tension as it moves. Isotonic contractions can be eccentric (lengthening) or concentric (shortening). Positive work is accomplished during concentric contraction and energy is released to exert force or lift a weight. In contrast, during eccentric contraction the muscle
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A
ISOTONIC Same tension; changing length
B
ISOMETRIC Same length; changing tension
Eccentric Muscle lengthens
Relaxed
Concentric Contracting Muscle shortens
FIGURE 20.20
Isotonic and isometric contraction. A In isotonic contraction, the muscle shortens, producing movement. B In isometric contraction, the muscle pulls forcefully against a load but does not shorten.
lengthens and absorbs energy. Eccentric contraction requires less energy to accomplish and often results in the development of pain and stiffness after unaccustomed exercise. The pain is known as delayed-onset muscle soreness (DOMS) and can be produced easily by running downhill or repetitively doing a type of exercise that the individual has not done for a lengthy period of time.
The movement of muscle groups
Muscles do not act alone but in groups, often under automatic control. When a muscle contracts and acts as a prime mover (agonist), the muscle that opposes it (antagonist) relaxes. This principle is easily tested by holding the right arm in the horizontal position in front of the body, then bending the elbow while feeling the biceps in the front and the triceps in the back with the other hand. The biceps is firm and the triceps is soft. When the elbow is extended, the biceps is soft and the triceps firm. Completing this movement causes the agonist and antagonist to change automatically; only the movement is commanded, not the
alternate contraction and relaxation of the specific muscle groups. Other associated actions may be seen during walking; as the foot leaves the ground, the paravertebral and gluteal muscles on the opposite sides of the body contract to maintain balance. An individual will notice the loss of the associated muscle’s action when paralysis offsets this process and decreases balance. If a person is partially paralysed, difficulty in maintaining balance is noticeable. THE EFFECT OF TRAINING ON MUSCLE
The concept of plasticity has been developed to describe the ability of skeletal muscle cells to alter the profile of the genes being expressed and the phenotype expressed in response to functional demand.6 How muscle cells respond depends on the type of exercise performed. The type (endurance or resistance), frequency, intensity and duration of exercise are all important. Resistance training to fatigue will involve increasing the bulk of muscle and increasing strength with increase in the diameter of individual
CHAPTER 20 The structure and function of the musculoskeletal system
sarcomeres. Submaximal endurance training will result in less bulky muscles with an improved endurance. This improved endurance correlates highly with increased numbers of mitochondria (biogenesis). Increase of mitochondrial numbers occurs in all forms of skeletal muscle cells if they are exercised and takes 4 to 6 weeks. Exercising muscles also produce angiogenic factors that promote the production of new blood vessels. If a particular type of exercise is consistently performed the type of muscle fibre will change to the type most suited to the exercise. Thus plasticity during training muscle involves mitochondrial biogenesis, angiogenesis and fibre type transformation.7 All of these effects are reversible in detraining that occurs as a result of immobility or weightlessness.
The clinical relevance of skeletal muscle • For some clinical procedures where muscle contraction is unwanted it is necessary to paralyse the appropriate muscle. The receptors in the neuromuscular junction that are a subgroup of cholinergic receptors known as nicotinic receptors (so-called because they are stimulated by nicotine) are the targets of two different classes of paralysing drugs. One class is known as depolarising, because the drug (suxamethonium) attaches to the receptor, causing the muscle fibre to depolarise (contract). You may notice fasciculations (small, involuntary contractions of parts of the muscle without any coordination) when using this drug. The drug remains attached to the receptor longer than acetylcholine (about 8 minutes) and is not degraded by the enzyme acetylcholine esterase (the enzyme that normally breaks down acetylcholine). Because of a wide range of contraindications this class of drug is typically only used in emergency situations, such as an emergency intubation. The other class is known as non-depolarising, because the muscle fibre does not depolarise. The drug (pancuronium or vecuronium) binds to the receptor and blocks the acetylcholine from binding. Non-depolarising drugs have varying speed of onset and length of action and are typically used for open bowel or laparoscopic surgery. • Various medications are injected into muscle. Generally a larger amount of medication may be injected intramuscularly than subcutaneously. Because the muscles are situated below the skin and subcutaneous fat, a longer needle is required. The speed of onset of drug action depends on the blood supply of the muscle but is slower than the intravenous route and the effect is longer lasting. Intramuscular sites include the upper arm (deltoid), thigh (vastus lateralis) and buttocks (ventrogluteal and dorsogluteal) — when the gluteal muscles are used, the site should be in the upper outer quadrant to avoid the sciatic nerve. The most common complications of muscle injections are due to damaging a nerve or accidental injection into a blood vessel (which can be avoided by a brief aspiration after the
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needle is inserted to check whether any blood enters the syringe). • Muscles and their connecting tendons may be subject to damage through overuse. The inflammatory response to this damage can influence the function of other body systems. One such overuse syndrome is carpal tunnel syndrome. Nine flexor tendons from activating muscles in the forearm run through the narrow space between the carpal bones and the transverse carpal ligament, the carpal tunnel. They share this tunnel with the median nerve. Any condition that causes a reduction in the capacity of the carpal tunnel may lead to entrapment of the median nerve. Compression can be caused by a variety of conditions that effectively reduce the size of the tunnel (bony or ligamentous changes) or increase the volume of tunnel components (inflammation of tendons, synovitis or tumour). Other conditions associated with carpal tunnel syndrome are hypothyroidism, rheumatoid arthritis, acromegaly and diabetes mellitus. The main symptoms of carpal tunnel syndrome are nocturnal paraesthesias of thumb, index and middle fingers. Numbness later occurs in this distribution. Atrophy of the abductor pollicis muscle may occur along with a weakness of precision grip. • The bacteria Clostridium botulinum, which may be present in canned or smoked food, causes the disease botulism after eating the contaminated food. The bacteria produce a toxin that prevents the release of acetylcholine into the neuromuscular junction, leading to a potentially fatal paralysis. The use of this toxin as Botox for cosmetic use and the treatment of cerebral palsy are discussed in Chapter 9. • When a person dies the ATP supply in the muscles becomes exhausted. As a result, all the cellular processes relying on ATP (such as the sodium–potassium pump and calcium pump, which return calcium ions to the sarcoplasmic reticulum) cease to function. The result is liberation of calcium ions into the muscle fibres, which then contract. Without ATP the cross-bridges cannot detach and so the muscles lock in the contracted state. Every muscle is affected and consequently the person’s body becomes very rigid. This state is known as rigor mortis. The dead person will remain in this state until lysosomal enzymes (released from all the cells as they lyse) break down the myosin approximately 36–62 hours after death.
FOCU S ON L EA RN IN G
1 Discuss how the organisation of muscle fibres in motor units allows a muscle to contract gently or forcibly. 2 Describe the processes of muscle excitation, coupling, contraction and relaxation. 3 Compare and contrast type I and type II muscle fibres.
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Ageing and the musculoskeletal system
F OCU S O N L E ARN IN G
1 Compare and contrast age-related bone density loss for males and females. 2 Describe age-related changes in joints. 3 Describe age-related changes in muscle.
the joint is related to the changes in ligaments and muscles. Bones in joints develop evidence of osteoporosis with fewer trabeculae and thinner, less dense bones, making them prone to fractures. Intervertebral disc spaces decrease in height. The rate of loss of height accelerates at age 70 years and beyond. Tendons shrink and harden. Ageing of muscles The function of skeletal muscle depends on many influences that are affected by ageing, including the nervous, vascular and endocrine systems. In the young child, the development of muscle tissue depends greatly on continuing neurodevelopmental maturation. Muscle fibre composition in adults does not change until late in life, but the variation between individuals increases with age. Muscle function remains trainable even into advanced age. Maintaining musculoskeletal fitness at any age can improve overall health.8 Muscle diseases have a definite association with specific age groups. Muscular dystrophies occur in children, and muscle disabilities related to rheumatic diseases usually occur in advancing age. Age-related loss in skeletal muscle is referred to as sarcopenia and is a direct cause of the age-related decrease in muscle strength. As the body ages, muscle mass and strength decline slowly; thus, strength is maintained into the 50s, with a slow decline in dynamic and isometric strength evident after age 70 years. Type II fibres also decrease. There is reduced RNA production, loss of mitochondrial function9 and reduction in the size of motor units. The regenerative function of muscle tissue remains normal in ageing individuals. As much as 30–40% of skeletal muscle mass and strength may be lost from the third to ninth decades. Muscle fatigue may also contribute to loss of function with ageing.10 Sarcopenia is thought to be secondary to progressive neuromuscular changes and diminishing anabolic hormones. Maximal oxygen intake declines with age. The basal metabolic rate is reduced and lean body mass decreases in the aged population.
AGEING
Ageing of bones Ageing is accompanied by the loss of bone tissue. Bones become less dense, less strong and more brittle with increasing age. The bone remodelling cycle takes longer to complete and the rate of mineralisation also slows. As women age, they experience loss of bone density, accelerated by the rapid bone loss that occurs during early menopause from increased osteoclastic bone resorption. By age 70 years, susceptible women have, on the average, lost 50% of their peripheral cortical bone mass. Bone mass losses to such an extent lead to deformity, pain, stiffness and high risk for fractures. Men experience bone loss also, but at later ages and much slower rates (about 3% of bone mass per decade) than women (about 8% of bone mass per decade). Also, initial bone masses in men are approximately 30% higher than in women; therefore, bone loss in men causes less risk of disability than for women. Men’s peak bone mass is related to their race, heredity, hormonal factors, physical activity and calcium intake during childhood. Bone loss in both sexes is related to smoking, calcium deficiency, alcohol intake and physical inactivity. Bone mass can be gained in healthy young women up to the third decade through physical, weight-bearing activity, intake of dietary calcium and other minerals, and use of oral contraceptives. Height is also lost with ageing because of intervertebral disc degeneration and, sometimes, osteoporotic spinal fractures. Stem cells in the bone marrow perform less efficiently, predisposing the elderly to acute and chronic illnesses. Such illnesses cause weakness and confusion and may increase the risk of injury or falling. Ageing of joints With ageing, cartilage becomes more rigid, fragile and susceptible to fibrillation because of more cross-linking of collagen and elastin, decreasing water content in the cartilage ground substance and decreasing concentrations of glycosaminoglycans. Decreased range of motion of
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chapter SUMMARY The structure and function of bones • Bones provide support and protection for the body’s tissues and organs, are important in mineral homeostasis and are the source of all blood cells. • Bone formation begins with the production of an organic matrix by bone cells. Bone minerals crystallise in and around collagen fibres in the matrix, giving bone its characteristic hardness and strength. • Bone tissue is continuously being resorbed and produced by osteoclasts and osteoblasts in a process known as remodelling. • Bones in the body are made up of compact bone tissue and spongy bone tissue. Compact bone is highly organised into haversian systems that consist of concentric layers of crystallised matrix surrounding a central canal that contains blood vessels and nerves. Dispersed throughout the concentric layers of crystallised matrix are small spaces containing osteocytes. Smaller canals, called canaliculi, interconnect the osteocyte-containing spaces. The crystallised matrix in spongy bone is arranged in bars or plates. Spaces containing osteocytes are dispersed between the bars or plates and interconnected by canaliculi. • There are 206 bones in the body divided into the axial skeleton and appendicular skeleton. Bones are classified by their shape as long, short, flat or irregular. Long bones have a broad end (epiphysis), broad neck (metaphysis) and narrow midportion (diaphysis), which contains the medullary cavity. • Bone injuries are repaired in stages. Haematoma formation provides the fibrin framework for the formation and organisation of granulation tissue. The granulation tissue provides a cartilage model for the formation and crystallisation of bone matrix. Remodelling restores the original shape and size to the injured bone.
The structure and function of joints • A joint is the site where two or more bones attach. Joints provide mobility to the skeleton. • Joints are classified as synarthroses, amphiarthroses or diarthroses, depending on the degree of movement they allow. • Joints are also classified by the type of connecting tissue holding them together. Fibrous joints are connected by dense fibrous tissue, ligaments or membranes. Cartilaginous joints are connected by fibrocartilage or hyaline cartilage. Synovial joints are connected by a
fibrous joint capsule. Within the capsule is a small fluidfilled space. The fluid in the space nourishes the articular cartilage, which covers the ends of the bones meeting in the synovial joint. • Articular cartilage is a highly organised system of collagen fibres and proteoglycans. The fibres firmly anchor the cartilage to the bone and the proteoglycans control the loss of fluid from the cartilage.
The structure and function of skeletal muscles • Skeletal muscle is made up of millions of individual fibres. • Whole muscles vary in size (from 2 cm to 60 cm) and shape (fusiform, pennate). They are encased in a threepart connective tissue framework. The fundamental concept of muscle function rests with the motor unit, defined as those muscle fibres innervated by a single motor neuron. • Satellite cells are dormant myoblasts; however, they can regenerate muscle when activated. • Muscle fibres contain bundles of myofibrils arranged in parallel along the longitudinal axis and include the muscle membrane, myofibrils, sarcotubular system, aqueous sarcoplasm and mitochondria. There are two types of muscle fibres: type I and type II. • Myofibrils and myofilaments contain the major muscle proteins, actin and myosin, which interact to form crossbridges during muscle contraction. The non-protein muscle constituents provide an energy source for contraction and regulate protein production (synthesis), enzyme systems and membrane stabilisation. • Muscle contraction includes excitation, coupling, contraction and relaxation. • Muscle strength is graded by the all-or-none principle and recruitment. Speed of contraction is affected by several factors: muscle fibre type, temperature, stretch and weight of the load. • There are two types of muscle contraction: isometric and isotonic. Isotonic contractions may be either eccentric or concentric. • Skeletal muscle requires a constant supply of adenosine triphosphate (ATP) and phosphocreatine to fuel muscle contraction and for growth and repair. ATP and phosphocreatine can be generated aerobically or anaerobically. • Skeletal muscle undergoes structural change involving mitochondrial biogenesis, angiogenesis and fibre type transformation in response to training.
Continued
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Ageing and the musculoskeletal system • The major effect of ageing on the skeletal system is loss of bone mass. For females loss of bone mass begins with menopause. Weight-bearing exercise and adequate calcium intake before menopause will maximise the length of time before bone mass-related health problems occur. Men experience bone loss later and at a slower rate than women.
• Sarcopenia, or age-related loss in skeletal muscle, is a direct cause of decrease in muscle strength. A slow decline in dynamic and isometric strength is evident after age 70 years. • The regenerative function of muscle tissue remains normal in the elderly. • Reduced basal metabolic rate and decreased lean body mass are also noted in the elderly.
CASE STUDY
A DULT Lara, 42-year-old mother of two, has worked as a keyboard operator inputting data since she left school at the age of 17. After the births of her two children she has struggled with weight control, particularly since she ceased being active in sport. Her doctor has diagnosed an underactive thyroid as contributing to her weight control issues and warned her she is on the verge of obesity. Recently at work, as a result of restructuring and a redundancy in her department, Lara’s job has expanded to also perform some of the work previously done by the redundant worker. For the past 6 weeks Lara has worked straight through her breaks and has been taking lunch at her desk. She has also been working an hour extra, 3 days a week. Last night Lara was awakened by pain from her left hand and wrist. In the morning the pain was replaced
with a tingling sensation in her left thumb, second, third and inner margin of the fourth fingers. She also notices that the fine motor skills of her left hand seem to have deteriorated somewhat. Concerned about what is happening to her Lara calls in sick and seeks an appointment with her doctor. Be prepared to research widely to answer the following questions. 1 Briefly describe the function at the neuromuscular junction. 2 What condition is Lara most likely suffering from? 3 Describe the distribution of the median nerve and use this information to explain the distribution of the paraesthesia (tingling) that Lara experienced. 4 What aspects of her history place Lara at increased risk of this condition? 5 What treatment options are there for this condition?
CASE STUDY
A GEING David has been fit and active throughout his life, and now at his 80th birthday he has been reminiscing with the family. Among photographs from his younger days members of his family notice that David used to be much bigger. He is proud of the fact that his body fat level is still low and he is still able to cycle. Family members are interested in the changes that have happened to David’s body and physical capability.
1 2 3 4 5
What is the name for the reduction in muscle mass David exhibits? What is a typical reduction of muscle mass between the third and ninth decades? Which muscle fibres are mostly affected? How will this fibre loss impact his capability? How will David’s strength be affected by this reduction in muscle mass? What strategies may be employed to minimise the effects of age-related decrease in muscular capability?
CHAPTER 20 The structure and function of the musculoskeletal system
REVIEW QUESTIONS 1 Draw a diagram of a long bone, labelling the diaphysis, epiphysis, periosteum, epiphyseal line/plate, cortical bone, spongy bone, red marrow, yellow (fat) marrow and articular cartilage. 2 Name 3 different bone cells and briefly describe their functions. 3 Discuss the purpose and process of remodelling. 4 Draw a diagram of a synovial joint, labelling the joint capsule, synovial membrane, spongy bone, joint cavity, articular cartilage, periosteum and epiphyseal line/plate.
5 Discuss the role of the skeletal system in maintaining mineral homeostasis. 6 Display the cross-bridge theory in a flow diagram. 7 Explain the difference between depolarising and non-depolarising paralysing drugs. 8 Discuss loss of bone mass in the elderly individual. 9 Explain muscular differences between sprinters and endurance runners, in relation to muscle fatigue. 10 Explain why sarcopenia occurs in the elderly individual.
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Key terms
CHAPTER
21
Alterations of musculoskeletal function across the life span Derek Nash and Paul McLiesh
Chapter outline Introduction, 515 Musculoskeletal injuries, 515 Skeletal trauma, 515 Support structures, 519 Disorders of bone and joints, 524 Metabolic bone disease, 524 Disorders of joints, 533 Infectious bone disease, 546 Disorders of skeletal muscle, 549 Contractures, 549
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Stress-induced muscle tension, 549 Disuse atrophy, 550 Fibromyalgia, 550 Integrative conditions related to the musculoskeletal system, 552 Lower back pain, 552 Bone pain, 553 Myasthenia gravis, 553
ankylosing spondylitis, 538 arthritis, 533 avulsion, 519 bowing fractures, 516 bursitis, 520 closed fracture, 558 clubfoot, 555 comminuted fracture, 515 complete fracture, 515 contractures, 549 delayed union, 518 developmental dysplasia of the hip, 556 dislocation, 519 disuse atrophy, 550 Duchenne’s muscular dystrophy, 554 endogenous osteomyelitis, 546 epicondylitis, 520 exogenous osteomyelitis, 546 fatigue fracture, 516 fibromyalgia, 550 fracture, 515 gout, 539 gouty arthritis, 539 greenstick fracture, 516 incomplete fracture, 515 inflammatory joint disease (arthritis), 533 insufficiency fractures, 516 juvenile rheumatoid arthritis, 537 kyphosis, 527 Legg-Calvé-Perthes disease, 531 linear fracture, 515 malunion, 518 muscle strain, 521 myoglobinuria, 522 non-union, 518 oblique fracture, 515 open fracture, 558 Osgood-Schlatter disease, 532 osteoarthritis, 542 osteochondroses, 531 osteomyelitis, 546 osteoporosis, 524 Paget’s disease (osteitis deformans), 530 pathological fracture, 516 post-exercise muscle soreness, 521 rheumatoid arthritis, 533 scoliosis, 532 septic arthritis, 549 spiral fracture, 516 sprains, 519 strain, 519 stress fractures, 516 subluxation, 519 tendonitis, 520 tophi, 539 torus fracture, 516 transchondral fracture, 516 transverse fracture, 516
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Introduction The musculoskeletal system is subject to a large number of disorders that affect people of all ages. Congenital conditions affect the newborn; the major cause of dysfunction through to adulthood is trauma; and in the elderly the effects of reducing bone density or accumulated wear and tear on the skeleton cause fractures and failure of joints. Musculoskeletal injuries have a major impact on patients, families and the community because of the increased support necessary to counteract the physical and psychological effects of reduced capability, pain and decreased quality of life. There are also financial and economic impacts, from direct costs of diagnosis and treatments to costs related to the loss of employment and decreased productivity.
Musculoskeletal injuries Musculoskeletal trauma is referred to as the ‘neglected disease’. Musculoskeletal injuries can occur due to a multitude of environments and situations, such as the workplace, home, motor vehicles and falls. Collectively, these injuries create a large burden to the healthcare system. For instance, in Australia, injury accounts for almost 500 000 hospitalisations annually1 with an estimated 4 million musculoskeletal injury encounters per year in general practice.2 Furthermore, trauma, often resulting in musculoskeletal injuries, is the leading cause of death in people aged 1 to 34 years for all socioeconomic levels. The different types of injuries are discussed in detail below.
Skeletal trauma Fractures
A fracture is a break in a bone. A bone fractures when force is applied that exceeds its tensile or compressive strength. The incidence of fractures varies for individual bones according to age and gender, with the highest incidence of fractures occurring in young males (between the ages of 15 and 24) and the elderly (65 years and older). Fractures of healthy bones, particularly the tibia, clavicle and distal (lower) humerus, tend to occur in young people as a result of trauma. Fractures of the hands and feet are often caused by accidents in the workplace. The incidence of fractures of the proximal (upper) femur, proximal humerus, vertebrae, wrist and pelvis is highest in older adults and is often associated with osteoporosis. Hip and other fragility fractures, the most serious outcome of osteoporosis, are occurring much more frequently as the populations of Australia and New Zealand are ageing.3 CLASSIFICATION OF FRACTURES
Fractures can be classified as complete or incomplete and open or closed (see Fig. 21.1). In a complete fracture the bone is broken all the way through, whereas in an incomplete fracture the bone is damaged but still in one piece. Complete and incomplete fractures also can be called open (formerly
FIGURE 21.1
Examples of types of bone fractures. A Oblique: fracture at oblique angle across both cortices. Cause: direct or indirect energy, with angulation and some compression. B Occult: fracture that is hidden or not readily discernible. Cause: minor force or energy. C Open: skin broken over fracture; possible soft-tissue trauma. Cause: moderate-to-severe energy that is continuous and exceeds tissue tolerances. D Pathological: transverse, oblique or spiral fracture of bone weakened by tumour pressure or presence. Cause: minor energy or force, which may be direct or indirect. E Comminuted: fracture with two or more pieces or segments. Cause: direct or indirect moderate-to-severe force. F Spiral: fracture that curves around cortices and may become displaced by twist. Cause: direct or indirect twisting energy or force with distal part held or unable to move. G Transverse: horizontal break through bone. Cause: direct or indirect energy towards bone. H Greenstick: break in only one cortex of bone. Cause: minor direct or indirect energy. I Impacted: fracture with one end wedged into opposite end of inside fractured fragment. Cause: compressive axial energy or force directly to distal fragment.
referred to as compound) if the skin is broken and closed (formerly called simple) if it is not. A fracture in which a bone breaks into two or more fragments is termed a comminuted fracture. Fractures are also classified according to the direction of the fracture line: a linear fracture runs parallel to the long axis of the bone; an oblique fracture
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occurs at an oblique angle to the shaft of the bone; a spiral fracture encircles the bone; and a transverse fracture occurs straight across the bone. Incomplete fractures tend to occur in the more flexible, growing bones of children. The three main types of incomplete fracture are greenstick, torus and bowing fractures. A greenstick fracture disrupts the outer surface of the bone (cortex), leaving the inner surface intact. The name is derived from the similar appearance of the damage sustained by a young tree branch (a green stick) when it is bent sharply. Greenstick fractures typically occur in the proximal metaphysis or diaphysis of the tibia, radius and ulna. In a torus fracture, the cortex buckles but does not break. Bowing fractures usually occur when longitudinal force is applied to bone. This type of fracture is common in children and usually involves the paired radius–ulna or fibula–tibia. A complete diaphyseal fracture occurs in one of the bones of the pair, which disperses the stress sufficiently to prevent a complete fracture of the second bone, which bows rather than breaks. A bowing fracture resists correction (reduction) because the force necessary to reduce it must be equal to the force that bowed it. Treatment of bowing fractures is also difficult because the bowed bone interferes with reduction of the fractured bone. Types of fractures are summarised in Table 21.1. Fractures may be further classified by cause as pathological, stress or transchondral fractures. A pathological fracture is a break at the site of a preexisting abnormality, usually by force that would not fracture a normal bone. Any disease process that weakens a bone (especially the cortex) predisposes the bone to pathological fracture. Pathological fractures are commonly associated with tumours, osteoporosis, infections and metabolic bone disorders. Stress fractures occur in normal or abnormal bone that experiences repeated stress, such as occurs during athletics. The stress is less than the stress that usually causes a fracture. Two types of stress fractures are recognised: fatigue fracture and insufficiency fracture. A fatigue fracture is caused by abnormal stress or torque applied to a bone with normal ability to deform and recover. Fatigue fractures usually occur in individuals who engage in a new or different activity that is both strenuous and repetitive (e.g. joggers, skaters, dancers, military recruits). Because gains in muscle strength occur more rapidly than gains in bone strength, the newly developed muscles place exaggerated stress on the bones that are not yet ready for the additional stress. The imbalance between muscle and bone development causes microfractures to develop in the cortex. If the activity is controlled and increased gradually, new bone formation catches up to the increased demands and microfractures do not occur. Runners employ the 10% rule to help avoid this problem, restricting their increase in distance (or time) to 10% per week. Insufficiency fractures are stress fractures that occur in bones lacking the normal ability to deform and recover; a fracture can occur as a result of normal weight-bearing or activity. Rheumatoid arthritis, osteoporosis, Paget’s
TABLE 21.1 Types of fractures TYPE OF FRACTURE
DEFINITION
Typical complete fractures Closed
Non-communicating wound between bone and skin
Open
Communicating wound between bone and skin
Comminuted
Multiple bone fragments
Linear
Fracture line parallel to long axis of bone
Oblique
Fracture line at an angle to long axis of bone
Spiral
Fracture line encircling bone (as a spiral staircase)
Transverse
Fracture line perpendicular to long axis of bone
Impacted
Fracture fragments pushed into each other
Pathological
Fracture at a point where bone has been weakened by disease (e.g. by tumours or osteoporosis)
Avulsion
A fragment of bone connected to a ligament or tendon breaks off from the main bone
Compression
Fracture wedged or squeezed together on one side of bone
Displaced
Fracture with one, both or all fragments out of normal alignment
Extracapsular
Fragment close to the joint but remains outside the joint capsule
Intracapsular
Fragment within the joint capsule
Typical incomplete fractures Greenstick
Break in one cortex of bone with splintering of inner bone surface; commonly occurs in children and the elderly
Torus
Buckling of cortex
Bowing
Bending of bone
Stress
Microfracture
Transchondral
Separation of cartilaginous joint surface (articular cartilage) from main shaft of bone
disease, osteomalacia, rickets, hyperparathyroidism and radiation therapy all cause bone to lose its normal ability to deform and recover — that is, the stress of normal weight-bearing or activity fractures the bone. Many of these conditions are referred to later in this chapter. A transchondral fracture consists of break-up and separation of a portion of the articular cartilage that covers the end of a bone at a joint as a result of trauma (joint structures are discussed in Chapter 20). Single or multiple sites may be fractured and the fragments may consist of
CHAPTER 21 Alterations of musculoskeletal function across the life span
cartilage alone or cartilage and bone. Typical sites of transchondral fracture are the distal femur, ankle, kneecap, elbow and wrist. Transchondral fractures are most prevalent in adolescents. PATHOPHYSIOLOGY
When a bone is fractured, the periosteum and blood vessels in the cortex, marrow and surrounding soft tissues are disrupted. Bleeding occurs from the damaged ends of the bone and from the neighbouring soft tissue. The volume of blood lost can be significant. For example, a simple fracture of the humerus can account for 200–300 mL of blood loss, a simple fracture of the femur loses 500–1000 mL of blood and a unilateral fracture of the pelvis can bleed 1000–1500 mL. A clot (haematoma) forms within the medullary canal, between the fractured ends of the bone and beneath the periosteum (see Fig. 21.2). Because blood flow to the injured area is disrupted (there is no oxygen supply) bone tissue immediately adjacent to the fracture dies. This dead tissue (along with any debris in the fracture area) stimulates an intense inflammatory response characterised by vasodilation, increased permeability allowing exudation of plasma, and infiltration by inflammatory leucocytes, growth factors and mast cells that simultaneously decalcify the fractured bone ends.
A A
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Within 48 hours after the injury, new blood vessels grow (in a process called angiogenesis) from surrounding soft tissue and the marrow cavity into the fracture area and blood flow to the entire bone increases. Phagocytic cells begin cleaning up the debris (there are many dead blood cells in the haematoma). Fibroblasts (collagen-forming cells) and osteoblasts (bone-forming cells) migrate into the damaged area (see Fig. 21.2). The fibroblasts lay down collagen to form a fibrocartilaginous callus and the osteoblasts produce matrix, which they mineralise to form spongy bone. The osteoblasts migrate inwards to mineralise the whole callus, forming a bony callus. The bone is effectively ‘splinted’ at this stage, which takes from 3 to 10 weeks to achieve but is still not as strong as pre-fracture. As the repair process continues, remodelling occurs (for months), during which unnecessary callus is resorbed and trabeculae are formed along lines of stress (see Fig. 21.3). The final structure is a response to the mechanical stress experienced by the bone (Wolff ’s law, see Chapter 20). CLINICAL MANIFESTATIONS
The signs and symptoms of a fracture include pain, unnatural alignment (deformity), swelling, muscle spasm, tenderness, impaired sensation and decreased mobility or limb function. The position of the bone segments is determined by the pull of attached muscles, gravity and the direction and size of the force that caused the fracture. Immediately after a bone is fractured, there is usually numbness in the fracture site because of trauma to the nerve or nerves at the site. The numbness may last up to
BB
CC
D D
EE
FIGURE 21.2
Bone healing (schematic representation). A Bleeding at broken ends of the bone with subsequent haematoma formation. B Organisation of haematoma into fibrous network. C Invasion of osteoblasts, lengthening of collagen strands and deposition of calcium. D Callus formation; new bone is built up as osteoclasts destroy dead bone. E Remodelling is accomplished as excess callus is reabsorbed and trabecular bone is laid down.
FIGURE 21.3
Exuberant callus formation following fracture. The excessive growth of callus is seen as the rough appearance rather than the smooth bone.
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20 minutes, during which time the injured person may use the fractured bone or bones while moving from the area. It is also possible to reduce (realign) the fracture during this time without any anaesthetic. However, once the numbness disappears, the subsequent pain is quite severe and incapacitating until relieved with medication and treatment of the fractured bones. The pain is related to muscle spasms at the fracture site, overriding of the fracture segments or damage to adjacent soft tissues. Pathological fractures usually cause changes in the angle of a limb or its apparent point of articulation (the point about which it bends compared to the body), painless swelling or generalised bone pain. Stress fractures are generally painful during and after activity. The pain is usually relieved by rest. Stress fractures also cause local tenderness and soft-tissue swelling. Transchondral fractures may be entirely asymptomatic or may be painful during movement. Range of motion in the joint is limited and movement may produce audible clicking sounds (crepitus). EVALUATION AND TREATMENT
Treatment of a displaced fracture involves two key approaches: (1) reduction: realigning the bone fragments close to their normal anatomic position; and (2) immobilisation: holding the fragments in place so that bone union can occur. Adequate immobilisation is often all that is required for healing of fractures that are not misaligned, such as by the application of a cast or splint. If the bones are misaligned, realignment of the bone segments needs to be commenced — several methods are available to reduce a fracture: closed reduction, traction and open reduction. Most fractures can be reduced by closed reduction, in which the bone is manually moved or manipulated into place without opening the skin, and can be maintained well with immobilisation by the use of a cast or splint. Traction may be used to accomplish or maintain reduction. When bone fragments are displaced (misaligned), weights are used to apply firm, steady traction (pull) and countertraction (pull in the other direction on the other side of the break) to the long axis of the bone. Traction stretches and fatigues muscles that have pulled the bone fragments out of place, allowing the distal fragment to align with the proximal fragment. Traction can be applied to the skin (skin traction), directly to the involved bone or distal to the involved bone (skeletal traction). Skin traction is used to a limit of 5 kg (may vary depending on the quality of the person’s skin however) of pulling force to realign the fragments or when the traction will be used for brief times only, such as before surgery or, for children with femoral fractures, for 3–7 days before applying a cast. A traction boot is applied to the skin, closed with self-adhering straps and then weights are attached to the foot area of the traction boot. In skeletal traction, a pin or wire is drilled through the bone below the fracture site and a traction bow, rope and weights are attached to the pin or wire to apply tension and to provide the pulling force to overcome the muscle spasm and help realign the fracture fragments. The amount
of weight used for skeletal traction can be much higher than skin traction and will be determined in response to the location and severity of the fracture. Open reduction is a surgical procedure that exposes the fracture site; the fragments are brought into alignment under direct visualisation. Some form of prosthesis, screw, plate, nail or wire is used to maintain the reduction (internal fixation), the soft tissues and skin are then closed. External fixation, a system of surgically placed pins and stabilising bars, is another method of maintaining fracture alignment. This method may be used when there is a need for fast surgical intervention (emergency situation) or there is significant risk of infection from contamination of the area. Bone grafts, using donor bone from the individual (autograft), cadaver (allograft) or bone substitutes (ceramic composites, bioactive cement), can fill voids in the bone. Regardless of whether reduction (realignment) is necessary, splints and plaster casts are used to immobilise and hold the bones in their correct anatomical position to allow for bone healing. Improper reduction or immobilisation of a fractured bone may result in non-union, delayed union or malunion: • Non-union is failure of the bone ends to grow together. The gap between the broken ends of the bone fills with dense fibrous and fibrocartilaginous tissue instead of new bone. • Delayed union is union that does not occur until approximately 8–9 months after a fracture. • Malunion is the healing of a bone in an incorrect anatomic position.
RESEARCH IN F CUS Vitamin D and fracture risk The beneficial effects of vitamin D on fracture risk are attributed to two explanations: (1) the prevention of bone loss in the elderly; and (2) the increase in muscle strength and balance mediated through vitamin D receptors in muscle tissue. In addition, vitamin D has been correlated with a significant reduction (22%) in the risk of falling in older people. Pooled analyses reveal that higher doses of 700–800 IU/day are better for reducing fractures than 400 IU/day. Previously, the recommendation for vitamin D in middle-aged and older adults was 400–600 IU/day. With new data and the uncertainty of intake recommendations, higher doses may be more effective (up to 2000 IU/day). However, because calcium was administered in combination with vitamin D in all but one of the higher-dose vitamin D trials, the independent effects of vitamin D alone could not be determined. Although the evidence is building, further research is still needed into whether and in what dose calcium adds value to fracture prevention with vitamin D.
CHAPTER 21 Alterations of musculoskeletal function across the life span
Dislocation and subluxation
Dislocation and subluxation are usually caused by trauma. Dislocation is the temporary displacement of one or more bones in a joint in which the opposing bone surfaces lose contact entirely. If the contact between the opposing bone surfaces is only partially lost, the injury is called a subluxation. Dislocation and subluxation are most common in persons younger than 20 years of age, as their bones are strong and resist fracture but the force disrupts the joint. However, they may be the result of congenital or acquired disorders that cause: (1) muscular imbalance, as occurs with congenital dislocation of the hip or neurological disorders; (2) failure of the articulating surfaces of the bones to match, as occurs with rheumatoid arthritis (see later in the chapter); or (3) joint instability. The joints most often dislocated or subluxated are the joints of the shoulder, elbow, wrist, finger, hip and patella. The shoulder joint most often injured is the glenohumeral joint. Traumatic dislocation of the elbow joint is common in the immature skeleton. In adults, an elbow dislocation is usually associated with a fracture of the ulna or head of the radius. Traumatic dislocation of the wrist usually involves the distal ulna and carpal bones. Any one of the eight carpal bones can be dislocated after an injury. Dislocation in the hand usually involves the metacarpophalangeal and interphalangeal joints. Considerable trauma is needed to dislocate the hip unless there has been a previous injury or surgery to this joint. Anterior hip dislocation is rare; it is caused by forced abduction, for example, when an individual lands on their feet after falling from an elevated height. Posterior dislocation of the hip can occur as a result of a car accident in which the flexed knee strikes the dashboard, causing the head of the femur to be pushed posteriorly from the hip joint. The knee is an unstable weight-bearing joint that depends heavily on the soft-tissue structures around it for support. It is exposed to many different types of motion (flexion, extension, rotation), and the dislocation can be anterior, posterior, lateral, medial or rotary. It is usually the result of an injury that occurs during motor vehicle accidents or sports activities. In addition, the meniscus within the knee joint may become damaged, usually by trauma. PATHOPHYSIOLOGY
Dislocations and subluxations can be accompanied by fracture because stress is placed on areas of bone not usually subjected to stress. In addition, as the bone separates from the joint, it may bruise or tear adjacent nerves, blood vessels, ligaments, supporting structures and soft tissue. Dislocations of the shoulder may damage the shoulder capsule and the axillary nerve. Damage to axillary nerves can cause anaesthesia to a small area of the upper arm and paralysis of the deltoid muscle. Dislocations may also disrupt circulation, leading to ischaemia (low blood supply) and possibly permanent disability of the affected extremity’s tissues. As joints disrupt during dislocation or subluxation
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there is a risk of an avulsion fracture. An avulsion fracture is where a part of a bone, attached to a ligament or tendon, is pulled off the rest of the bone. CLINICAL MANIFESTATIONS
Signs and symptoms of dislocations or subluxations include pain, swelling, limitation of motion and joint deformity. Pain may be caused by the presence of inflammatory chemicals (such as bradykinin; see Chapter 13) and exudate in the joint or associated tendon and ligament injury. Joint deformity is usually caused by muscle contractions that exert pull on the dislocated or subluxated joint. Limitation of the range of motion of the joint or limb results from swelling in the joint (with associated pain) or the displacement of bones. EVALUATION AND TREATMENT
Evaluation of dislocations and subluxations is based on clinical manifestations and x-ray imaging. Treatment consists of reduction and immobilisation for 2–6 weeks and exercises to maintain normal range of motion in the joint. Ensuring that there is no lasting neurological damage to the nerves in that area is also important, so ongoing neurovascular assessment is vital. Depending on which joint is injured, healing is usually complete within months to sometimes years, although some joints may be at risk of further dislocations again in the future (particularly from a reduced force than was originally required).
Support structures
Sprains and strains of tendons and ligaments
Tendon and ligament injuries can accompany fractures and dislocations. A tendon is a fibrous connective tissue that attaches skeletal muscle to bone. A ligament is a band of fibrous connective tissue that connects bones where they meet in a joint. Tendons and ligaments support the bones and joints and either allow or limit motion. Tendons and ligaments can be torn, ruptured or completely separated from bone at their points of attachment. A tear in a tendon is commonly known as a strain. Major trauma can tear or rupture a tendon at any site in the body. Most commonly injured are the tendons of the hands and feet, knee (patellar), upper arm (biceps and triceps), thigh (quadriceps), ankle and heel (Achilles). Ligament tears are commonly known as sprains. Ligament tears and ruptures can occur at any joint but are most common in the wrist, ankle, elbow and knee joints. A complete separation of a tendon or ligament from its bony attachment site is known as an avulsion and is commonly seen in young athletes, especially sprinters, hurdlers and runners. Strains and sprains are classified as first degree (least severe), second degree and third degree (most severe). PATHOPHYSIOLOGY
When a tendon or ligament is torn, an inflammatory exudate (a fluid that has been filtered from the blood, containing inflammatory chemicals) develops between the torn ends.
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Later, granulation tissue containing macrophages (to remove the damaged tissue), fibroblasts (to make collagen) and capillary buds (growing new blood vessels — angiogenesis) grow inwards from the surrounding soft tissue and cartilage to begin the repair process. Within 4–5 days after the injury, collagen formation begins. At first, collagen formation is random and disorganised. As the collagen fibres become associated with preexisting tendon fibres, they become organised to run along the lines of stress. Eventually the new and surrounding tissues fuse into a single mass. As reorganisation takes place, the healing tendon or ligament separates from the surrounding soft tissue. Usually a healing tendon or ligament lacks sufficient strength to withstand strong pull for at least 4–5 weeks after the injury (a ruptured Achilles tendon may take 6 months to heal). If strong muscle pull does occur during this time, the tendon or ligament ends may separate again, causing the tendon or ligament to heal in a lengthened shape with an excessive amount of scar tissue that renders the tendon or ligament functionless.
A
Humerus
Lateral epicondyle Annular ligament
Ulna
B
Gastrocnemius muscle (Lateral head) (Medial head)
CLINICAL MANIFESTATIONS
Tendon and ligament injuries are painful and are usually accompanied by soft-tissue swelling, changes in tendon or ligament contour and dislocation or subluxation of bones. The pain is generally sharp and localised and tenderness persists over the distribution of the tendon or ligament. Following a ruptured Achilles tendon, patients often report a sensation of being kicked in the heel by someone else despite this not occurring. Depending on the tendon or ligament involved, such injuries may result in decreased mobility, instability and weakness of the affected joints, even with prompt treatment. EVALUATION AND TREATMENT
Evaluation is based on clinical manifestations, stress radiography, arthroscopy (using an endoscope to view the interior of the tissue) or arthrography (an x-ray examination in which a contrast medium is used to better visualise the damage). When possible, treatment consists of suturing the tendon or ligament ends closely together. If this is not possible because of the extent of damage, tendon or ligament grafting may be necessary. Long-term rehabilitation exercises help ensure regaining of nearly normal functions, but recovery may be complicated by posttraumatic arthritis.
Tendonitis, epicondylitis and bursitis
Trauma can cause painful inflammation of tendons (tendonitis) and bursae (bursitis). Other causes of damage to tendons include reduced tissue perfusion, mechanical irritation, crystal deposits, postural misalignment and hypermobility in a joint. Achilles tendonitis is inflammation of the Achilles tendon, one that is often inflamed. Epicondylitis is inflammation of a tendon where it attaches to a bone at its origin. Epicondylar areas of the humerus, radius or ulna and around the knee are most often inflamed. Lateral epicondylitis, commonly called
Olecranon bursa Medial epicondyle Olecranon Coronoid process
Soleus muscle Achilles tendon
Calcaneus
FIGURE 21.4
Tendonitis and epicondylitis. A Medial or lateral epicondyles of humerus, site of epicondylitis. B Achilles tendon, site of commonly occurring tendonitis.
‘tennis elbow’ (although most affected people are not tennis players), is likely caused by irritation of the extensor carpi radialis brevis tendon and the resulting degradation. Medial epicondylitis, referred to as ‘golfer’s elbow’, is inflammation of the medial humeral epicondyle (see Fig. 21.4). Epicondylitis is also related to work activities that involve cyclic flexion and extension of the elbow or cyclic pronation, supination, extension and flexion of the wrist that generate loads to the elbow and forearm region.4 A longitudinal study indicates that three sets of risk factors affect the incidence of epicondylitis. They include biochemical constraints and psychosocial and personal factors (including social support at work).5 Bursae are small sacs lined with synovial membrane and filled with synovial fluid that act to provide a slippery, cushioning surface to reduce friction for tissues of the body. They are typically located between tendons, muscles and bones near major joints in the body. Acute bursitis occurs primarily in the middle years and is caused by trauma. Chronic bursitis can result from repeated
CHAPTER 21 Alterations of musculoskeletal function across the life span
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TABLE 21.2 Muscle strain
FIGURE 21.5
Olecranon bursitis. A case of olecranon bursitis in a patient with rheumatoid arthritis. A rheumatoid nodule is also shown.
trauma. Septic bursitis is caused by wound infection or bacterial infection of the skin overlying the bursae. Bursitis commonly occurs in the shoulder, hip, knee and elbow (see Fig. 21.5). PATHOPHYSIOLOGY
In addition to tearing of the tendon, evidence also exists of tissue degeneration and disorganised collagen formation.6 Initial inflammatory changes cause swelling of the area, limiting movements and causing pain. Microtears cause bleeding, oedema and pain in the involved tendon or tendons. At times, after repeated inflammations, calcium may be deposited in the tendon. The calcium is usually spontaneously reabsorbed by the body. Usually bursitis is an inflammation that is reactive to overuse or excessive pressure. The inflamed bursal sac becomes engorged and the inflammation can spread to adjacent tissues. The inflammation may decrease with rest, ice and aspiration of the fluid. (Inflammation is discussed in Chapter 13.) CLINICAL MANIFESTATIONS
Clinical manifestations are usually localised to one side of the joint. Generally there is local tenderness and more pain with active motion than with passive motion. With tendonitis, the pain is localised over the involved tendon. Pain and sometimes weakness limit joint movement. The onset of pain may be gradual or sudden in bursitis and pain may limit active movement in the joint. Shoulder bursitis impairs arm abduction. Bursitis in the knee produces pain when climbing stairs, and crossing the legs is painful in bursitis of the hip. Lying on the side of the inflamed bursa is also very painful. Signs of infectious bursitis may include the presence of a puncture site, warmth and erythema (red appearance of the skin due to dilation of capillaries), prior corticosteroid injection, severe inflammation or an adjacent source of infection, such as an infected total joint replacement.
TYPE
MANIFESTATIONS
TREATMENT
First degree (example: bench press in untrained athlete)
Muscle overstretched
Ice should be applied 5 or 6 times in the first 24–48 hours; gradual resumption of full weight-bearing after initial rest for up to 2 weeks; exercises individualised to specific injury
Second degree (example: any muscle strain with bruising and pain)
Muscle intact with some tearing of fibres, pain
Treatment similar to that for first-degree strains
Third degree (example: traumatic injury)
Caused by tearing of fascia
Surgery to approximate ruptured edges; immobilisation and non-weight-bearing for 6 weeks
EVALUATION AND TREATMENT
The evaluation of tendonitis, epicondylitis and bursitis is based on clinical manifestations, physical examination, arthroscopy, arthrography and possibly MRI. Treatment includes immobilisation of the joint with a sling, splint or cast; systemic analgesics; ice or heat applications; or local injection of an anaesthetic and a corticosteroid to reduce inflammation. Physical therapy to prevent loss of function begins after acute inflammation subsides.
Muscle strains
Mild injury such as muscle strain is usually seen after traumatic or sports injuries. Muscle strain is a general term for local muscle damage. It is often the result of sudden, forced motion causing the muscle to become stretched beyond normal capacity. Strains often involve the tendon as well. Muscles are ruptured more often than tendons in young people; the opposite is true in the older population. Muscle strain may be chronic when the muscle is repeatedly stretched beyond its usual capacity. Haemorrhage into the surrounding tissue and signs of inflammation may also be present. Regardless of the cause of trauma, skeletal muscle cells are usually able to regenerate. Regeneration may take up to 6 weeks and the affected muscle should be protected during that time. Degrees of acute muscle strain, together with their manifestations and treatment, are summarised in Table 21.2.
Post-exercise muscle soreness
Also known as delayed onset muscle soreness (DOMS) post-exercise muscle soreness relates to soreness of the muscles most usually after unaccustomed eccentric contraction. The degree of soreness is related to the duration and intensity of exercise, with the degree of pain being more related to the intensity. Fewer motor units are activated
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to produce the same force during eccentric exercise compared to concentric exercise. Thus higher forces are experienced by the muscle fibres and their surrounding connective tissue structures. There is evidence of free erythrocytes and mitochondria in the extracellular spaces suggesting cellular damage. Neutrophils increase and phagocytes are present in the muscle fibres after 1–3 days post exercise. In animal models, regeneration of muscle injured in this way is complete within 2 weeks. In humans, although it is a common condition, the morbidity (soreness and reduced muscle performance) is temporary.
Myoglobinuria
Myoglobinuria — the presence of myoglobin in the urine — can be a life-threatening complication of severe muscle trauma or secondary to a rare, genetically linked condition known as malignant hyperthermia. Myoglobinuria is so named because the principal manifestation of the condition is an excess of myoglobin (an oxygen-carrying intracellular muscle protein) in the urine. Muscle damage, with disruption of the sarcolemma (cell membrane of the muscle fibre), releases the myoglobin from the cells, which then enters the bloodstream. This death of some skeletal muscle cells is known as rhabdomyolysis. However, large amounts of myoglobin released into the blood becomes nephrotoxic (toxic to nephrons) and may cause acute renal failure (see Chapter 30). The most severe form is often called crush syndrome. Less severe local forms are called compartment syndromes. Crush syndrome first gained notoriety in the reports of injuries seen after the London air raids in World War II. More recently, it has been reported in individuals found unresponsive and immobile for long periods, usually after a drug overdose as the compression of the muscle for an extended time restricts the blood circulation in the area, and leads to rhabdomyolysis, which then causes myoglobinuria. Myoglobinuria also can be seen after viral infections, administration of cholesterol-lowering drugs known as statins, certain anaesthetic agents, cocaine, amphetamines, heroin, alcoholism with subsequent muscle tremors, tetanus, heat stroke, electrolyte disturbances and fractures. Excessive muscular activity also has been implicated in reports of myoglobinuria in athletes (such as long-distance runners and skiers) and military recruits. Status epilepticus, electroconvulsive therapy and high-voltage electrical shock are also associated with severe and sometimes fatal myoglobinuria. PATHOPHYSIOLOGY
The primary requirement to develop myoglobinuria is damage to muscle fibres allowing the release of myoglobin. This damage may occur directly, as in the case of trauma, or as a result of any event that injures the sarcolemma. In the case of compartment syndromes the usual cause is ischaemia. The muscles of the limbs are organised within their non-elastic fascias. Many of the blood vessels (and nerves) are located deep to the fascia (see Fig. 21.6). Thus any event (like a fracture, direct trauma with bleeding and
Posterior tibial neurovascular bundle Fascia
Deep posterior compartment
1 Superficial posterior compartment
Fibula
2
3
Interosseous membrane
Lateral compartment Anterior compartment
Tibia Anterior tibial neurovascular bundle
4
FIGURE 21.6
The muscle compartments of the lower leg. The muscle compartments consist mainly of the (1) superficial, (2) deep posterior, (3) lateral and (4) anterior compartments.
swelling) that raises the pressure within the fascia can result in a compartment syndrome, as the pressure increases within the enclosed space of the muscle compartment. An increase in compartment volume may be caused by haematoma associated with a fracture or trauma and associated inflammation causing oedema. Even the weight of a limp extremity can generate enough pressure to reduce venous return. With continuing arterial supply the volume of the compartment increases. Whatever the cause, as the pressure within the compartment rises, the circulation becomes further compromised. Muscle necrosis occurs within 4–8 hours after releasing myoglobin. The myoglobin is toxic to the tubular cells of the kidneys. The pathogenesis of compartment syndrome and crush syndrome is outlined in Fig. 21.7. CLINICAL MANIFESTATIONS
When myoglobin is released from the muscle cells into the circulation, it can cause a visible, dark reddish brown pigmentation of the urine.7 Only 200 grams of muscle need be damaged to cause visible changes in the urine. The damaged cells also release intracellular enzymes, potassium and phosphate into the serum. One of the enzymes, creatine kinase (involved in creating phosphocreatine, a rapidly available energy source in skeletal muscle and the brain), may reach 2000 times normal levels (normal levels are 5–25 U/mL for women and 5–35 U/mL for men). The risk of renal failure correlates directly with the amount of serum creatine kinase, potassium and phosphorus levels in the blood. The most significant clinical manifestation of acute compartment syndrome is unresolved and disproportionate pain associated with changes to the neurovascular status of the involved limb.
CHAPTER 21 Alterations of musculoskeletal function across the life span
523
Local pressure Initial events
leading to Local tamponade resulting in Muscle/capillary necrosis further promoting
promoting Oedema contributing to
Rising compartment pressure causing Neural injury Compartment tamponade compressing compressing nerves blood vessels
Muscle ischaemia
CONCEPT MAP
Limb compression causes
Compartment syndrome
releasing potassium
leading to
Muscle infarction releasing myoglobin resulting in
Myoglobinaemia precipitating Renal failure leading to
Acidosis/hyperkalaemia ECF shift causing promoting
Crush syndrome
Cardiac arrhythmia Shock contributing to
FIGURE 21.7
The pathogenesis of compartment syndrome and crush syndrome caused by prolonged muscle compression. ECF = extracellular fluid.
EVALUATION AND TREATMENT
The manifestation of myoglobinuria for those with the genetic condition of malignant hyperthermia occurs during anaesthesia. Clinicians need to carefully assess the background of these individuals to diagnose potential malignant hyperthermia — a family history of anaesthetic problems and previous untoward anaesthetic experiences (muscle cramping, unexplained fevers, dark urine) are criteria that require further clarification before administration of a volatile halogen anaesthetic, such as isoflurane, or the muscle relaxant succinylcholine. Priorities in treatment of myoglobinuria include identifying and treating the underlying disorder and preventing life-threatening renal failure. Malignant hyperthermia and myoglobinuria can be treated by infusing dantrolene sodium. Diluting the pigment using intravenous fluids and administration of mannitol, sodium bicarbonate and frusemide to ‘flush’ the kidneys have been advocated to prevent renal failure. Secondary problems include electrolyte imbalance, volume depletion, acidosis, hyperuricaemia, hyperkalaemia and calcium imbalance. These imbalances need specific treatment. Short-term dialysis may also be necessary.
Compartment syndromes may require emergency treatment when blood flow to the affected extremity is compromised because of increased compartmental pressure, leading to ischaemia and oedema.8 When clinical evaluation is inconclusive, the rising compartment pressure can be directly measured by inserting a wick catheter, needle or slit catheter into the muscle. Pressures greater than 30 mmHg (normal = 0–8 mmHg) impair capillary flow.9 When conservative treatment fails to relieve the pressure, a fasciotomy may be necessary.9 In this procedure the fascia is incised parallel to the muscle to reduce the intracompartmental pressure. Because of the risk of infection and the added complication of wound closure, this procedure is one of last resort. Compartments often affected are the anterior tibial and deep posterior tibial compartments in the leg and the gluteal compartments in the buttocks. FOCU S ON L EA RN IN G
1 Describe the process of fracture repair. 2 Compare and contrast the repair processes involved with strains and sprains.
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Disorders of bone and joints Metabolic bone disease
Metabolic bone disease is a generalised term that accounts for a range of disorders characterised by abnormal bone structure that is caused by an altered metabolism, which may be the result of genetics, diet or hormones. These disorders often cause disability that becomes worse with ageing. In Australia, approximately 30% of the population had arthritis, and other musculoskeletal disorders affect 6.9 million people.10
Osteoporosis
As the populations of Australia and New Zealand age, the incidence of osteoporosis will increase. In an Australian
2015 fact sheet 9% of the population over 50 years of age was identified as having osteoporosis.11 Osteoporosis, or porous bone, is a disease in which bone tissue is normally mineralised but the mass (density) of bone is decreased and the structural integrity of trabecular (spongy) bone is impaired. Cortical (compact) bone becomes more porous and thinner, making bone weaker and prone to fractures (see Figs 21.8 and 21.9). The World Health Organization (WHO) has defined postmenopausal osteoporosis based on bone density.12 Individual bone density is compared with the mean bone mineral density of a young-adult reference population; in other words, the degree of loss of bone mineral density (osteoporosis) is compared to the optimal level of that of a young adult. Fig. 21.10 shows the progression from normal bone mineral density to severe osteoporosis. The disease can be: (1) generalised, involving Normal bone mineral density
Low bone density (osteopenia)
Osteoporosis
Severe osteoporosis
FIGURE 21.8
Vertebral body. Osteoporotic vertebral body (right) shortened by compression fractures compared with a normal vertebral body. Note that the osteoporotic vertebra has a characteristic loss of horizontal trabeculae and thickened vertical trabeculae.
NORMAL
FIGURE 21.10
The progression from normal bone mineral density through various stages to severe osteoporosis. With each stage, there is further loss of bone mineral density.
OSTEOPENIA
OSTEOPOROSIS
SEVERE OSTEOPOROSIS
Compact (cortical bone)
Spongy (trabecular bone)
FIGURE 21.9
Osteoporosis in cortical and trabecular bone. While both compact and trabecular (spongy) bone vulnerable to osteoporosis, the effects on the trabecular bone can appear to be worse to the loss of the trabecules or beams of bone tissue.
CHAPTER 21 Alterations of musculoskeletal function across the life span
major portions of the axial skeleton; or (2) regional, involving one segment of the appendicular skeleton. Throughout a lifetime bone responds to the stresses placed on it through the process of remodelling (see Chapter 20). This process involves removal of old bone (resorption) and creation of new bone (formation). Weight-bearing exercise increases bone mineral density. During childhood and the teenage years, new bone is added faster than old bone is removed. Consequently, bones become larger, heavier and denser. Peak bone mass or maximum bone density and strength is reached around age 30. After age 30, bone resorption slowly exceeds bone formation. In women, bone loss is most rapid in the first years after menopause, but persists throughout the postmenopausal years.13 Men lose bone density with ageing but because they begin with a higher bone density and their rate of loss is less than that of women, they reach osteoporotic levels at an older age than do women (see Research in Focus: Osteoporosis in men). The major risks for those with osteoporosis are fractures. By the age of 90, about 17% of males have had a hip fracture, compared with 32% of females. Over half of all adults hospitalised for hip fracture do not return to their former level of functioning.14 In Australia the lifetime risk of a fracture due to osteoporosis after 50 years of age is 42% for women and 27% for men.15 Vertebral fractures also occur in the later years of life; however, they are more difficult to ascertain because people are unaware of the fracture. The degree of compression necessary to define a vertebral fracture is not standardised.15 Thus, the true prevalence is unknown, but fractures do increase in frequency by the sixth and seventh decades. Vertebral fracture prevalence in men is close to that in women.16 Osteoporosis is the foremost underlying cause of fractures in the elderly. It affects more than half of women aged 60 and older and nearly one-third of men aged 60 and older in both New Zealand17 and Australia.18 Total costs related to osteoporosis are estimated at A$7 billion annually in Australia19 and at NZ$1.5 billion annually in New Zealand.20 Osteoporosis is most common in smaller statured people. Interestingly, larger people have a lower incidence of osteoporosis because their skeletons have become more massive through the process of remodelling and achieved a higher peak bone mass.21 The cause of generalised osteoporosis remains uncertain. Bone strength is not defined by bone mass alone (as measured by bone mass density) but also by the microscopic structure of the bone. Thus, other variables include mineral crystal size and shape, brittleness, vitality of the bone cells, structure of the bone proteins, integrity of the trabecular network and the ability to repair tiny cracks.22,23 In spongy bone, the positioning of trabecular structures is important in providing strength. Because bone density relates to quantity of bone, quality of bone is not accurately identified by bone density testing. Therefore, bone density testing may or may not accurately identify those who will go on to suffer a fracture.
RESEARCH IN F Osteoporosis in men
525
CUS
With the emphasis on osteoporosis in women, the cellular and molecular aspects of male idiopathic osteoporosis (idiopathic meaning cause unknown) are poorly understood. The major difference in bone physiology between males and females is in the level of gonadal hormones. Although hypogonadism is related to bone loss in men, and androgen levels decline with age in men, it is not at all clear that reduced androgen levels are related to bone loss in older men. Testosterone is possibly anabolic at the bone level, and testosterone increases muscle mass, which indirectly results in higher bone density. In peripheral tissue, testosterone is converted to oestrogen, which prevents excessive bone resorption. Oestrogen is necessary to bone in men as well as in women. Men who have a deficiency of the enzyme that converts testosterone to oestrogen develop osteoporosis and are excessively tall because of the failure to fuse growth plates. Thus, oestrogen plays a vital role in the maintenance of bone in men as well as women. Guidelines produced in the United States in 2016 show that the risk of fractures is increased in both men and women taking glucocorticoid medications that is usually controlled by use of antiresorptive therapy. The use of antiresorptive therapy is recommended at a bone mineral density (T-score) of less than -2.5 or a history of hip or spine fracture. Long term use of this therapy increases the risk of atypical femur fractures that can be reduced in women, or men taking glucocorticoid therapy, who achieve a bone mineral density greater than -2.5 and have no other risk factors by having a ‘holiday’ from the medication for 2 to 3 years.
Osteoporosis is a complex, multifactorial chronic disease that often progresses silently for decades until fractures occur. It is the most common disease that affects bone. It is not necessarily a consequence of the ageing process because some elderly people retain strong, relatively dense bones.24 A progressive loss of bone mass may continue until the skeleton is no longer strong enough to support itself. Eventually, bones can fracture spontaneously. As bone becomes more fragile, falls or bumps that would not have caused fracture previously now do cause a fracture. Osteoporosis appears to be most severe in the spine, wrists and hip (see Fig. 21.11). Postmenopausal osteoporosis is bone loss that occurs in middle-aged and older women. It can occur because of oestrogen deficiency as well as oestrogen-independent age-related mechanisms (e.g. secondary causes such as hyperparathyroidism and decreased mechanical stimulation) (see Fig. 21.12). Oestrogen deficiency can also increase with stress, excessive exercise (particularly weight-bearing activities) and low body weight. Postmenopausal changes include a substantial increase in bone removal. There is an imbalance between the activities of the osteoclasts (bone
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A
B
FIGURE 21.11
Osteoporosis as a result of disuse. A X-ray taken just before wrist ligament reconstruction. B X-ray obtained 2 months later. Notice the extent of the osteopenia evident in the second image.
Genetic factors Physical activity
Nutrition
PEAK BONE MASS
MENOPAUSE • Decreased serum oestrogen • Increased IL-1, IL-6, TNF levels • Increased osteoclast activity
AGEING • Decreased replicative activity of osteoprogenitor cells • Decreased synthetic activity of osteoblasts • Decreased biological activity of matrix-bound growth factors • Reduced physical activity
OSTEOPOROSIS FIGURE 21.12
The pathophysiology of postmenopausal and senile osteoporosis. Factors which can contribute to the decline of bone density after menopause include lowering of oestrogen levels with increased osteoclast activity (which cause bone resorption). Factors which contribute to further decline of bone density with increased age include loss of function of the osteoblasts (which cause bone deposition) and decreased physical activity.
destroyers) and osteoblasts (bone formers). Oestrogen helps osteoclast apoptosis (programmed cell death), so its decline is associated with survival of the bone-removing osteoclasts. Other causes may include a combination of inadequate dietary calcium intake and lack of vitamin D, possibly decreased magnesium, lack of exercise (particularly weight-bearing exercise), low body mass and family history.25
Excessive phosphate intake, chiefly through the intake of soft drinks and junk foods, interferes with the calcium/ phosphate balance. Glucocorticoids (e.g. cortisone) also induce osteoporosis. Oestrogen replacement (through hormone replacement therapy, known as HRT) can slow bone loss around the time of menopause; however, osteoporosis and fractures are still common in older women who have used oestrogen continuously since menopause.25,26 It has been found that serum androgens may influence bone density in women. Androgens (i.e. testosterone) have long been recognised as stimulants of bone formation. Increasing age in both men and women is associated with declining levels of oestrogen and androgen, leading to losses in bone mineral density.27 In addition, progesterone deficiency may be related to osteoporosis. Decreases in weight-bearing exercise are associated with osteoporosis as well. Other risk factors are identified in Box 21.1. Intake of dietary minerals is important for skeletal health. Reduced intake or malabsorption of dietary minerals is a factor in the development of osteoporosis.28 Calcium absorption from the intestine decreases with age and studies of individuals with osteoporosis show that their calcium intake is lower than that of age-matched controls. Other mineral deficiencies may also be important, including magnesium. Deficiencies of vitamins, particularly vitamins C and D, and both deficiencies and excesses of protein also contribute to bone loss. Excessive intakes of caffeine, phosphorus, alcohol and nicotine along with low body weight (less than 57 kg) have also been considered risk factors. In addition, significant differences in the trace elements (zinc, copper, manganese) have been noted in the bones and hair of unaffected individuals compared to those with osteoporosis.29 Skeletal homeostasis depends on a narrow range of plasma calcium and phosphate concentrations, which are maintained by the endocrine system. Therefore, endocrine dysfunction ultimately can cause metabolic bone disease. In addition to declining levels of sex steroids, the hormones most commonly associated with osteoporosis are parathyroid hormone, cortisol, thyroid hormone and growth hormone (see Fig. 21.13). (Endocrine function is discussed in Chapters 10 and 11.) PATHOPHYSIOLOGY
It has been emphasised that remodelling is a normal feature of bone. Osteoclasts (bone-destroying cells) and osteoblasts (bone-building cells) are continually working to maintain bone with a structure that is responsive to, and structurally able to withstand the stresses it experiences. To understand osteoporosis it is useful to have some knowledge of the interrelationship between osteoclasts and osteoblasts. Ultimately the number of osteoblasts is controlled by hormones, cytokines (intracellular communication molecules that control cell activity — cyto for cell and kines for action) and other chemical messengers. There is one cytokine that appears particularly important. It exerts its effect by binding to a receptor on osteoclast precursor cells (cells
CHAPTER 21 Alterations of musculoskeletal function across the life span
BOX 21.1
Risk factors for osteoporosis
Genetic • Family history of osteoporosis • Family origins from any of the original peoples of Europe, the Middle East or North Africa • Increased age • Female sex Anthropometric • Small stature • Thin build • Low bone mineral density Hormonal and metabolic • Early menopause • Late menarche • Nulliparity (not bearing offspring) • Obesity • Cushing’s syndrome • Weight below healthy range • Acidosis • Hyperparathyroidism Dietary • Low dietary calcium and vitamin D • Low endogenous magnesium • Excessive sodium intake • High caffeine intake • Anorexia • Malabsorption Lifestyle • Sedentary • Smoker • Alcohol consumption (excessive) • Low-impact fractures as an adult • Inability to rise from a chair without using one’s arms Illness and trauma • Renal insufficiency • Rheumatoid arthritis • Spinal cord injury • Systemic lupus Drugs • Corticosteroids • Dilantin • Gonadotrophin-releasing hormone agonists • Aromatase inhibitors • Loop diuretics • Methotrexate • Heparin • Cyclosporin
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that combine to form osteoclasts) causing them to multiply and become activated. The bone matrix creates a decoy receptor for this same cytokine. If the cytokine binds to the decoy receptor there will be no effect on the osteoclasts. Thus the balance between the amounts of cytokine, the number of receptors on the osteoclast precursors and the number of decoy receptors determines the rate at which bone is resorbed. Any alteration to this balance can lead to osteoporosis. Glucocorticoid-induced osteoporosis is characterised by increased bone resorption and decreased bone formation. Glucocorticoids (e.g. cortisone) increase formation of the cytokine and reduce production of its decoy receptor by osteoblasts. Age-related bone loss begins in the fourth decade. The cause remains unclear, but it is known that decreased serum growth hormone and insulin-like growth factor levels (both of which stimulate osteoclasts), along with increased binding of the cytokine and decreased production of the decoy receptor, affect osteoblast and osteoclast function. Loss of trabecular bone in men proceeds with thinning of trabecular bone rather than complete loss, as is noted in women (see Fig. 21.14).30 Men have approximately 30% greater bone mass than women, which may be a factor in their later involvement with osteoporosis (see Fig. 21.15). In addition, men have a more gradual decrease in testosterone and oestrogen (and possibly progesterone), thereby maintaining their bone mass longer than women.31 The reduction in weight-bearing activity with increasing age is another factor promoting bone loss. CLINICAL MANIFESTATIONS
The specific clinical manifestations of osteoporosis depend on the bones involved. The most common manifestations, however, are pain and bone deformity. Unfortunately the condition develops insidiously and these manifestations occur only in an advanced disease state. By the time a person experiences symptoms there is little possibility of them being able to reverse the effect of bone loss to previous levels. Fractures are likely to occur because the trabeculae of spongy bone become thin and sparse and compact bone becomes porous. As the bones lose volume, they become brittle and weak and may collapse or become misshapen. Vertebral collapse causes kyphosis (from the Greek kyphos meaning hump) and diminishes height (see Fig. 21.16). Fractures of the long bones (particularly the femur and humerus), distal radius, ribs and vertebrae are most common. Fracture of the neck of the femur — a broken hip — tends to occur in older or elderly women with osteoporosis. Fatal complications of fractures include fat or pulmonary embolism, pneumonia, haemorrhage and shock. Approximately 20% of individuals may die as a result of surgical complications. Male osteoporosis is usually secondary osteoporosis. The following seem to help prevent primary osteoporosis: adequate dietary intake of calcium, vitamin D, magnesium and possibly boron; a regular regimen of weight-bearing exercise; and avoidance of tobacco, glucocorticoids and alcoholism.
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CONCEPT MAP
Sun exposure Age Dietary intake of vitamin D cause Calcium intake
leads to
Production or effect of dihydroxyvitamin D resulting in Intestinal calcium absorption
Physical activity
stimulating causes Secretion of growth hormone or anabolic steroids
Vitamin K intake or effectiveness
leads to
PTH secretion
Hypo-oestrogenism leading leading to leads to to Enhanced osteoclast activity (excessive bone resorption)
Impaired osteoblast actions (decreased bone formation) result in
causing Inflammation
Bone loss FIGURE 21.13
The pathophysiology of osteoporosis. The changes that lead to bone loss. Dihydroxyvitamin D = vitamin D component that aids calcium absorption; PTH = parathyroid hormone.
Men
Trabecular bone
Old
Young Women
Net bone loss
Men
Absolute amount of bone
Formed
Old Women
Perforation
Resorbed
Resorbed
Thinning FIGURE 21.15
FIGURE 21.14
The mechanism of loss of trabecular bone in women and trabecular thinning in men. Bone thinning predominates in men because of reduced bone formation. Loss of connectivity and complete trabeculae predominates in women.
Bone loss in men and women. The absolute amount of bone resorbed on the inner bone surface and formed on the outer bone surface is more in men than in women during ageing.
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A
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B
FIGURE 21.16
Kyphosis. A This elderly woman’s condition was caused by a combination of spinal osteoporotic vertebral collapse and chronic degenerative changes in the vertebral column. B The x-ray demonstrates the marked curvature of the spine seen in kyphosis. The head and neck are bent forward and the total chest volume is markedly reduced.
EVALUATION AND TREATMENT
Generally, osteoporosis is detected on x-rays as increased radiolucency (transparency) of bone. By the time abnormalities are detected by radiological examination, up to 25–30% of bone tissue may have been lost. Dual x-ray absorptiometry (DXA) (commonly known as the bone density test) is the gold standard for detecting and monitoring osteoporosis. Ultrasound is more cost effective but it does not directly measure the fracture risk sites. Quantitative CT scans are also helpful. Other evaluation procedures include tests for levels of serum calcium, phosphorus and alkaline phosphatase and protein electrophoresis. Serum and urinary biochemical markers are useful in monitoring bone turnover.12 The goals of osteoporosis treatment are to slow down the rate of calcium and bone loss and to stop the deterioration before it progresses too far. Treatment includes increasing the dietary intake of calcium to 1500 mg/day along with vitamin D supplements to increase the intestinal absorption of calcium. High intake of phosphorus may neutralise calcium, interfering with its benefits. Magnesium supplementation may increase bone growth by stimulating cytokine activity in bone.32,33 Postmenopausal women may be given oestrogen and progestins to prevent bone loss. However, combined oestrogen–progestin therapy increases the risk for invasive breast cancer, and may increase the risk for heart disease (see ‘Women and coronary heart disease’ in Chapter 23), stroke and pulmonary embolism, and therefore is not warranted for routine osteoporosis prevention although the
risk of some disease may not be as high as previously thought. Other steroid agents — for example, raloxifene, a selective oestrogen receptor modulator that provides the beneficial effects of oestrogen on bone without the negative effects on breast and endometrial tissue — may also be prescribed. Regular, moderate weight-bearing exercise can slow down the bone loss and, in some cases, reverse demineralisation because the mechanical stress of exercise stimulates bone formation. It is important to reduce the risk of falls and enhance bone quality. An exercise program to enhance strength has the added benefits of reducing the risk of falls and promoting bone quality. The elderly population are at a greater risk of falls due to normal changes associated with ageing such as worsening eyesight, inner ear related imbalances, touch sensitivities and slowing response times. These normal changes when combined with other risk factors can increase the risk of falls and contribute to a much higher incidence of fall-related trauma. The consequence of a simple fall that results in a fragility fracture can be severe. Following a fracture of the proximal femur up to 28% of sufferers will die within one year and 24–75% of individuals will not return to their pre-fracture level of independence.34 New medications formulated to prevent or treat osteoporosis are currently being prescribed and evaluated. There are new treatments that may rebuild the skeleton. The anabolic or bone-building drug parathyroid hormone has been widely studied and the results are encouraging. Parathyroid hormone directly stimulates bone formation, particularly in trabecular bone.35
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RESEARCH IN F CUS Current treatments for osteoporosis Over the last 15 years a number of newer pharmaceutical treatment options have been developed and released for use in the treatment of osteoporosis. Previously the standard treatment was hormone replacement therapy which more recently has been shown to increase, in some groups, the risk of cancer, cardiac disease and venous thromboembolism. The first of the newer treatment options were the bisphosphonates group such as alendronate, risedronate, ibandronate and zoledronic acid which act to limit osteoclast bone resorption. A number of earlier medications had demonstrated some increased adverse outcomes and required specific administration regimens such as administering the medication early in the day and ensuring the person was sitting upright. Some of the newer generation of medications such as denosumab, raloxifene and calcitonin also act to reverse or slow bone loss. These too have some limitations in treatment times and there is debate about increased risk of some cancers and the benefit of longer-term treatment. Medications such as teriparatide, a type of parathyroid hormone, act to stimulate bone growth but can also have side effects that limit their use in treatment to 2 years. The use of calcium and vitamin D supplements should continue in the treatment of osteoporosis as well as the maintenance of a balanced diet (high in calcium), appropriate exposure to sunlight and regular weight-bearing exercise. The American Society for Bone and Mineral Research has recommended that for patients with a low risk of fracture therapy and a higher bone density, treatment can be discontinued after 3–5 years. Some of the medications will remain stored in the skeletal system and continue to influence bone loss for years following discontinuation of the medication. For those individuals with a higher risk of fracture and a lower bone density consideration of long-term treatment or medication change is advised. Some researchers are investigating other more ‘natural’ non-pharmaceutical alternatives for the treatment of osteoporosis.
PAGET’S DISEASE
Paget’s disease (osteitis deformans) is a state of increased metabolic activity in bone characterised by abnormal and excessive bone remodelling, both resorption and formation. Chronic accelerated remodelling eventually enlarges and softens the affected bones. Paget’s disease can occur in any bone but most often affects the vertebrae, skull, sacrum, sternum, pelvis and femur. The disease process may occur in one or more bones without causing significant clinical manifestations. Paget’s disease occurs with increasing frequency in people as they age; it is rarely identified before 50 years of age and reaches a prevalence of almost 10% in the ninth decade of life. Men are more often affected than women at a ratio of 1.8 to 1. The disease is often symptomless and diagnosis is made
by x-ray and radioisotope bone scan. Autopsy data from England and Germany indicate that approximately 3–4% of the population older than 40 years of age have Paget’s disease. It is most prevalent in Australia, Great Britain, New Zealand and the United States. The disease affects several members of the same family in 5–25% of cases. The cause of Paget’s disease is unknown, but there appears to be a strong genetic component.36 A viral connection to Paget’s disease has also been proposed.37 PATHOPHYSIOLOGY
Paget’s disease is a focal process that begins with frantic excessive osteoclastic resorption of spongy bone, followed by furious deposition of bone by large numbers of osteoblasts. The deposited bone is disorganised rather than lamellar and is soft as a result. The trabeculae diminish and bone marrow is replaced by extremely vascular fibrous tissue. Paget’s disease causes lesions that may be solitary or occur in multiple sites. Lesions tend to localise in the axial skeleton, including the skull, spine and pelvis. If the disease becomes more widespread, the proximal femur and tibia may become involved. CLINICAL MANIFESTATIONS
Paget’s disease varies in presentation from a single lesion to involvement of multiple bones. The manifestations depend on which bones are affected. In the skull, abnormal remodelling is first evident in the frontal or occipital regions; then it encroaches on the outer and inner surfaces of the entire skull. The skull thickens and assumes an asymmetric shape. Thickened segments of the skull may compress areas of the brain, producing altered mentality and dementia. Growth of new bone putting pressure on cranial nerves causes sensory abnormalities, impaired motor function, deafness (because of involvement of the middle ear ossicles or compression of the auditory nerve), atrophy of the optic nerve and obstruction of the lacrimal duct. As a result, headache is commonly noted. In the spinal column the vertebral bodies collapse leading to kyphosis. In long bones, resorption begins in the subchondral regions of the epiphysis and extends into the metaphysis and diaphysis. Softening of the femur and tibia causes them to bow. Stress fractures are common in the lower extremities and they often heal poorly with excessive and poorly distributed callus. EVALUATION AND TREATMENT
Evaluation of Paget’s disease is made on the basis of characteristic bone deformities and radiographic findings of irregular bone trabeculae with a thickened and disorganised pattern. Early disease is detected by bone scanning that shows increased metabolic activity. Alkaline phosphatase and urinary hydroxyproline (a derivative of the amino acid proline, involved in collagen production) are elevated. Many individuals require no treatment if the disease is localised and not symptomatic. Treatment during active disease is for pain relief, prevention of deformity or fracture. Bisphosphonates are the treatment of choice: they bind to bone minerals, rapidly reducing resorption.
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Osteochondroses The osteochondroses are a series of childhood diseases involving areas of significant tensile or compressive stress (i.e. tibial tubercle, Achilles insertion, hip). They are characterised into two groups according to cause. The first group are caused by localised death of bone (osteonecrosis) in an apophyseal or epiphyseal centre (e.g. Legg-Calvé-Perthes disease), while the second group is the result of abnormalities of mineralisation of cartilage due to a genetically determined normal variation or trauma (e.g. Osgood-Schlatter disease). Legg-Calvé-Perthes disease Legg-Calvé-Perthes disease is a common osteochondrosis usually occurring in children between the ages of 3 and 10 years, with a peak incidence at 6 years. The disorder affects both legs in 10–20% of children and boys are affected five times more often than girls, perhaps because boys have a more poorly developed blood supply to the femoral head (hip joint) than do girls of the same age. The role of genetics is unclear, but family history is positive in 20% of cases. This disease which runs its natural course in 2–5 years, is presumably produced by recurrent interruption of the blood supply to the femoral head. The ossification centre first becomes necrotic (osteonecrosis) and then is gradually replaced by live bone. Several causative theories have been proposed, including a generalised disorder of epiphyseal cartilage growth, thyroid deficiency, trauma, infection and blood-clotting disorders. However increases in thrombotic disorders in children with Legg-Calvé-Perthes were not found. Children are often delayed in skeletal age by 2 years, making some believe that Legg-Calvé-Perthes is actually a systemic skeletal dysplasia. Another study has shown the risk of Legg-Calvé-Perthes is five times greater in children exposed to passive smoke than those who are not. Joint space (black area)
Femoral Epiphyseal head plate
The primary feature of Legg-Calvé-Perthes is an avascular necrosis of the epiphyseal growth centre in the femoral head. The disease has four stages: 1 In the first (incipient) stage lasting several weeks, the synovial membrane and joint capsule are swollen, due to oedema (fluid accumulation) and hyperaemia (an increased blood supply; see Fig. 21.17). 2 In the second (necrotic) stage (lasting 6–12 months), there is death of bone tissue, such that the femoral head actually shrinks. The epiphyseal centre also becomes necrotic. 3 In the third (regenerative) stage lasting 1–3 years, the dead femoral head assumes a more normal shape as it is replaced by procallus formation. The procallus consists of early stages of healing, and progresses to include substances needed for mature bone, including fibrous connective tissue matrix, deposition of collagen and calcification. 4 During the fourth (residual) stage the femoral head is remodelled and the newly formed bone is organised into spongy bone. Injury or trauma precedes the onset in approximately 30–50% of children with Legg-Calvé-Perthes. For several months the child complains of a limp and pain that can be referred to the knee, inner thigh and groin. The pain is usually aggravated by activity and relieved by rest and anti-inflammatory drugs. The typical physical findings include spasm on rotation of the hip, limitation of internal rotation and abduction (movement away from the centre of the body) and hip flexion–adduction deformity. If the child is walking, an abnormal gait termed an antalgic abductor lurch, or ‘Trendelenburg’ gait, is apparent. Associated muscle atrophy may occur. The goals of treatment are to reduce deformity, preserve the soundness of the femoral head and acetabulum, and maintain spasm-free and pain-free range of motion in the
Necrotic bone
Procallus
Remodelled bone
Metaphysis Cyst
Femoral neck Normal hip joint
Incipient stage
Necrotic stage Regenerative stage Residual stage
FIGURE 21.17
Stages of Legg-Calvé-Perthes disease, a form of osteochondrosis. This disease is characterised by loss of normal bone tissue which is eventually remodelled over time. Continued
PAEDIATRICS
Paediatrics and disorders of bones
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hip joint. Currently, most children can be managed with anti-inflammatory medications and activity modification during periods of synovitis (inflammation of the synovial membrane). Serial radiographs over a number of years are obtained to monitor the progress of the disease and to ensure that the femoral head remains in contact with the acetabulum. Surgery may be necessary if the femoral head becomes subluxated or displaced from its normal position in the acetabulum (see Figs 21.18 and 21.19). Children older than 6 years of age (by bone age) have a worse prognosis due to poorer remodelling potential. Older children require surgery more often to avoid poor structural agreement of the femoral head in the acetabulum (congruence). Poor congruence predisposes to early osteoarthritis, with nearly 50% requiring hip arthroplasty by age 40. Osgood-Schlatter disease Osgood-Schlatter disease causes microfractures of the tubercle of the tibia (the insertion point of the patellar tendon) and associated patella tendonitis. The disease occurs most often in preadolescents and adolescents who participate in sports and is more prevalent in boys than in girls. It is one of the most common ailments reported in adolescents involved in sports. The severity of the lesion varies from mild tendonitis to a complete separation of part of the tibial tubercle. The mildest form of Osgood-Schlatter disease causes ischaemic (avascular) necrosis in the region of the tibial tubercle,
with excessive cartilage formation during the stages of repair. In more severe cases, the abnormality involves a true apophyseal separation of the tibial tubercle with avascular necrosis. The child complains of pain and swelling in the region around the patellar tendon and tibial tubercle, which becomes prominent and is tender to direct pressure. The pain is most severe after physical activity that involves vigorous quadriceps contraction (jumping or running) or direct local trauma to the tibial tubercle area. The goal of treatment is to decrease the stress at the tubercle. Often a period of 4–8 weeks of restriction from strenuous physical activity is sufficient. Bracing with a tubercle band can be very helpful. If the pain is not relieved, a cast or knee immobiliser is required, a situation that is particularly difficult if the condition is bilateral. Gradual return to activity is permitted after 8 weeks, but a further 8 weeks is necessary before strenuous physical activity to allow for revascularisation, healing and ossification of the tibial tubercle. With skeletal maturity and closure of the apophysis, Osgood-Schlatter disease resolves. Scoliosis Scoliosis is principally a lateral deviation of the spine. There are three main types of scoliosis: (1) idiopathic (unknown cause); (2) congenital (due to bone deformity); and (3) teratological (because of another systemic syndrome such as cerebral palsy). Eighty per cent of all
FIGURE 21.18
FIGURE 21.19
Pelvis of a 7-year-old boy with Legg-Calvé-Perthes disease. The femoral head is flat and extruded from the edge of the joint. This hip is at risk for early arthritis if left to revascularise and heal in this position.
Surgical replacement of the femoral head of a 7-year-old boy with Legg-Calvé-Perthes disease. As the Perthes heals, the ball has taken on a round shape that matches the socket well.
CHAPTER 21 Alterations of musculoskeletal function across the life span
scoliosis is idiopathic, which may have a genetic component. True structural scoliotic deformity involves not only a side-to-side curve but also rotation; curves without rotation may result from another cause such as unequal limb length or splinting from pain (see Fig. 21.20). Although girls and boys are equally affected, once the curve becomes more than 20°, girls are five times more likely to be affected. Ninety-eight per cent of curves are apex right thoracic. If a left thoracic curve appears in the adolescent with idiopathic scoliosis, MRI is performed to rule out a neurological aetiology. MRI should also be used to assess kypho- (round back) scoliosis, loss of abdominal reflexes, children who also have exertional headaches or a congenital curve. Idiopathic curves increase while a child is growing and progression can be very rapid during growth spurts. When idiopathic curves become 25° or greater and the child is skeletally immature, bracing is required. Curves of more than 50° will progress after skeletal maturity, so spinal fusion is required to stop progression. Early diagnosis is therefore necessary so that bracing can be attempted in the hope of halting progression before the need for surgery. Children are required to wear the brace for 16 hours per day and gaining full compliance can be difficult. Nevertheless, bracing is the only non-operative measure known to slow scoliotic progression. Chiropractic manipulation,
F O CUS O N L E A R N IN G
1 Discuss the development of osteoporosis. 2 Compare and contrast osteoporosis and Paget’s disease. 3 Describe the pathophysiology of Legg-Calvé-Perthes disease. 4 Discuss the development of Osgood-Schlatter disease.
Disorders of joints
Joint disorders are usually accompanied by joint inflammation and hence may be referred to as inflammatory joint diseases. Interestingly, osteoarthritis has been previously referred to as a non-inflammatory joint disease; however, because there are some inflammatory processes involved, osteoarthritis may now be referred to as an inflammatory condition.38
Inflammatory joint disease
Inflammatory joint disease is commonly called arthritis. Typical of inflammatory joint disease is inflammatory damage or destruction in the synovial membrane or articular cartilage and systemic signs of inflammation:
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physical therapy, exercise and diet regimens have not been shown to alter natural history. Bracing is less successful in teratological or congenital curves; therefore, these conditions may require surgical intervention more often.
FIGURE 21.20
Idiopathic scoliosis. Scoliosis screening involves viewing the individual from behind, which discloses scapular asymmetry caused by not only curvature but also true rotation of the spine.
fever, leucocytosis (elevated numbers of leucocytes), malaise, anorexia and increased levels of fibrinogen in the blood. Inflammatory joint disease can be infectious or non-infectious. In infectious inflammatory joint disease, invasion of the joint by bacteria, mycoplasmas (bacteria without a cell wall), viruses, fungi or protozoa (single-celled animals) causes inflammation. These agents gain access to the joint through a traumatic wound, surgical incision or contaminated needle, or they can be delivered by the bloodstream from sites of infection elsewhere in the body — typically bones, heart valves or blood vessels. There are two causes of non-infectious inflammatory joint disease: (1) inappropriate immune reactions; and (2) deposition of crystals of monosodium urate in the synovial fluid. Rheumatoid arthritis and ankylosing spondylitis (from the Greek ankylos, bent, and spondylos, meaning vertebrae) are non-infectious inflammatory diseases caused by immune reactions and possibly hyper-sensitivity reactions;39,40 gouty arthritis is a non-infectious inflammatory disease caused by crystal deposition. RHEUMATOID ARTHRITIS
Rheumatoid arthritis is a systemic, inflammatory autoimmune disease associated with swelling and pain in
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multiple joints (autoimmune diseases are described in Chapter 15). Because this is an autoimmune condition it tends to have a bilateral presentation and includes systemic symptoms. The condition first affects the synovial membrane, which lines the joint cavity (see Fig. 20.9). Eventually, inflammation may spread to the articular cartilage, fibrous joint capsule and surrounding ligaments and tendons, causing pain, joint deformity and loss of function (see Fig. 21.21). The joints most commonly affected are in the fingers, feet, wrists, elbows, ankles and knees, but the shoulders, hips and cervical spine may also be involved, as well as the tissues of the lungs, heart, kidneys and skin. Rheumatoid arthritis is classified according to factors including the number of joints affected (Box 21.2). Rheumatoid arthritis is estimated to affect over 445 000 Australians with a prevalence rate of 2.1%, the majority (63%) of which are females. Indigenous people have a higher prevalence of the disease at almost double the rate for non-Indigenous individuals.41 In 2007 the prevalence in New Zealand was 3.5% of the population. There is evidence of hormonal involvement because disease symptoms lessen during pregnancy and intensify in the postpartum period. The frequency of rheumatoid arthritis increases from
BOX 21.2
arthritis
A
B
Classification criteria for rheumatoid
American College of Rheumatology/European League Against Rheumatism 2010 criteria 1 Joint involvement (0–5) One medium-to-large joint (0) Two to ten medium-to-large joints (1) One to three small joints (large joints not counted) (2) Four to ten small joints (large joints not counted) (3) More than ten joints (at least one small joint) (5) 2 Serology (0–3) Negative RF and negative ACPA (0) Low positive RF or low positive ACPA (2) High positive RF or high positive ACPA (3) 3 Acute-phase reactants (0–1) Normal CRP and normal ESR (0) Abnormal CRP or abnormal ESR (1) 4 Duration of symptoms (0–1) Less than 6 weeks (0) 6 weeks or more (1) Points are shown in parentheses. Cutpoint for rheumatoid arthritis 6 points or more. Patients can also be classified as having rheumatoid arthritis if they have: (a) typical erosions; (b) long-standing disease previously satisfying the classification criteria. KEY: RF – rheumatoid factor, ACPA – anti-citrullinated protein antibody, CRP – C-reactive protein, ESR – erythrocyte sedimentation rate.
FIGURE 21.21
Rheumatoid arthritis of the hand. A Note swelling from chronic synovitis of the metacarpophalangeal joints, marked ulnar drift, subcutaneous nodules and subluxation of the metacarpophalangeal joints with extension of the proximal interphalangeal joints and flexion of the distal joints. Note also the deformed position of the thumb. B An x-ray of a patient with rheumatoid arthritis. There is joint narrowing (triangles) and lateral deformation.
CHAPTER 21 Alterations of musculoskeletal function across the life span
the third decade onwards, affecting 5% or more of the population aged 70 years and older. Besides inflammation of the joints, rheumatoid arthritis can cause fever, malaise, rash, lymph node or spleen enlargement and Raynaud’s phenomenon (transient lack of circulation to the fingertips and toes). Despite intensive research, the cause of rheumatoid arthritis remains obscure. It is likely to be a combination of genetic factors interacting with inflammatory mediators. Long-term smoking and a positive family history are associated with the development of rheumatoid arthritis.42,43 Rheumatoid arthritis also has seasonal variations and is worse in the winter months.
Pannus Cartilage Synovial fluid
Macrophage
Lymphocytes
Interdigitating cell Subintima
PATHOPHYSIOLOGY
Cartilage damage in rheumatoid arthritis is the result of at least three processes: (1) neutrophils and other cells in the synovial fluid become activated, breaking down the surface layer of articular cartilage; (2) cytokines (see Chapter 12), particularly TNF-α, stimulate the release of pro-inflammatory compounds (especially IL-1) and cause the chondrocytes to attack cartilage; and (3) the synovium digests nearby cartilage, releasing inflammatory molecules. Several types of leucocytes are attracted out of the circulation and to the synovial membrane. The inflammatory phagocytes (neutrophils, macrophages) ingest the immune complexes and are stimulated to release powerful enzymes that degrade synovial tissue and articular cartilage (see Fig. 21.22). The immune system’s B and T lymphocytes are also activated. The B lymphocytes are stimulated to produce more rheumatoid factors (auto-antibodies) and the T lymphocytes produce enzymes that amplify and continue the inflammatory response (see Fig. 21.23). Inflammatory and immune processes have several damaging effects on the synovial membrane. The synovial membrane thickens and puts pressure on nearby small venules, reducing the supply of blood. The reduced circulation, coupled with the increased metabolism from the proliferation and enlargement of the cells in the synovial membrane, leads to a local hypoxia and metabolic acidosis. Acidosis stimulates the release of enzymes from synovial cells into the surrounding tissue that break down tissue, initiating erosion of the articular cartilage and causing inflammation in the supporting ligaments and tendons. Inflammation causes haemorrhage, coagulation and fibrin deposition on the synovial membrane, in the intracellular matrix and in the synovial fluid. Over denuded areas of the synovial membrane, fibrin develops into granulation tissue called pannus. (Granulation tissue is the initial tissue produced in the process of healing; see Chapter 13.) Pannus formation does not lead to synovial or articular regeneration but rather to formation of scar tissue, which immobilises the joint. CLINICAL MANIFESTATIONS
The onset of rheumatoid arthritis is usually insidious, although as many as 15% of cases have an acute onset. Rheumatoid arthritis begins with general systemic
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Plasma cell
FIGURE 21.22
Synovitis. Inflamed synovium showing typical arrangements of macrophages (red) and fibroblastic cells.
manifestations of inflammation, including fever, fatigue, weakness, anorexia, weight loss and generalised aching and stiffness. Local manifestations also appear gradually over a period of weeks or months. Typically, the joints become painful, tender and stiff. Pain early in the disease is caused by pressure from swelling. Later in the disease, pain is caused by sclerosis of subchondral bone and new bone formation. Stiffness usually lasts for about an hour after rising in the morning and is thought to be related to synovitis. Initially the joints most commonly involved are the metacarpophalangeal joints (base of the finger), proximal interphalangeal joints (middle of the finger) and wrists, with later involvement of larger weight-bearing joints. Joint swelling, which is widespread and symmetric, is caused by increasing amounts of inflammatory exudate (leucocytes, plasma, plasma proteins) in the synovial membrane, hyperplasia (an increase in cell numbers) of inflamed tissues and formation of new bone. On palpation, the swollen joint feels warm and the synovial membrane feels boggy. The skin over the joint may have a ruddy, cyanotic hue and may look thin and shiny. An inflamed joint may lose some of its mobility. Even mild synovitis can lead to loss of range of motion, which becomes evident after inflammation subsides. Extension becomes limited and is eventually lost if flexion contractures form. Loss of range of motion can progress to permanent deformities of the fingers, toes and limbs, including ulnar deviation of the hands, boutonnière and swan-neck
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CONCEPT MAP
Antigen — environmental agent, infectious agent? Genetic susceptibility
predisposes
that release cytokines stimulating
leads to Activation of helper T cells and probably B lymphocytes
activating
Synovial macrophages and fibroblasts stimulate
liberating more Cytokines
causing Formation of rheumatoid factor leading to Formation of autoimmune complexes and probable deposition in joint tissue
that Activates osteoclasts
Fibroblasts are stimulated to Chondrocytes Synovial cells
Proliferate
resulting in Joint injury
stimulating Enzyme release
B lymphocytes
ultimately leading to
Pannus formation that damages the Joint destruction Cartilage fibrosis joint leading to
ultimately leading to
FIGURE 21.23
Model of pathogenesis of rheumatoid arthritis. Rheumatoid arthritis is an autoimmune disease of a genetically susceptible host triggered by an unknown antigenic agent. This chronic autoimmune reaction occurs with activation of CD4+ helper T cells, possibly other lymphocytes, and the local release of inflammatory cytokines and mediators that eventually destroys the joint. T cells stimulate cells in the joint to produce cytokines that are key mediators of synovial damage. Apparently, immune complex deposition also plays a role. TNF-α and IL-1, as well as some other cytokines, stimulate synovial cells to proliferate and produce other mediators of inflammation and enzymes that all contribute to destruction of cartilage. Pannus is a mass of synovium and synovial stroma with inflammatory cells, granulation tissue and fibroblasts that grows over the articular surface and causes its destruction.
deformities of the finger joints, plantar subluxation of the metatarsal heads of the foot and hallux valgus (angulation of the great toe towards the other toes). Flexion contractures of the knees and hips are also common. Joint deformities cause the physical limitations experienced by those with rheumatoid arthritis (see Fig. 21.21). Loss of joint motion is quickly followed by secondary atrophy of the surrounding muscles. With secondary muscle atrophy, the joint becomes unstable, which further aggravates joint pathology. Two complications of chronic rheumatoid arthritis are caused by excessive amounts of inflammatory exudate in the synovial cavity. One complication is the formation of cysts in the articular cartilage or subchondral bone. Occasionally, these cysts communicate with the skin surface (usually the sole of the foot) and can drain through
passages called fistulae (singular: fistula). The second complication is rupture of a cyst or of the synovial joint itself, usually caused by strenuous physical activity that places excessive pressure on the joint. Rupture releases inflammatory exudate into adjacent tissues, thereby spreading inflammation. Extrasynovial rheumatoid nodules, or swellings, are observed in areas of pressure or trauma in 20% of individuals with rheumatoid arthritis. Each nodule is a collection of inflammatory cells surrounding a central core of fibrinoid and cellular debris. T lymphocytes are the main leucocytes in the nodule. B lymphocytes, plasma cells and phagocytes are found around the edges. Nodules are most often found in subcutaneous tissue over the extensor surfaces of the elbows and fingers. Less common sites are the scalp, back, feet, hands, buttocks and knees.
CHAPTER 21 Alterations of musculoskeletal function across the life span
Rheumatoid nodules may also invade the skin, cardiac valves, pericardium, pleura, lung tissue and spleen. These nodules are identical to those encountered in some individuals with rheumatic fever and are characterised by central tissue necrosis surrounded by proliferating connective tissue. Also noted are large numbers of lymphocytes and occasional plasma cells. Acute glaucoma may result with nodules forming on the sclera. Pulmonary involvement may result in diffuse pleuritis (inflammation of the pleura) or multiple nodules within the tissue of the lungs. Diffuse pulmonary fibrosis may occur because of immunologically mediated immune complex deposition. Rheumatoid nodules within the heart may cause valvular deformities, particularly of the aortic valve leaflets, and pericarditis (inflammation of the pericardium). Lymphadenopathy (swelling) of the nodes close to the affected joints may develop. Rheumatoid nodules within the spleen result in splenomegaly (enlarged spleen). Blood vessels may show an acute inflammatory response as is noted in other immunological/inflammatory states. Thromboses in involved vessels may give rise to myocardial infarctions (see Chapter 23), cerebrovascular occlusions (see Chapter 9), mesenteric infarction (often causing necrosis in the gut), kidney damage (typical of systemic autoimmune conditions) and vascular insufficiency in the hands and fingers (Raynaud’s phenomenon). The vascular changes are primarily noted in individuals receiving steroid therapy; thus, there is some concern that the therapy may play a role in initiating these lesions. Changes in skeletal muscle are often noted in the form of nonspecific atrophy secondary to joint dysfunction. EVALUATION AND TREATMENT
Evaluation of rheumatoid arthritis is done by physical examination, x-ray of the joint and serological tests for
537
rheumatoid factor and circulating immune complexes. The American College of Rheumatology lists the following diagnostic criteria for rheumatoid arthritis that have widespread use, including within Australia and New Zealand: 1 morning stiffness lasting more than 1 hour 2 arthritis of three or more joint areas 3 arthritis of the hand joints 4 symmetric arthritis 5 rheumatoid nodules over extensor surfaces or bony prominences 6 serum rheumatoid factor 44 7 x-ray changes (hand and wrist). The presence of four or more of the numbered criteria is diagnostic of rheumatoid arthritis. Criteria 1–4 with joint signs or symptoms must be present for 6 weeks. Treatment for the orthopaedic components of the disease can be nonsurgical or surgical. Nonsurgical treatment includes resting the inflamed joint and whole-body rest for several hours daily; use of hot and cold packs; physical therapy; patient education; aggressive, early intervention using disease-modifying antirheumatic drugs and biological response modifiers; a diet high in kilojoules and vitamins; corticosteroids; and anti-inflammatory drugs taken orally or injected into the joint. Intraarticular injection of a radionuclide can be used to treat synovitis. Surgical synovectomy may be done early in the disease to decrease inflammatory effusion and remove pannus. Surgery is used to correct deformity or mechanical deficiency in intermediate or late stages of the disease and includes arthrodesis (surgical fusion of the two bones so the joint becomes immoveable), arthroplasty (surgical repair of the joint) or total joint replacement. There is evidence that total fasting substantially reduces joint pain, swelling, morning stiffness and other symptoms in individuals with rheumatoid arthritis.
Juvenile rheumatoid arthritis Juvenile rheumatoid arthritis is the childhood form of rheumatoid arthritis and accounts for 5% of all cases of rheumatoid arthritis. Juvenile rheumatoid arthritis has three distinct modes of onset: oligoarthritis (fewer than three joints), polyarthritis (more than three joints) and Still’s disease (severe systemic onset). Juvenile rheumatoid arthritis differs from rheumatoid arthritis in several ways: • Oligoarthritis is more common. • Large joints are most commonly affected. • Chronic uveitis (an inflammation of the anterior chamber of the eye) is common if the antinuclear antibody is positive; examination by an ophthalmologist is required every 6 months to avoid vision loss. • Rheumatoid nodules and rheumatoid factor are usually absent. Rheumatoid factor–positive children have a worse prognosis.
• Subluxation and ankylosis may occur in the cervical spine if disease progresses. • Rheumatoid arthritis that continues through adolescence can have severe effects on growth and adult morbidity. Many children with oligoarthritis who are ‘seronegative’ (whose blood tests negative for rheumatoid factor or antinuclear antibody) will resolve their symptoms over time. Systemic onset, or ‘seropositivity’, of the disease is more likely consistent with lifelong arthritis. Long-term studies have shown that one-third to half of patients with juvenile rheumatoid arthritis have active disease 10 years later. Treatment is therefore supportive, not curative. Non-steroidal anti-inflammatories are a mainstay, and methotrexate (typically an anti-cancer medication) is also being used with success. The aims are to minimise inflammation and deformity.
PAEDIATRICS
Paediatrics and disorders of joints
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ANKYLOSING SPONDYLITIS
PATHOPHYSIOLOGY
Ankylosing spondylitis is a chronic, inflammatory joint disease characterised by stiffening and fusion (ankylosis) of the spine and sacroiliac joints. Like rheumatoid arthritis, ankylosing spondylitis is a systemic, autoimmune disease. However, the two conditions respond to different antigens. In the case of rheumatoid arthritis the synovial membrane is affected, whereas in ankylosing spondylitis it is the point at which the tendons and ligaments attach to bone that is affected (known as the enthesis). The end result is fibrosis, ossification and fusion of the joint, usually beginning with the sacroiliac joints and progressing up the vertebral column. Ankylosing spondylitis usually develops in late adolescence and young adulthood, with peak incidence at about 20 years of age, and affects slightly more men than women. There is a wide range of presentations from asymptomatic sacroiliitis (inflammation of the sacroiliac joint) to progressive disease that affects many body systems. Secondary ankylosing spondylitis affects older age groups and is often associated with other inflammatory diseases (e.g. psoriatic arthropathy, inflammatory bowel disease, Reiter’s syndrome — a reactive arthritis). The cause of ankylosing spondylitis is unknown, but a genetic predisposition to the disease has been suggested.45
Ankylosing spondylitis begins with inflammation of fibrocartilage in cartilaginous joints (see Chapter 14) between the sacrum and ilia (plural of ilium). Inflammatory cells infiltrate the joint and begin to damage fibrocartilage and bone in the joint structures. Repair of the damage is mediated by fibroblasts that produce and secrete collagen. This collagen forms scar tissue that is eventually calcified. With time, all the cartilaginous structures of the joint are replaced by ossified scar tissue, causing the joint to fuse or lose flexibility. The eroded bone is repaired in the normal process of bone repair and remodelling (see Chapter 20). The new bone has to grow outwards to connect with the ligaments that have been eroded by the inflammatory response and, as a consequence, the shape of the vertebral bodies changes — they lose their concave anterior contour and appear square. The spine assumes the classic bamboo spine appearance of ankylosing spondylitis (see Fig. 21.24). CLINICAL MANIFESTATIONS
The most common signs and symptoms of early ankylosing spondylitis are low back pain and stiffness that may be persistent or intermittent. It is often worse after prolonged rest and is alleviated by physical activity. Early morning stiffness usually accompanies the low back pain and the individual typically has difficulty sitting up or twisting the
RESEARCH IN F CUS New rheumatoid arthritis treatments and diagnosis
Ossification of discs, joints and ligaments of spinal column
Classification and diagnosis Changes to the previous criteria (the American College of Rheumatology) for classification of rheumatoid arthritis were made in 2015 in response to limitations to identifying individuals with early arthritis that went on to become rheumatoid arthritis. Risk factors such as elevated body mass index and vitamin D status have a potential impact on the development of the disease (although the evidence is weak). However smoking has been shown to double the risk of developing the disease. Current literature shows the severity of the overall disease burden may be lessening. Treatment Innovative new therapies for rheumatoid arthritis treatment continue to emerge. In addition to pharmaceutical agents, biological and genetic agents are gaining increasing attention. New treatments are targeted at specific cytokines, inhibition of chemokines, and complement activation, and investigational therapies include T cell or T cell receptor vaccination. In the meantime, the disease-modifying antirheumatic drugs (DMARDs) continue to be widely used for these patients.
FIGURE 21.24
Ankylosing spondylitis. Characteristic posture and primary pathological sites of inflammation and resulting damage.
CHAPTER 21 Alterations of musculoskeletal function across the life span
spine. Forward flexion, rotation and lateral flexion of the spine are restricted and painful. Early pain and resultant loss of motion are caused by the underlying inflammation and reflex muscle spasm rather than by soft tissue or bony fusion. As the disease progresses, the normal convex curve of the lower spine (lumbar lordosis) diminishes and concavity of the upper spine (kyphosis) increases. The individual becomes increasingly stooped. The thoracic spine becomes rounded, the head and neck are held forward on the shoulders and the hips are flexed (see Fig. 21.16). Inflammation in the tendon insertions of the muscles of the chest wall can cause pleuritic chest pain and restricted chest movement. The pain is usually worse on inspiration. Movement in the diaphragm is normal and full. Pressure on the anterior chest wall over the sternum, ribs and costal cartilages may show tenderness. Tenderness over the pelvic brim may cause discomfort at night and interfere with sleep because turning onto the iliac crests causes pain. Tenderness over the ischial tuberosities may make sitting on hard seats unbearable. Tenderness in the heels may contribute to a limp or cautious placement of the feet during walking. Along with low back pain, many individuals have peripheral joint involvement, uveitis, fibrotic changes in the lungs and cardiomegaly, aortic incompetence, amyloidosis and Achilles tendonitis. Symptoms may include fatigue, weight loss, low-grade fever, hypochromic anaemia and an increased erythrocyte sedimentation rate. EVALUATION AND TREATMENT
Diagnosis of ankylosing spondylitis is made from the history and physical examination, x-ray and serum analysis for the presence of the relative antigen (HLA-B27). The erythrocyte sedimentation rate and C-reactive protein are elevated throughout the disease. Alkaline phosphatase levels are often elevated. Early precise diagnosis allows implementation of a usually effective, conservative, life-long treatment. Treatment of individuals with ankylosing spondylitis is directed at controlling pain, maintaining mobility and controlling inflammation. Prevention of deformity and maintenance of mobility require a continuous program of physical therapy. Exercises are performed several times each day to maintain chest expansion, full extension of the spine and complete range of motion in the proximal joints. Non-steroidal anti-inflammatory drugs often provide temporary symptom relief within 48 hours. Analgesic medications are prescribed to suppress some of the pain and stiffness and to facilitate exercise. The medications do not prevent disease progression, but they do provide relief from symptoms. Biological response modifying agents, such as infliximab, which inhibits TNF-α, may be useful in treating ankylosing spondylitis.46,47 Surgical procedures, such as osteotomy, total hip replacement and cervical spinal fusion, and radiation therapy are sometimes used to provide relief for individuals with end-stage disease or intolerable deformity. Individuals should stop smoking to lessen pulmonary problems.
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GOUT
Gout is a syndrome caused by defects in uric acid metabolism and characterised by inflammation and pain of the joints. Either excessive uric acid production or underexcretion of uric acid by the kidneys will cause hyperuricaemia. When the uric acid becomes sufficiently concentrated, it crystallises, forming insoluble crystals that are deposited in connective tissues throughout the body. Crystallisation in synovial fluid causes acute, painful inflammation of the joint, a condition known as gouty arthritis. With time, crystal deposition in subcutaneous tissues causes the formation of small, white nodules, or tophi, that are visible through the skin. Crystal aggregates deposited in the kidneys can form urate renal stones and lead to renal failure. Gout is predominantly a disease of men. The peak age of onset in males is between 40 and 60 years, whereas it is somewhat later in females. The plasma urate concentration is the single most important determinant of the risk of developing gout (see Table 21.3). The solubility of urate is critical to the development of crystals. Urate is more soluble in plasma and urine than in synovial fluid. The solubility of urate also decreases with decreasing temperature. Initial deposits are often in the joint of the great toe where temperatures are lower than the body core. The pathways of production of uric acid are shown in Fig. 21.25. PATHOPHYSIOLOGY
The pathophysiology of gout is closely linked to purine metabolism (or cellular metabolism of purines — adenine and guanine from DNA and RNA) and kidney function. At the cellular level, purines are used for the production of several products, including ATP and nucleic acids. Uric acid is a breakdown product of purine nucleotides (urate production and elimination are illustrated in Fig. 21.25). Some individuals with gout have an accelerated rate of purine production accompanied by an overproduction of uric acid. Even with restricted purine consumption, these individuals continue to overproduce uric acid. Other individuals break down purine nucleotides at an accelerated rate that also results in an overproduction of uric acid. In
TABLE 21.3 Mean urate concentrations by age and gender CHARACTERISTIC
MEAN URATE LEVELS
Prepuberty
0.20 mmol/L
Males
Steep rise to 0.30 mmol/L
Females (puberty to after premenopause)
Slow rise to approximately 0.24 mmol/L
Females (after menopause)
0.28 mmol/L
Hyperuricaemia Males
> 0.42 mmol/L
Females
> 0.36 mmol/L
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Part 3 Alterations to protection and movement
Production
Metabolism
Elimination
Dietary purine Purine production
Body purine nucleotides
Purines
Tissue nucleic acids
Uric acid
Intestinal excretion Renal excretion
FIGURE 21.25
Uric acid production and elimination. Uric acid is derived from purines ingested or produced from ingested foods, as well as being recycled after cell breakdown. Uric acid is then eliminated through the kidneys and gastrointestinal tract.
addition, production of uric acid can be caused by an increased turnover of nucleic acids, which is associated with an increased turnover of cells at other body sites. The increased turnover of nucleic acids leads to increased levels of uric acid with a compensatory increase in purine production. Most uric acid is eliminated from the body through the kidneys. Urate is filtered at the glomerulus and undergoes reabsorption, as well as being excreted into urine. In primary gout, urate excretion by the kidneys is sluggish, which may result from a decrease in glomerular filtration of urate or increased urate reabsorption. In addition, monosodium urate crystals are deposited in renal interstitial tissues, causing impaired urine flow. (Kidney function is described in Chapter 28.) The exact process by which crystals of monosodium urate are deposited in joints and induce gouty arthritis is unknown, but several mechanisms may be involved, including the following: • monosodium urate precipitates at the periphery of the body, where lower body temperatures may reduce the solubility of monosodium urate • albumin or glycosaminoglycan levels decrease, which causes decreased urate solubility • changes in ion concentration and decreases of pH enhance urate deposition • trauma promotes urate crystal precipitation. The monosodium urate crystals may form in the synovial fluid or in the synovial membrane, cartilage or other connective tissues in joints and elsewhere, such as in the heart, earlobes and kidneys. Evidence suggests that an acute attack of gout is the result of the formation of crystals rather
than the releasing of the crystals from connective tissues into the synovial fluid. Monosodium urate crystals can stimulate and perpetuate the inflammatory response (see Fig. 21.26), during which neutrophils are attracted out of the circulation and phagocytose (ingest) the crystals. The neutrophils subsequently die and release both the crystals and the lysosomal enzymes that cause tissue damage and further stimulate inflammation. CLINICAL MANIFESTATIONS
Gout is manifested by: (1) an increase in serum urate concentration (hyperuricaemia); (2) recurrent attacks of monarticular arthritis (inflammation of a single joint); (3) deposits of monosodium urate monohydrate (tophi) in and around the joints; (4) renal disease involving glomerular, tubular and interstitial tissues and blood vessels; and (5) the formation of renal stones. These manifestations appear in three clinical stages: 1 Asymptomatic hyperuricaemia. The serum urate level is elevated but arthritic symptoms, tophi and renal stones are not present; may persist throughout life. 2 Acute gouty arthritis. Attacks develop with increased serum urate concentrations; tends to occur with sudden or sustained increases of hyperuricaemia but also can be triggered by trauma, drugs and alcohol. 3 Tophaceous gout. The third and chronic stage of disease; can begin as early as 3 years or as late as 40 years after the initial attack of gouty arthritis. Progressive inability to excrete uric acid leads to tophi appearing in cartilage, synovial membranes, tendons and soft tissue. Trauma is the most common aggravating factor. The great toe is subject to chronic strain in walking and subsequently an acute gout attack may follow long walks. Trauma associated with occupations such as truck driving also may precipitate an attack. Attacks of gouty arthritis occur abruptly, usually in a peripheral joint (see Fig. 21.26C). The primary symptom is severe pain. Approximately 50% of initial attacks occur in the metatarsophalangeal joint of the great toe (a condition known as podogra). The other 50% involve the heel, ankle, instep of the foot, knee, wrist or elbow. The pain is usually noted at night. Within a few hours the affected joint becomes hot, red and extremely tender and may be slightly swollen. Lymphangitis (inflammation of lymph vessels) and systemic signs of inflammation (leucocytosis, fever, elevated sedimentation rate) are occasionally present. Untreated, mild attacks usually subside in several hours but may persist for 1 or 2 days. Severe attacks may persist for several days or weeks. When the individual recovers, the symptoms resolve completely. The helix of the ear (outer fold) is the most common site of tophi, which are the characteristic diagnostic lesions of chronic gout. Tophi do not usually appear until at least 10 years after the first gout attack. They produce irregular swellings of the fingers, hands, knees and feet. Tophi commonly form lumps along the ulnar surface of the forearm, the tibial
CHAPTER 21 Alterations of musculoskeletal function across the life span
A
Overproduction of uric acid
541
Underexcretion of uric acid
Hyperuricaemia
Formation of monosodium urate crystals Lipoprotein coating IgG coating
Crystals in synovial fluid
Responding cell stimulates
Chemotactic factors
inhibits
Neutrophil, leucocyte, monocyte, fibroblast, synoviocyte, renal cell
Lysosomal enzymes
PGE 2
IL-1 IL-6
Oxygen radicals
Collagenase
Tissue damage and continued inflammation
B Monosodium urate crystallisation
Phagocytosis by leucocyte
Fusing of vacuolar and lysosomal membranes
Shedding of preformed crystals from tophi
Hydrogen bonding between crystal surface and lysosomal membrane
Rupture of phagolysosome and disruption of leucocyte
Inflammation
C
FIGURE 21.26
The pathogenesis of acute gouty arthritis. A Depending on the urate crystal coating, a variety of cells may be stimulated to produce a wide range of inflammatory mediators. IgG = immunoglobulin G; PGE2 = prostaglandin E2; IL = interleukin. B The sequence of events in the production of inflammatory response to urate crystals. C Gouty tophus on the right foot.
surface of the leg, the Achilles tendon and olecranon bursae. Tophi may produce marked limitation of joint movement and eventually cause grotesque deformities of the hands and feet. Although the tophi themselves are painless, they often cause progressive stiffness and persistent aching of the affected joint. Tophi in the upper extremities may cause nerve compressions, such as carpal tunnel syndrome, while
tophi in the lower extremities may cause tarsal tunnel syndrome. They also may erode and drain through the skin. Kidney stones (see Chapter 30) are 1000 times more prevalent in individuals with primary gout than in the general population. The stones may be any size, from the size of a grain of sand or a piece of gravel to much larger
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deposits. Renal stones can form in the collecting tubules, pelvis or ureters, causing obstruction, dilation and atrophy of the more proximal tubules and leading eventually to acute renal failure. Stones deposited directly in renal interstitial tissue initiate an inflammatory reaction that leads to chronic renal disease and progressive renal failure. TREATMENT
The first objective of gout treatment is to terminate the acute gouty attack as promptly as possible. Once the inflammatory process has subsided, attention is directed to prevent recurring attacks, prevent or reverse complications associated with urate deposits in the joints and kidneys, and prevent formation of kidney stones. Acute gouty arthritis is treated with anti-inflammatory drugs. The drugs of choice are colchicine, non-steroidal anti-inflammatory agents (especially indomethacin) and allopurinol. Colchicine is useful in those unable to take non-steroidal antiinflammatories. Once infection has been ruled out, hydrocortisone may be injected into the joint to relieve pain. Ice also may relieve some of the inflammation of the joint. Weight-bearing on the involved joint is to be avoided until the acute attack subsides. After the attack the individual is put on a low-purine diet, with high fluid intake to increase
Bone cysts
Bone
urinary output. Uricosuric drugs (e.g. probenecid or sulfinpyrazone) increase the excretion of urate by blocking its reabsorption by the kidney tubules. Antihyperuricaemic drugs (e.g. allopurinol) reduce serum urate concentrations by inhibiting the formation of urate. Ensuring those at risk of acute gouty attack are well hydrated is essential, especially following admission due to trauma. OSTEOARTHRITIS
Osteoarthritis is effectively a wearing out of the joint (see Fig. 21.27). It therefore predominantly affects the weight-bearing joints. Osteoarthritis tends to occur in men and women older than 40 years of age and becomes more common with increasing age. It is a leading cause of pain and disability in the elderly. Australian data from the 2011–2012 National Health Survey48 show age-adjusted prevalence is higher in females (10.2%) than males (5.6%). In 2007 the prevalence of osteoarthritis in New Zealand was 8.7% of the population.49 It usually occurs in those who put exceptional stress on joints, as do obese people, gymnasts, long-distance runners and marathoners, and basketball, soccer and football players. Many of these people develop osteoarthritis at earlier ages than usual. A previously torn anterior cruciate ligament or meniscectomy (surgical
Sclerotic bone
Osteophytes
Cartilage Joint capsule Cartilage fragments
NORMAL
Periarticular fibrosis
OSTEOARTHRITIS • Irregular joint space • Fragmented cartilage • Loss of cartilage • Sclerotic bone • Cystic change
Calcified cartilage
OSTEOARTHRITIS — ADVANCED • Osteophytes • Periarticular fibrosis • Calcified cartilage
FIGURE 21.27
Osteoarthritis. A schematic of the pathology of osteoarthritis. Fragmentation and loss of cartilage denude the bone, which undergoes sclerosis (stiffening). Osteophytes (bone spurs) form on the lateral sides and protrude into the soft tissue, causing irritation, inflammation and fibrosis (excessive fibrous connective tissue).
CHAPTER 21 Alterations of musculoskeletal function across the life span
removal of the meniscus of the knee) increases the risk for accelerated osteoarthritis of the knee.50,51 See Box 21.3 for risk factors for osteoarthritis. Osteoarthritis is characterised by localised loss and damage of articular cartilage, new bone formation of joint margins (osteophytosis), subchondral bone changes, variable degrees of mild synovitis and thickening of the joint capsule (see Fig. 21.28). Pathology centres on load-bearing areas. Advancing disease reveals narrowing of the joint space
BOX 21.3
Risk factors for osteoarthritis
• Trauma, sprains, strains, joint dislocations and fractures • Long-term mechanical stress — athletics, ballet dancing or repetitive physical tasks • Inflammation in joint structures • Joint instability from damage to supporting structures • Neurological disorders (e.g. diabetic neuropathy, neuropathic joint disease) in which pain and proprioceptive reflexes are diminished or lost • Congenital or acquired skeletal deformities • Haematological or endocrine disorders, such as haemophilia (which causes chronic bleeding into the joints) or hyperparathyroidism (which causes bone to lose calcium) • Drugs (e.g. colchicine, indomethacin, steroids) that stimulate the collagen-digesting enzymes in the synovial membrane
because of cartilage loss, osteophytes (bone spurs) and sometimes changes in the subchondral bone. Osteoarthritis can arise in any synovial joint but is commonly found in the hips, hands and spine (see Fig. 21.29). It involves a complex interaction of cytokines, growth factors, matrix molecules and enzymes. PATHOPHYSIOLOGY
Articular cartilage is normally a dynamic tissue: the chondrocytes (cartilage-forming cells) continuously replace the tissue in the same way that bone is continually replaced. In osteoarthritis this process becomes disrupted — the primary defect in osteoarthritis is loss of articular cartilage.52 Early in the disease, articular cartilage loses its glistening appearance, becoming yellow-grey or brownish grey. As the disease progresses, surface areas of the articular cartilage flake off and deeper layers develop longitudinal fissures that extend to the subchondral bone. Synovial fluid fills the fissures and may enter the underlying bone, forming cysts. The cartilage becomes thin and may be absent over some areas, leaving the underlying bone (subchondral bone) unprotected. Consequently, the unprotected subchondral bone becomes sclerotic (dense and hard). Fragments of bone and cartilage become free floating and enter the joint cavity. Formation of new bone and cysts usually occurs near the joint margins, forming osteophytes. As the joint loses its integrity there is trauma to the synovial membrane causing a nonspecific inflammation, or synovitis. CLINICAL MANIFESTATIONS
Clinical manifestations of osteoarthritis typically appear during the fifth or sixth decade of life, although asymptomatic,
results in stimulating
causing
leading to
Acquired risk factors • Age • Obesity • Metabolic conditions • Malalignment • Joint trauma or injury
Muscle weakness
contributing to
Alteration in chondrocyte function
promoting
results in Synovial inflammation
stimulates
Cytokine release
causes
Bone remodelling
FIGURE 21.28
Summary of the pathophysiology of osteoarthritis with emphasis on structural damage to the cartilage and alteration in chondrocyte function.
CONCEPT MAP
Genetic influences increase the • Biochemical abnormalities predispose to risk of in collagen and proteoglycans and bone formation Structural damage • Congenital hip dysplasia to cartilage Enzyme release with degradation of collagen and proteoglycans
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Rheumatoid arthritis
Osteoarthritis
FIGURE 21.29
The distribution of involved joints in the two most common forms of arthritis — rheumatoid arthritis and osteoarthritis. Dark circles are shown over the involved joint areas.
articular surface changes will have been occurring for 10 or 20 years. Pain that is initially described as aching and difficult to localise and is aggravated by weight-bearing is a common presentation of the disease. It is usually aggravated by use of the joint and relieved by resting the joint and is unilateral in nature. Later in the course of the disease night pain may be experienced that is not relieved by rest and may be accompanied by paraesthesias (numbness, tingling or prickling). Sometimes pain is referred to another part of the body. For example, osteoarthritis of the lumbosacral spine may mimic sciatica, causing severe pain in the back of the thigh along the course of the sciatic nerve. Osteoarthritis in the lower cervical spine may cause brachial neuralgia (pain in the arm) aggravated by movement of the neck. Osteoarthritic conditions in the hip cause pain that may be referred to the lower thigh and knee area. Sleep deprivation adds to the stress of the chronic pain of osteoarthritis. Physical examination of the person with osteoarthritis usually shows general involvement of both peripheral and central joints. Peripheral joints most often involved are in the hands, wrists, knees and feet. Central joints most often
afflicted are in the lower cervical spine, lumbosacral spine, shoulders and hips (see Fig. 21.29). Joint structures are capable of generating a limited number of signs and symptoms. The primary signs and symptoms of joint disease are pain, stiffness, enlargement or swelling, tenderness, limited range of motion, muscle wasting, partial dislocation and deformity. Range of motion is limited to some degree, depending on the extent of cartilage degeneration and any swelling of the affected joint. Frequently, joint motion is accompanied by crepitus (a crackling sound or grating sensation in a joint). As osteoarthritis of the lower extremity progresses, the person may begin to limp noticeably (see Fig. 21.30). Having a limp is distressing because it affects the person’s independence and ability to do usual activities of daily living. The affected joint is also more symptomatic after use, such as at the end of a period of strenuous activity. EVALUATION AND TREATMENT
Evaluation consists of clinical assessment and radiological studies, CT scan, arthroscopy and MRI. Treatment is either
CHAPTER 21 Alterations of musculoskeletal function across the life span
545
A
FIGURE 21.30
Typical varus deformity of knee osteoarthritis. The osteoarthritis causes deformity of the knee such that the legs lose their normal alignment.
conservative or surgical. Conservative treatment includes rest of the involved joint until inflammation, if present, subsides; range of motion exercises to prevent joint capsule contraction; use of a cane, crutches or walker to decrease weight-bearing; and analgesic and anti-inflammatory drug therapy to reduce swelling and pain. In addition, weight loss is recommended if obesity is present (obese people are five times more likely to have osteoarthritis of the knees and twice as likely to have osteoarthritis of the hips as people of normal weight; see Research in Focus: Body weight and osteoarthritis). Intraarticular injection of hyaluronic acid has also been successful in decreasing knee pain with osteoarthritis.53 Speculation regarding the use of the cartilage-supporting agents glucosamine and chondroitin has prompted mixed results from studies, some claiming benefit and others finding no effect.54,55 There is a contemporary focus on developing and testing medications for the treatment of osteoarthritis such as disease-modifying osteoarthritis drugs (DMOAD) although there is no clear evidence yet of effective treatments.56 Surgery is used to improve joint movement, correct deformity or malalignment or implant an artificial joint (see Fig. 21.31). The intervention rate (which is much lower than the incidence rate) for major joint surgery is 1.9 per 1000 in Australia and 1.2 per 1000 in New Zealand. These rates are increasing.57
B
Inguinal ligament
Iliopsoas bursa
Trochanteric bursa
Femoral artery
Ischiogluteal bursa
FIGURE 21.31
Musculoskeletal anatomy of the hip. A An artificial hip is shown at a 4.5 year follow-up x-ray alongside B, an anatomical drawing of an actual hip joint.
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Causative microorganisms of osteomyelitis according to age
RESEARCH IN F CUS Body weight and osteoarthritis
BOX 21.4
Longitudinal studies have shown obesity to be a major risk factor in developing osteoarthritis of the knee. In addition to altered biomechanics, increased weight may make subchondral bone stiffer and thus less capable of handling joint impact loading.
Newborns Staphylococcus aureus Group B streptococcus Gram-negative enteric rods Infants Staphylococcus aureus Haemophilus influenzae (decreasingly secondary to immunisation) Older children Staphylococcus aureus Pseudomonas Salmonella Neisseria gonorrhoea Adolescents and adults Pseudomonas Mycobacterium tuberculosis
F OC US O N L E ARN IN G
1 Analyse the effects of juvenile and adult rheumatoid arthritis. 2 Discuss both the causes and the development of gout. 3 Briefly describe the pathophysiology of osteoarthritis and critically analyse the risk factors for this condition.
less
common
Infectious bone disease
Infectious bone disease is expensive, difficult to treat and often culminates in extensive physical disability. Several factors contribute to the difficulty in treating bone infection: • Bone contains multiple microscopic channels that are too small to be accessed by the cells and biochemicals of the body’s immune system. Once bacteria gain access to these channels, they are able to proliferate undisturbed. • The microcirculation of bone is highly vulnerable to damage and destruction by bacterial toxins. Vessel damage causes local thrombosis (blockage) of the small vessels, which leads to ischaemic necrosis (lack of perfusion causing death) of bone. • Bone cells have a limited capacity to replace bone destroyed by infections. Osteoclasts are stimulated by infection to resorb bone, opening up channels in the bone so that cells of the immune system can gain access to the infected bone. At the same time, however, resorption weakens the structural integrity of the bone. New bone formation usually lags behind resorption and the haversian systems in the new bone are incomplete.
Osteomyelitis
Osteomyelitis (osteo meaning bone and myelo meaning marrow) is an infection of the bone and marrow that can be caused by an infective agent (see Box 21.4). Antibiotic medications and often surgical interventions are used to fight these infections. With modern treatments morbidity and mortality resulting from osteomyelitis have fallen drastically. With present management, serious long-term effects occur for less than 15% of cases. Osteomyelitis is usually caused by bacteria; however, fungi, parasites and viruses can also cause bone infection. The infection may originate from the bloodstream or from a surgical procedure (Fig. 21.32).
1
2
3
5
4
FIGURE 21.32
The routes of infection to the joint. 1 Via the blood stream. 2 Dissemination from osteomyelitis. 3 Spread from an adjacent soft-tissue infection. 4 Diagnostic or therapeutic measures. 5 Penetrating damage by puncture or cutting.
Exogenous osteomyelitis is an infection that enters from outside the body — for example, through open fractures, penetrating wounds or surgical procedures. The infection spreads from soft tissues into adjacent bone. Endogenous osteomyelitis (also referred to as haematogenous osteomyelitis) is caused by pathogens carried in the blood from sites of infection elsewhere in the body. The infection spreads from bone to adjacent soft tissues. Endogenous osteomyelitis is commonly found in infants, children and the elderly. In infants, incidence rates among
CHAPTER 21 Alterations of musculoskeletal function across the life span
males and females are approximately equal. In children and older adults, however, males are more commonly affected. Osteomyelitis in children usually begins as an abscess in the metaphysis of a long bone where blood flow is sluggish and bacteria can collect. The periosteum may peel off the affected bone leading to necrosis of the bone. New bone can develop inside the now extended periosteum. These changes may be visualised by x-ray and signify the need for surgical debridement as well as antibiotic treatment. In adults, endogenous osteomyelitis is more common in the spine, pelvis and small bones. Microorganisms reach the vertebrae through arteries, veins or lymphatic vessels. The spread of infection from pelvic organs to the vertebrae is well documented. Vaginal, uterine, ovarian, bladder and intestinal infections can lead to iliac or sacral osteomyelitis. Cutaneous, sinus, ear and dental infections are the primary sources of bacteria in endogenous bone infections. Soft-tissue infections, disorders of the gastrointestinal tract, infections of the genitourinary system and respiratory infections are also sources of bacterial contamination. In addition, infections that occur after total joint replacements are sometimes the cause. The vulnerability of a specific bone depends on the anatomy of its vascular supply. Staphylococcus aureus is the usual cause of osteomyelitis.58–60 Exogenous osteomyelitis can be caused by human bites or fist blows to the mouth. Superficial animal or human bites inoculate local soft tissue with bacteria that later spread to underlying bone. Deep bites can introduce microorganisms directly onto bone. The most common infecting organism in human bites is Staphylococcus aureus. In animal bites, the most common infecting organism is Pasteurella multocida, which is part of the normal mouth flora of cats and dogs. Direct contamination of bones with bacteria can also occur in open fractures or dislocations with an overlying skin wound from contaminated material present during the injury. Intervertebral disc surgery and surgical procedures involving insertion of foreign objects such as metal plates or artificial joints are associated with exogenous osteomyelitis.
PATHOPHYSIOLOGY
Regardless of the source of the pathogen, the pathological features of bone infection are similar to those in any other body tissue. The invading pathogen provokes an intense inflammatory response. As always, the inflammatory response dilates blood vessels flowing to the affected area and constricts those leading away from it, leading to vascular engorgement. An associated increase in permeability causes oedema. Leucocytes attend, releasing inflammatory chemicals and phagocytosing bacteria; abscesses form. Once inflammation is initiated, the small terminal vessels thrombose and exudate seals the bone’s canaliculi. Inflammatory exudate extends into the metaphysis and the marrow cavity and through small metaphyseal openings into the cortex. In children, exudate that reaches the outer surface of the cortex forms abscesses that lift the periosteum off underlying bone. Lifting of the periosteum disrupts blood vessels that enter bone through the periosteum, depriving underlying bone of its blood supply; this leads to necrosis of the affected bone, producing sequestrum, an area of devitalised bone. Lifting of the periosteum also stimulates the osteoblasts into intense activity as they lay down new bone that can partially or completely surround the infected bone. This layer of new bone surrounding the infected bone is called an involucrum. Openings in the involucrum allow the exudate to escape into surrounding soft tissue and ultimately through the skin by way of sinus tracts (see Fig. 21.33). In adults, this complication is rare because the periosteum is firmly attached to the cortex and resists displacement.
Subperiosteal abscess (pus)
Periosteum Initial infection
Local injections and venous punctures are significant causes of exogenous osteomyelitis. Exogenous osteomyelitis of the arm and hand bones tends to occur in those who abuse drugs. In general, persons who are chronically ill, have diabetes or alcoholism or are receiving large doses of steroids or immunosuppressive drugs are particularly susceptible to exogenous osteomyelitis or recurring episodes of this disease.
Epiphyseal line Sequestrum (dead bone)
Blood supply blocked
Initial site of infection
First stage
547
Pus escape Involucrum (new bone formation) Second stage
FIGURE 21.33
Osteomyelitis showing sequestration and involucrum. The bone infection in ostoemyelitis can have significant adverse effects on a large region of bone tissue.
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Instead, infection disrupts and weakens the cortex, which predisposes the bone to pathological fracture.
A
CLINICAL MANIFESTATIONS
Clinical manifestations of osteomyelitis vary with the age of the individual, the site of involvement, the initiating event, the infecting organism and whether the infection is acute, subacute or chronic. Acute osteomyelitis causes abrupt onset of inflammation. If an acute infection is not completely eliminated, the disease may become subacute or chronic. • In subacute osteomyelitis, signs and symptoms are usually vague. • In the chronic stage, infection develops slowly or is silent between exacerbations. The microorganisms persist in small abscesses or fragments of necrotic bone and produce occasional flare-ups of acute osteomyelitis. The progression from acute to subacute osteomyelitis may be the result of inadequate or inappropriate therapy or the development of drug-resistant microorganisms. In children, radiographic bone changes take 2–3 weeks to develop. Initially, osteomyelitis presents as pain, swelling and warmth. Children will often present with fever, an elevated white blood cell count (50–70%), elevated C-reactive protein (98%) and elevated erythrocyte sedimentation rate (90%). Blood culture is positive in only 40% of cases. Without changes on plain radiograph, bone scans can help define the location of infection. In infants, where osteomyelitis can be multifocal in up to 40% of cases, bone scans identify other locations of infection that may need surgical intervention (see Fig. 21.34). Treatment of osteomyelitis consists of appropriate antibiotic management for 6 weeks. If blood cultures are negative, bone aspirate must determine the bacterial cause of the infection. If bony changes exist on plain radiographs, surgical debridement accompanies antibiotic treatment. In the adult, osteomyelitis has an insidious onset. The symptoms are usually vague and include fever, malaise, anorexia, weight loss, and pain in and around the infected areas. Oedema may or may not be evident. Recent infection (urinary, respiratory, skin) or instrumentation (catheterisation, cystoscopy (endoscopy of the urinary bladder), myelography (x-ray visualisation of the spinal cord after injection of contrast medium), discography (x-ray of the spinal column disc/s after injection of contrast medium)) usually precedes the onset of symptoms. Single or multiple abscesses (Brodie’s abscesses) characterise subacute or chronic osteomyelitis. Brodie’s abscesses are well-defined lesions 1–4 cm in diameter, usually in the ends of long bones and surrounded by dense ossified bone matrix. The abscesses are thought to develop when the infectious microorganism has become less virulent or the individual’s immune system is resisting the infection somewhat successfully. In exogenous osteomyelitis, signs and symptoms of soft-tissue infection predominate. Inflammatory exudate in the soft tissues disrupts muscles and supporting structures
B
FIGURE 21.34
The pathogenesis of acute osteomyelitis differs with age. A In infants younger than 1 year the epiphysis is nourished by arteries penetrating through the physis, allowing development of the condition within the epiphysis. B In children up to 15 years of age, the infection is restricted to below the physis because of interruption of the vessels.
and forms abscesses. Low-grade fever, lymphadenopathy (enlargement of the lymph nodes), local pain and swelling usually occur within days of contamination by a puncture wound. EVALUATION AND TREATMENT
Laboratory data show an elevated white cell count. Radiographic studies include radionuclide bone scanning, CT scans and MRI. MRI with gadolinium contrast shows both bone and soft tissue, providing more accurate assessment of infection.60 A specimen of the infected bony tissue or associated exudate may be obtained to identify the specific pathogen present. Treatment of osteomyelitis includes antibiotics and debridement with bone biopsy. Each individual is treated according to their signs.
CHAPTER 21 Alterations of musculoskeletal function across the life span
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Septic arthritis is an infection of the joint space. This condition is always a surgical emergency. The bacteria, and the activities of white cells (leucocytes) fighting the bacteria, can quickly destroy the articular cartilage of the joint and affect the blood supply to the epiphyseal bone nearby. Neither of these complications is easy to treat, and either one can lead to a lifetime of disability. Septic arthritis can occur primarily or secondarily to osteomyelitis that breaks out of the metaphysis of the bone into the joint space. The metaphysis of the paediatric hip, shoulder, proximal radius and distal lateral tibia are all located within the joint capsule and therefore osteomyelitis in these regions must be carefully monitored for secondary septic arthritis. The most common sites for septic arthritis are the knees, hips, ankles and elbows. Children with septic arthritis present with severe joint pain, ‘pseudoparalysis’ (apparent loss of muscle power
Biodegradable antibiotic-impregnated bioabsorbable beads have benefited many individuals.61,62 Chronic conditions may require surgical removal of the inflammatory exudate followed by continuous wound irrigation with antibiotic solutions in addition to systemic treatment with antibiotics. Chronic infections may not be able to be treated fully and long-term antibiotic therapy may be required to suppress the infection. Treatment options should also involve an infectious disease healthcare professional. Any artificial implant (prosthesis) may need to be removed surgically as it significantly reduces the ability to treat the infection efficiently.
F O CUS O N L E A R N IN G
1 Compare and contrast the routes of infection in osteomyelitis. 2 Describe the pathophysiology of osteomyelitis. 3 Discuss the reasons for reduced mobility in septic arthritis.
Disorders of skeletal muscle Muscle and associated soft-tissue damage through trauma and overuse is an issue faced by many athletes and sportspeople. Muscle weakness and fatigue are common symptoms. In many cases, neural, traumatic and psychogenic causes are the reason for the failure to generate force (weakness) or maintain force (fatigue) seen in myopathies. Muscular symptoms also arise from a variety of causes unrelated to the muscle itself. Secondary muscular
without actual paralysis) or marked guarding to motion of the joint, inability to bear weight and malaise, often with anorexia. Children appear quite ill with this diagnosis. Non-pyogenic (not pus forming) arthritis, such as juvenile rheumatoid arthritis, can be difficult to distinguish clinically from septic arthritis because both can lead to malaise and an elevated erythrocyte sedimentation rate. An elevation in C-reactive protein, fever and complete inability to bear weight is more common with septic arthritis. Blood cultures are positive in 30–40% of cases. Culture taken from the affected joint positive for pus defines the diagnosis and determines the bacterial aetiology. As in osteomyelitis, Staphylococcus aureus is the most common bacterial cause. After surgical debridement of the joint, antibiotics are required for 2–3 weeks. Long-term follow-up to assess damage to the joint cartilage or bone is required.
phenomena (contracture, stress-related muscle tension, immobility) are common disorders that influence muscular function. The ability of the nervous system to modify or control motor performance means that it has a large effect on muscular function. In this section we restrict our discussion to inherited and acquired disorders.
Contractures
Contractures can be physiological or pathological. A physiological muscle contracture occurs even though there is no action potential in the sarcolemma. Muscle shortening occurs because of failure of the calcium pump in the presence of plentiful ATP. A physiological contracture is seen in McArdle’s disease and malignant hyperthermia. The contracture is usually temporary if the underlying pathology is reversed. A pathological muscle contracture is a permanent muscle shortening caused by muscle spasm or weakness. Heel cord (Achilles tendon) contractures are examples of pathological contractures. They are associated with plentiful ATP and occur in spite of a normal action potential. The most common form of contracture is seen in conditions such as muscular dystrophy and central nervous system injury. The restriction of joint movement as a result of scar tissue formation in the flexor tissues of a joint is also known as contracture. This type of contracture is most common after a burn injury. An example could be contracture of burned tissues in the palm of the hand leading to a flexion contracture of the fingers.
Stress-induced muscle tension
Abnormally increased muscle tension has been associated with chronic anxiety as well as a variety of stress-related
PAEDIATRICS
Paediatrics and septic arthritis
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muscular symptoms, including neck stiffness, back pain and headache. Tension-type headaches have a very high prevalence. There is no convincing description of the pathophysiology of stress-induced muscle tension. Various forms of treatment have been used to reduce the muscle tension associated with stress. Biofeedback, progressive relaxation training, yoga and meditation are examples of stress-reduction therapies. Biofeedback uses an integrated electromyogram to make recordings from the skin surface. It is particularly useful in individuals who have a connection between skeletal muscle tension and pain. Progressive relaxation training emphasises the individual’s ability to perceive the difference between tension and relaxation. This technique involves sequential tensing and a relaxing environment. The individual is taught to practise this routine daily, often with the use of audio instructions. By teaching the individual to recognise excessive contraction of skeletal muscle, the idea is to enhance the person’s ability to relax specific muscle groups to relieve tension and thus reduce central nervous system arousal, as well as autonomic nervous system arousal.
Disuse atrophy
The term disuse atrophy describes the reduction in normal size of muscle fibres after prolonged inactivity from bed rest, trauma (as a result of application of a cast), local nerve damage or from chronic injuries or disease such as spinal cord injury. It is an example of the body responding to lack of use. Decreased muscle activity reduces muscle mass through reduced protein production and increased proteolysis (breakdown of protein), probably by reactive oxygen radical regulation.63 The effects of lack of use can become apparent rather quickly. With bed rest, the normal individual loses muscle strength from baseline levels at a rate of 3% per day. Immobilisation leads to a reduction in strength as well as increasing fatigability. Oxidative capacity of the mitochondria is decreased. The connective tissues supporting muscle also undergo change. Ligaments, tendons and articular cartilage require use to maintain functionality. Alterations of structure and function of connective tissues become apparent after 4 to 6 days and remain after normal activity resumes. Changes to the structure of collagen fibres may underlie these changes. Bed rest is also associated with cardiovascular, respiratory and urinary system changes putting those individuals at increased risk of complications such as infections, venous thromboembolism and loss of strength. Having a cast in place on a limb produces noticeable atrophy in a month. Also, as people age, their muscles atrophy and become weaker, a condition known as sarcopenia. Inactivity also affects the integrity of bone. As the bone experiences less stress the resorption of bone continues but formation ceases. The effects of reduced stress on the skeletal system are particularly apparent in astronauts spending extensive time in zero gravity conditions. Measures to prevent atrophy include frequent forceful isometric muscle contractions (contractions without muscle shortening) and passive lengthening exercises. Bone mineral
density is influenced by the load magnitude of the exercise rather than the frequency. If reuse is not restored within 1 year, regeneration of muscle fibres becomes impaired.
Fibromyalgia
Fibromyalgia is a chronic musculoskeletal syndrome characterised by diffuse pain, fatigue and tender points (increased sensitivity to touch). The absence of systemic or localised inflammation and the presence of fatigue and disturbed sleep are common. However, fibromyalgia has often been misdiagnosed or completely dismissed by clinicians due to the similar clinical presentations to other conditions (see the list below). A common misdiagnosis has been chronic fatigue syndrome. Eighty to ninety per cent of individuals affected are women and the peak age is 30–50 years. While the incidence is unknown, the prevalence is reported to be 2% and increases with age.64 Although more common than rheumatoid arthritis, its cause is still unknown. The aetiology of fibromyalgia has been debated for more than a century. It is unlikely that it is caused by a single factor. The most common precipitating factors include the following: • flu-like viral illness • chronic fatigue syndrome • human immunodeficiency virus (HIV) infection • Lyme’s disease (a tick-transmitted bacterial infection) • physical trauma • persistent stress • chronic sleep disturbance. Certain rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus, may coexist with fibromyalgia.65 PATHOPHYSIOLOGY
It is unproven but has long been suspected that muscle is the end organ responsible for the pain and fatigue. Some studies have documented metabolic alterations — lower ATP, lower adenosine diphosphate (ADP) and higher concentrations of adenosine monophosphate — and more alterations in the number of capillaries and fibre area in individuals with fibromyalgia than in study control subjects. Most studies have demonstrated that increased muscle tenderness in fibromyalgia is a result of generalised pain intolerance, possibly related to functional abnormalities within the central nervous system (see Fig. 21.35).66 A chronic stress response may be involved in producing lower levels of serotonin (a neurotransmitter). There is increasing evidence that fibromyalgia involves the sympathetic nervous system. Individuals with fibromyalgia may have an adrenal hyporesponsiveness. CLINICAL MANIFESTATIONS
The prominent symptom of fibromyalgia is diffuse, chronic pain. The locations of 9 pairs of tender points for diagnostic classification of fibromyalgia are shown in Fig. 21.36. Tenderness in 11 of these 18 points is necessary for diagnosis,
CHAPTER 21 Alterations of musculoskeletal function across the life span
Somatosensory cortex
together with
Hypothalamus regulatory change
Precipitating factors: muscle microtrauma, deconditioning, sleep disturbances
lead to Pain Fatigue Depression manifest by
Serotonin Endorphins Substance P
Skin hyperactivity
Ascending and descending pathways
Cutaneous nociception
feed information to Muscle contraction, deconditioning
Sympathetic outflow
further stimulating
Spinal cord
feed information to
Muscle nociception
FIGURE 21.35
A theoretical pathophysiological model of fibromyalgia.
Occiput Suboccipital muscle insertions Trapezius Midpoint of the upper border Supraspinatus Above the medial border of the scapular spine Gluteal Upper outer quadrants of buttocks Greater trochanter Posterior to the trochanteric prominence
Low cervical Anterior aspects of the intertransverse spaces at C5–C7
Second rib Second costochondral junctions Lateral epicondyle 2 cm distal to the epicondyles Knee Medial fat pad proximal to the joint line
FIGURE 21.36
The location of specific tender points for diagnostic classification of fibromyalgia. Main sites include the cervical (neck) and trapezius (shoulder), as well as various other locations.
CONCEPT MAP
Pre-existing factors: serotonin receptors, endorphins
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along with a history of diffuse pain. The only reliable finding on examination is the presence of multiple tender points. The pain often begins in one location, especially the neck and shoulders, but then becomes more generalised. People describe the pain as burning or gnawing. Fatigue is profound. The effect on everyday life is considerable. Fatigue is most notable when arising from sleep and in mid-afternoon. Headaches and memory loss are common complaints. There is a strong association between fibromyalgia, Raynaud’s phenomenon and irritable bowel syndrome. Individuals with fibromyalgia are light sleepers and wake frequently. Almost 25% of individuals seek psychological support for depression. Anxiety, particularly in regard to their diagnosis and future, is almost universal. EVALUATION AND TREATMENT
As manifestations of chronic, generalised pain and fatigue are present in many musculoskeletal (e.g. rheumatic) disorders, these disorders should be discounted before diagnosis of fibromyalgia. Treatment should be highly individualised.65 No one regimen of medication has been proven to treat fibromyalgia successfully. Certain central nervous system active medications, most notably the tricyclic antidepressants, amitriptyline and cyclobenzaprine, have performed significantly better than placebos in controlled trials.65 These medications administered 1–2 hours before bedtime provide a better sleep. Amitriptyline significantly improves pain, morning stiffness and sleep but not tender points. Low-impact exercise in the amounts suggested for normal health and fitness may also help. One of the most important aspects of treatment is education and reassurance (see Box 21.5).
Educating and providing reassurance for individuals with fibromyalgia
BOX 21.5
• Stress that the illness is real, not imagined. • Explain that fibromyalgia is presumably not caused by infection. • Explain that fibromyalgia is not a deforming or deteriorating condition. • Explain that fibromyalgia is neither life threatening nor markedly debilitating, although it is an irritating presence. • Discuss the role of sleep disturbances and the relationship of neurohormones to pain, fatigue, abnormal sleep and mood. • Reassure that although the cause is unknown, some information is known about the physiological changes responsible for the symptoms. • Use muscle ‘spasms’ and, perhaps, low muscle blood flow to lay the groundwork for exercise recommendations. • Assist the individual to use aerobic exercise to reduce stress and increase rapid eye movement (REM) sleep.
FOCU S ON L EA RN IN G
1 Describe the causes and analyse the effects of contracture. 2 Analyse the treatment options for stress-induced muscle tension. 3 Discuss cellular responses to increased and decreased functional demand and how these responses relate to disuse atrophy. 4 Describe the clinical manifestations of fibromyalgia.
Integrative conditions related to the musculoskeletal system Lower back pain
Lower back pain is a common health issue and a considerable problem for many individuals in Australia and New Zealand. Approximately 80% of individuals will experience lower back pain in their lifetime, but for 90% the pain will be short lived. Back pain is the second most common symptom reported at general practitioners. It has been estimated that more than 3 million Australians67 and approximately 1 million New Zealanders68 have lower back pain. Furthermore, it has been estimated that the cost of lower back pain in Australia is more than $1 billion annually.69 Lower back pain affects the area between the lower rib cage and gluteal muscles and often radiates into the thighs. About 1% of individuals with acute lower back pain have sciatica — pain along the distribution of a lumbar nerve root. Sciatica is often accompanied by neurosensory and motor deficits, such as tingling, numbness and weakness. Men and women are equally affected, with women reporting lower back symptoms more often after 60 years of age. In addition, back pain is common in children, especially in the adolescent years. The increase in back pain in children has been associated with heavy, inappropriate schoolbags and inappropriate posture when sitting. PATHOPHYSIOLOGY
Most cases of lower back pain are idiopathic and no precise diagnosis is possible. The local processes involved in lower back pain range from tension caused by tumours or disc prolapse, bursitis, synovitis, rising venous and tissue pressure (found in degenerative joint disease), abnormal bone pressures, problems with spinal mobility, inflammation caused by infection (as in osteomyelitis), bony fractures or ligamentous sprains to pain referred from viscera or the posterior peritoneum. General processes resulting in lower back pain include bone diseases such as osteoporosis or osteomalacia. Risk factors include occupations that require repetitious lifting in the forward bent-and-twisted position; exposure to vibrations caused by vehicles or industrial machinery; obesity; and cigarette smoking. Osteoporosis increases the
CHAPTER 21 Alterations of musculoskeletal function across the life span
risk of spinal compression fractures and may be why elderly women report more symptoms than men. Genetic predispositions for lower back pain have also been reported. The most commonly encountered causes of lower back pain include lumbar disc herniation, degenerative disc disease, spondylosis and spinal stenosis. Anatomically, lower back pain must come from innervated structures, but deep pain is widely referred and varies. The nucleus pulposus has no intrinsic innervation, but when extruded or herniated through a prolapsed disc, it irritates the dural membranes and causes pain referred to the segmental area. The interspinous bursae can be a source of pain between L3, L4, L5 and S1, but also may affect L1, L2 and L3 spinous processes. The anterior and posterior longitudinal ligaments of the spine and the interspinous and supraspinous ligaments are abundantly supplied with pain receptors, as is the ligamentum flavum. All of these ligaments are vulnerable to traumatic tears (sprains) and fracture. Muscle injury may contribute to lower back pain, with sprains and strains the most common diagnoses. EVALUATION AND TREATMENT
Diagnosis of lower back pain is based on physical examination, electromyelography, CT scans with or without myelography, MRI and nerve conduction studies. Most individuals with acute lower back pain benefit from a nonspecific short-term treatment of bed rest, analgesic medications, exercises, physical therapy and education. Surgical treatments, specifically discectomy and spinal fusions, are used for individuals not responding to conservative, nonsurgical management. Individuals with chronic lower back pain are also prescribed anti-inflammatory and muscle-relaxant medications and are instructed to follow exercise programs. Aerobic exercises are a popular treatment and seem to be more effective than traction or lower back exercises. Spinal surgery has a limited role in curing chronic lower back pain.
Bone pain
Pain is associated with trauma to the skeletal system. Although no nociceptors (pain receptors) have been found within the osteon, the periosteum and endosteum are richly supplied. Pain may be experienced due to stimulation of these receptors, the release of inflammatory chemicals (e.g. bradykinin), the presence of any oedema or the spasm of muscles. Bone pain is also associated with many metabolic diseases. The pain can be very severe, and in many conditions attempts to manage the pain can dominate the treatment of the condition. The pain of osteoarthritis becomes more evident as the condition progresses. Early in the course of the condition it is aggravated by use and relieved by rest, but later it may become persistent and no longer relieved
553
by rest. With scoliosis the pain is described as very severe and often related to the degree of curvature. Patients with Paget’s disease experience a pain that is usually described as dull, but may be shooting and knife-like. Various other conditions, such as multiple myeloma, pancreatitis and sickle cell disease, can give rise to a bone pain that may be debilitating. With multiple myeloma the pain is usually precipitated by movement, while in pancreatitis bone pain may be severe enough to require the use of narcotics. In children, bone and joint pain is associated with a wide variety of conditions such as rheumatic fever, systemic lupus erythematosus, juvenile rheumatoid arthritis, bursitis, osteomyelitis, osteosarcoma, acute leukaemia and some viral conditions like measles, influenza and chickenpox.
Myasthenia gravis
Myasthenia gravis is a very rare autoimmune condition that is outlined here because it illustrates the specificity of the immune response and normal cellular function in the region of the neuromuscular junction. The disease process begins when the immune system recognises the acetylcholine receptor of the neuromuscular junction as an antigen. The B cells of the immune system are stimulated and produce antibodies that specifically bind to the receptor. This binding blocks the receptor and stimulates a local inflammatory response. The muscle fibre responds by withdrawing the affected receptors from the sarcolemma and producing new ones that are displayed in the neuromuscular junction. Cells bearing receptors for neurotransmitters and hormones normally have a continual process of recycling the receptors where old ones are internalised and new ones are produced. In the case of the muscle fibre, as soon as new receptors are displayed they are bound by antibodies. This action highlights both the specificity and the effectiveness of antibodies. The muscle fibre eventually becomes exhausted and reduces its rate of production of receptors. Individuals with myasthenia gravis will suffer progressive muscle weakness usually initially causing drooping of the eyelids and later resulting in a generalised weakness. Medication seeks to counteract the cause of the condition. Acetylcholine esterase inhibitors (e.g. neostigmine) increase the effectiveness of the released acetylcholine and prednisone reduces the inflammatory response. Because this is an autoimmune condition, the person faces medication for the rest of their life. FOCU S ON L EA RN IN G
1 Explain the cause of bone pain. 2 Analyse the treatment for myasthenia gravis.
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Muscular dystrophy The muscular dystrophies are a group of familial disorders that cause degeneration of skeletal muscle fibres. Ongoing genetic research has helped improve detection of carriers and define not only the inheritance pattern but also the DNA sequence of the various types. The most common singular type, Duchenne’s muscular dystrophy, is discussed here.
A
PATHOPHYSIOLOGY
Duchenne’s muscular dystrophy is a myopathy caused by mutations in a gene located on the short arm of the X chromosome. This mutation causes a protein thought to be responsible for maintaining the cytoskeleton of the muscle cell to be produced with an abnormal structure, to be reduced or to be absent (see Fig. 21.37). The same protein also occurs in the brain and about one-third of
C
D
B
FIGURE 21.37
Duchenne’s muscular dystrophy. A Patient with late-stage Duchenne’s muscular dystrophy showing severe muscle loss. B Gower’s sign in a young boy with Duchenne’s muscular dystrophy. C Transverse section of gastrocnemius muscle from a normal boy. D Transverse section of gastrocnemius muscle from a boy with Duchenne’s muscular dystrophy. Normal muscle fibre is replaced with fat and connective tissue.
PAEDIATRICS
Paediatrics and integrative conditions
CHAPTER 21 Alterations of musculoskeletal function across the life span
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people with Duchenne’s muscular dystrophy show mental retardation. As an X-linked inherited disorder, Duchenne’s muscular dystrophy affects only boys, with any male child of a known female carrier having a 50% risk of showing the condition. The overall incidence is 1 : 3500 male births.
to inactivity, leads to pathological fractures. Studies cite that bisphosphonates, such as those used in osteogenesis imperfecta or osteoporosis, slow bone loss. Death, usually from progressive pulmonary or cardiac weakness, ensues by the 20s. Only 25% of individuals with Duchenne’s muscular dystrophy reach the age of 21 years.
CLINICAL MANIFESTATIONS
EVALUATION AND TREATMENT
Duchenne’s muscular dystrophy causes muscle bulk to reduce through removal of muscle fibres. In the younger child the fibres regenerate, but become nonfunctional with time. Fibrous connective tissue and fat eventually replace muscle fibres. Duchenne’s muscular dystrophy is usually identified at about 3 years of age, with parents noting slow motor development or regression of motor tasks. Sitting, standing and walking become laboured and the child is clumsy, falls frequently and has difficulty climbing stairs. Muscular weakness always begins in the pelvic girdle, causing a waddling gait. Hypertrophy (enlargement) of the calf muscles is apparent in 80% of cases. The method of rising from the floor by ‘climbing up the legs’ (Gowers’ sign) is characteristic and is caused by weakness of the lumbar and gluteal muscles. The foot assumes a talipes equinovarus position (rotated internally; see Fig. 21.38) and the child tends to walk on the toes because of weakness of the muscles in the front of the lower leg (tibialis and peroneus). The deep tendon reflexes are usually depressed or absent. Contractures and wasting of the muscles lead to muscular atrophy and deformity of the skeleton. Scoliosis can occur and is relentlessly progressive; curves of more than 20° are treated surgically to maintain pulmonary function and to slow the progression to a wheelchair. Children usually lose their ability to walk by age 8–10 years. Progressive osteopenia (low bone density), due
Diagnosis is confirmed by measurement of the serum enzyme, creatine kinase. Creatine kinase is increased to more than 20 times the normal level because it is liberated into the bloodstream with muscle death. Although there is no effective cure for Duchenne’s muscular dystrophy, maintaining function for as long as possible is the primary goal. Activity helps maintain muscle function, but strenuous exercise may hasten the breakdown of muscle fibres. Both Muscular Dystrophy Australia and the Muscular Dystrophy Association of New Zealand note the possibility of treatment with steroids to maintain muscle strength and function. This treatment significantly lengthens the period of time a child can still walk but does not alter the life span. Range-of-motion exercises, bracing and surgical release of contracture deformities are used to maintain normal function. Genetic counselling is recommended. With X-linked inheritance, male siblings of an affected child have a 50% chance of being affected and female siblings have a 50% chance of being carriers. Because of its tragic course, prenatal screening for Duchenne’s muscular dystrophy is encouraged. Possible female carriers are urged to have serum creatine kinase levels determined, which can be elevated in 60–80% of those affected. Female carriers have an increased risk of developing dilated cardiomyopathy (enlarged heart) later in life. Congenital defects Clubfoot Clubfoot, or congenital equinovarus, describes a deformity in which the forefoot is adducted and supinated (turned inwards and ‘face up’; see Table 21.4) and the heel is in varus (turned inwards) and equines (points down) (see Figs 21.38 and 21.39). Clubfoot deformity can be positional (correctable passively), idiopathic or teratological (as a result of another syndrome, such as spina bifida). Idiopathic clubfoot usually occurs in 1 : 1000 live births, with males twice as likely as females to be affected. Incidence of clubfoot shows ethnic variation; for example, in the Polynesian Islands incidence is close to 75 : 1000 live births. EVALUATION AND TREATMENT
FIGURE 21.38
An infant with bilateral congenital talipes equinovarus. This infant shows significant deformity in the feet, which can potentially have good outcomes after corrective measures.
In idiopathic clubfoot, manipulation and casting above the knee, as described by Ponseti, begun soon after birth and correctly done, can correct the forefoot deformity in more than 95% of cases. Hindfoot equinus often requires lengthening of the Achilles tendon, which can Continued
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TABLE 21.4 Terms used to describe foot abnormalities TERM
DEFINITION
Position Abduction
Lateral deviation away from the midline of the body
Adduction
Lateral deviation towards the midline of the body
Eversion
Twisting of the foot outwards along its long axis
Inversion
Twisting of the foot inwards on its long axis
Dorsiflexion
Bending of the foot upwards and backwards
Plantar flexion
Bending of the foot downwards and forwards
Abnormality Talipes
Congenital abnormality of the foot (clubfoot)
Pes
Acquired deformity of the foot
Varus
Inversion and adduction of the heel and forefoot
Valgus
Eversion and abduction of the heel and forefoot
Equinus
Plantar flexion of the foot in which the heel is lower than the toes
Calcaneus
Dorsiflexion of the foot in which the heel is lower than the toes
Planus
Flattening of the medial longitudinal arch of the foot (flatfoot)
Cavus
Elevation of the medial longitudinal arch of the foot (high arch)
Equinovarus
Coexistent equinus and varus deformities
Calcaneovarus
Coexistent calcaneus and varus deformities
Equinovalgus
Coexistent equinus and valgus deformities
Calcaneovalgus Coexistent calcaneus and valgus deformities Note: The positions listed can all be achieved by voluntary movement of the normal foot; an abnormality exists if the foot is fixed in one or more of the positions while at rest.
be performed in a clinic under local anaesthetic. Achilles tenotomy (cutting the tendon) can be safely performed with local anaesthetic until 8 or 9 months of age. After this age, a formal lengthening and repair under general anaesthesia is required. Bracing is required until age 3. Idiopathic feet that are not correctable by these procedures
FIGURE 21.39
Idiopathic clubfoot. Idiopathic clubfoot displaying forefoot adduction (towards the midline of body), supination (upturning) and hindfoot equinus (pointing downwards). Note the skin creases along the arch and back of heel.
require surgical posteromedial release, which includes lengthening of the Achilles, posterior tibialis and flexor tendons, and surgical release of the capsules of the ankle, subtalar and midfoot joints. Some sculpting of the bones around the ankle (most often the talus and calcaneus) is usually necessary to align the foot. Teratological feet are usually stiffer and up to 90% require posteromedial release. From 25% to 50% of children requiring posteromedial release may need a second operative procedure with growth; a large number of those with teratological feet also may need a second procedure. Developmental dysplasia of the hip Developmental dysplasia of the hip describes imperfect development of the hip joint and can affect the femoral head or the acetabulum, or both. Although most often present congenitally, dysplasia may develop later in the newborn or infant period. Like clubfoot, developmental dysplasia of the hip can be idiopathic or teratological. Teratological hips (because of another cause such as cerebral palsy or spina bifida) are more difficult to treat and often need surgical intervention. In idiopathic developmental dysplasia of the hip, 70% of cases involve the left side only, 10–15% are bilateral and girls are four times as likely to be affected. A positive family history,
CHAPTER 21 Alterations of musculoskeletal function across the life span
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breech presentation and oligohydramnios (low amniotic fluid) all predispose children to developmental dysplasia of the hip. Children in these groups are considered high risk and must be carefully evaluated with physical examination and, possibly, ultrasound. Variants of idiopathic developmental dysplasia of the hip are dislocated hip (no contact between the femoral head and acetabulum), subluxated hip (partial contact only) and acetabular dysplasia (the femoral head is located properly but the acetabulum is shallow). Idiopathic instability of the hip ranges from 3 : 1000 to 7 : 1000, but a true dislocation is only 1 : 1000. EVALUATION AND TREATMENT
Clinical examination is the mainstay of diagnosis. The examination must be performed on a relaxed infant for accuracy. A positive Ortolani’s sign (hip dislocated, but reducible) or Barlow’s sign (hip reduced, but dislocatable) is an absolute indication for treatment. Other indicators for further evaluation are limitation of abduction or apparent shortening of the femur (Galeazzi’s sign). Asymmetric skin folds at the groin crease may also be observed. In children younger than 4 months old, bracing with a Pavlik harness is successful in 90% of cases. A Barlowpositive hip (hip reduced, but dislocatable) is easier to treat with a Pavlik harness and success reaches 95–98%. An Ortolani-positive hip (hip dislocated, but reducible) must be followed closely with ultrasound and exam; the success rate with Pavlik is 70% in this situation. If a stable reduction is not attained within 2–3 weeks of treatment, the Pavlik harness should be abandoned. A partially reduced hip puts pressure on the rim of the acetabulum by the femoral head and can worsen dysplasia (abnormal cell proliferation and growth) and make treatment more difficult. In older children or cases where the Pavlik harness has failed, closed reduction of the hip and spica (body) casting under general anaesthesia is required. The spica cast is worn for 3 months. Children older than 12 months require surgery on the joint, femur or acetabulum, or all three (see Fig. 21.40). The incidence of excellent outcome falls steadily with age, emphasising the need for early diagnosis and treatment. Non-accidental trauma The incidence of non-accidental trauma is high. Over 225 000 children are suspected of being harmed or at
F O CUS O N L E A R N IN G
1
Outline the genetic basis of Duchenne’s muscular dystrophy.
2
Outline the treatment options for clubfoot.
3 Define 2 variations of developmental dysplasia of the hip and discuss the treatment of each. 4 List 3 warning signs that might indicate non-accidental trauma.
FIGURE 21.40
Surgically treated bilateral hip dislocation. Postoperative x-ray of 5-year-old child after femoral, acetabular and joint surgery bilaterally. The plates will be removed once the child heals. The extent of surgery necessitated staged (i.e. one side at a time) intervention.
risk of harm from abuse and/or neglect in Australia yearly, with comparable rates in New Zealand. Although evidence for cases of abuse is often incomplete, cases of abuse of over 40 000 children in both Australia and New Zealand have been reported recently. The rate of child abuse in both countries shows an increasing trend. Maltreatment may be psychological, sexual or physical. Thirty per cent of children who have been physically abused are seen by an orthopaedist. Accurate and appropriate referrals to child protection agencies are not only legally mandated but also essential for the wellbeing of the child. An abused child who is returned to the same situation without intervention has a 10–15% chance of subsequent mortality. Children who are not yet walking and present with a long bone fracture have more than a 75% chance of that fracture being caused by non-accidental trauma. ‘Corner’ metaphyseal fractures (where a small fragment shears off the side of the metaphysis) are nearly always indicative of abuse, but occur only 25% of the time. Fractures at multiple stages of healing also suggest abuse; however, osteogenesis imperfecta or other causes of systemic osteomalacia must be ruled out. The most common presentation is a transverse tibia fracture. After walking age, only 2% of long bone fractures are the result of non-accidental trauma.
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chapter SUMMARY Musculoskeletal injuries • The most serious musculoskeletal injury is a fracture. A bone can be completely or incompletely fractured. A closed fracture leaves the skin intact. An open fracture has an overlying skin wound. The direction of the fracture line can be linear, oblique, spiral or transverse. Greenstick, torus and bowing fractures are examples of incomplete fractures that occur in children. Stress fractures occur in normal or abnormal bone that is subjected to repeated stress. Fatigue fractures occur in normal bone subjected to abnormal stress. Normal weight-bearing can cause an insufficiency fracture in abnormal bone. • Dislocation is complete loss of contact between the surfaces of two bones. Subluxation is partial loss of contact between two bones. As a bone separates from a joint, it may damage adjacent nerves, blood vessels, ligaments, tendons and muscle. • Tendon tears are called strains and ligament tears are called sprains. A complete separation of a tendon or ligament from its attachment is called an avulsion. • Myoglobinuria (rhabdomyolysis) can be a serious lifethreatening complication of severe muscle trauma.
Disorders of bones and joints • Metabolic bone diseases are characterised by abnormal bone structure. • In osteoporosis the density or mass of bone is reduced because the bone-remodelling cycle is disrupted. • Excessive and abnormal bone remodelling occurs in Paget’s disease. • Avascular diseases of the bone are collectively referred to as osteochondroses and are caused by an insufficient blood supply to growing bones. • Legg-Calvé-Perthes disease is one of the most common osteochondroses. This disorder is characterised by epiphyseal necrosis or degeneration of the head of the femur, followed by regeneration or recalcification. • Osgood-Schlatter disease is characterised by tendonitis of the anterior patellar tendon and inflammation or partial separation of the tibial tubercle caused by chronic irritation, usually as a result of overuse of the quadriceps muscles. The condition is seen primarily in muscular, athletic adolescent males. • Scoliosis is a lateral curvature of the spinal column that can be caused by congenital malformations of the spine, poliomyelitis, skeletal dysplasias, spastic paralysis and unequal leg length, but it is most often idiopathic. • As a result of improved imaging technology, inflammation has been identified as an important feature of osteoarthritis.
• Rheumatoid arthritis is an inflammatory joint disease characterised by inflammatory destruction of the synovial membrane, articular cartilage, joint capsule, and surrounding ligaments and tendons. Rheumatoid nodules may also invade the skin, lung and spleen, and involve small and large arteries. Rheumatoid arthritis is a systemic disease that affects the heart, lungs, kidneys and skin, as well as the joints. • Juvenile rheumatoid arthritis is an inflammatory joint disorder characterised by pain and swelling. Large joints are most commonly affected. • Ankylosing spondylitis is a chronic, inflammatory joint disease characterised by stiffening and fusion of the spine and sacroiliac joints. It is a systemic, immune inflammatory disease. • Gout is a syndrome caused by defects in uric acid metabolism, with high levels of uric acid in the blood and body fluids. Uric acid crystallises in the connective tissue of a joint where it initiates inflammatory destruction of the joint. • Osteoarthritis is a common, age-related disorder of the synovial joints. The primary defect is loss of articular cartilage. • Osteomyelitis is a bone infection most often caused by bacteria. Bacteria can enter bone from outside the body (exogenous osteomyelitis) or from infection sites within the body (endogenous osteomyelitis). • Septic arthritis is always a surgical emergency. The bacteria present and the leucocytes fighting them act to degrade the articular cartilage and the blood supply to the nearby epiphyseal bone. The condition can lead to a lifetime of disability.
Disorders of skeletal muscle • A pathological contracture is permanent muscle shortening caused by muscle spasticity, as seen in central nervous system injury or severe muscle weakness. • Stress-induced muscle tension can be treated using progressive relaxation training and biofeedback to reduce muscle tension. • Fibromyalgia is a chronic musculoskeletal syndrome characterised by diffuse pain and tender points. Unknown but suspected is that muscle is the end organ responsible for the pain and fatigue. Most sufferers are female and the peak age is 30–50 years. • Atrophy of muscle fibres and overall diminished size of the muscle are seen after prolonged inactivity. Isometric contractions and passive lengthening exercises decrease atrophy to some degree in immobilised patients.
CHAPTER 21 Alterations of musculoskeletal function across the life span
Integrative conditions related to the musculoskeletal system • Lower back pain is a common health problem in Australia and New Zealand. • Lower back pain affects the area between the lower rib cage and gluteal muscles and often radiates into the thighs. • Lower back pain must come from innervated structures, but deep pain is widely referred and varies. • Bone pain is often associated with skeletal trauma and metabolic diseases.
Paediatrics and integrative conditions • The muscular dystrophies are a group of genetically transmitted diseases characterised by progressive atrophy of skeletal muscles. There is an insidious loss of strength in all forms of the disorder with increasing disability and deformity. The most common type is Duchenne’s muscular dystrophy.
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• Clubfoot is a common deformity in which the foot is twisted out of its normal shape or position. Clubfoot can be positional, idiopathic or teratological. • Developmental dysplasia of the hip is an abnormality in the development of the femoral head or acetabulum, or both. Like clubfoot, it can be idiopathic or teratological. It is a serious and disabling condition in children if not diagnosed and treated. • Non-accidental trauma must be considered with any long bone injury in the preambulatory child. • The presence of soft-tissue injury, corner fractures and multiple fractures at different stages of healing is extremely helpful for making a diagnosis of nonaccidental trauma. • When non-accidental trauma is suspected, a child must be evaluated radiographically for other fractures, heat trauma and retinal haemorrhage. • All social strata are at risk of non-accidental trauma and healthcare providers are legally responsible to report suspected cases of non-accidental trauma.
CASE STUDY
A DU LT Michael is a 52-year-old self-employed bricklayer who normally lives independently with his wife and three children in rural South Australia. Michael has always been active and played sport all his life; he was a keen runner and would regularly take long runs in the evenings until 4 or 5 years ago. He has been experiencing a gradual increase in pain in his right knee over the past 2 years. The pain is diffuse around the knee and seems to be worse after he leaves work at night. He does not remember a specific injury or time when the pain started. He takes paracetamol or medications containing ibuprofen regularly but these are not so effective at managing the pain lately. There are no episodes of his knee locking or ‘giving way’ but the pain has been getting worse which is restricting his ability to walk and work normally so he has just been to see his local doctor.
1 2 3 4 5
6
Identify the diagnostic studies that Michael should have requested by his doctor. Make a provisional diagnosis for Michael. Identify what lifestyle factors may have played a role in the development of this disease process. What are the possible conservative treatment options for Michael now? What are the modifiable lifestyle factors that may assist in reducing the severity of the symptoms and stop the disease progressing? Explain the potential surgical options for Michael in the future.
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CASE STUDY
A G EING Cveta is 65 years old and experienced menopause 15 years ago. She remembers having her first period at the age of 16 years. Throughout her life she has maintained a slim appearance, which may be due in part to her smoking, which has been at the rate of a pack of cigarettes a day since her late teens. Cveta spent the first 30 years of her life in Yugoslavia before emigrating to Australia. Although she now has a good diet, this was not always the case. When she lived in Yugoslavia vegetables were plentiful, but dairy products were scarce. She has not had a very active life, but she enjoys her life in Brisbane as the climate allows her to be outside frequently. Lately, she has felt the odd twinge of lower back pain and her 35-yearold daughter has wondered whether her mother is a little shorter than previously. This week Cveta experienced a visit
to the local Accident and Emergency Department after she slipped and fell on a wet floor, fracturing her distal left radius. Cveta has been referred back to her general practitioner for a check-up as the magnitude of the trauma would not have been expected to fracture a bone. 1 Outline the most important diagnostic study to request for Cveta. 2 Explain the risk factors evident in Cveta’s life that would justify requesting the study in Question 1. 3 Name the condition that Cveta most likely has. 4 Discuss the alterations that Cveta can make to her lifestyle to minimise the effects of this condition. 5 Advise Cveta’s daughter to help her avoid the same outcome as her mother.
REVIEW QUESTIONS 1 Draw a flow diagram to summarise fracture repair. 2 Differentiate between a sprain and a strain. 3 Explain why myoglobinuria can be a dangerous development after trauma to the muscular system. 4 Provide a strategy that could be communicated to a middle-aged person about how to minimise sarcopenia. 5 Outline the risk factors for osteoporosis. 6 How does juvenile rheumatoid arthritis differ from the adult form?
7 Describe how rheumatoid arthritis affects other organ systems (skin, heart, lungs and kidneys). 8 Explain how uric acid (or urates) causes gout to develop. 9 Outline the risk factors for osteoarthritis. 10 Explain why people experience bone pain if there are no pain receptors in the bone itself.
Key terms afterload, 585 angiogenesis, 573 arteries, 564 atrium, 567 atrioventricular node, 579 atrioventricular valves, 568 autoregulation, 602 autorhythmic cells, 580 Bainbridge reflex, 588 baroreceptor reflex, 588 bundle branches, 579 bundle of His, 579 cardiac action potentials, 579 coronary circulation, 573 coronary perfusion pressure, 601 diastole, 571 electrocardiogram (ECG), 581 end-diastolic volume, 584 endothelium, 592 end-systolic volume, 584 excitation-contraction coupling, 577 intercalated discs, 577 left bundle branch, 579 lymph, 603 lymph nodes, 604 metabolic hypothesis, 602 mitral and tricuspid complex, 569 mitral valve, 569 myocardial contractility, 586 myogenic hypothesis, 602 P wave, 581 Poiseuille’s law, 595 PR interval, 581 preload, 584 pulmonary circulation, 564 Purkinje fibres, 579 QRS complex, 582 QT interval, 582 refractory period, 578 right bundle branch, 579 semilunar valves, 569 sinoatrial node, 579 skeletal muscle pump, 594 ST segment, 582 systemic circulation, 564 systole, 571 total peripheral resistance, 597 T wave, 582 TP segment, 582 tricuspid valve, 569 tunica externa, 589 tunica intima, 589 tunica media, 589 vasoconstriction, 589 vasodilation, 589 veins, 564 venous return, 584 ventricle, 567
CHAPTER
The structure and function of the cardiovascular and lymphatic systems
22
Thomas Buckley Chapter outline Introduction, 564 The circulatory system, 564 The structure of the heart, 564 The size and location of the heart, 564 The heart wall, 565 Heart chambers and great vessels, 567 Valves of the heart, 568 Heart sounds, 569 Blood flow during the cardiac cycle, 571 The coronary circulation, 572 Coronary arteries, 573 Collateral arteries, 573 Coronary capillaries, 574 Coronary veins and lymphatic vessels, 575 Structures that control heart function, 576 Myocardial cells, 576 Myocardial excitation-contraction coupling, 577 Myocardial relaxation, 578 Myocardial metabolism, 578 The cardiac conduction system, 579 Action potentials of the cardiac conduction system, 580 Cardiac innervation, 580 The electrocardiogram, 581
Factors affecting cardiac performance, 583 Preload, 584 Afterload, 585 Myocardial contractility, 586 Heart rate, 586 The physiology of cardiovascular control, 587 Cardiovascular control centres in the brain, 587 Neural reflexes, 588 Atrial receptors, 588 Hormones and biochemicals, 589 The systemic circulation, 589 Blood vessels, 589 Arteries, 589 Capillaries, 589 Endothelium, 592 Veins, 593 Blood pressure and blood flow, 594 Factors affecting blood flow, 595 Regulation of blood pressure, 597 Regulation of the coronary circulation, 601 The lymphatic system, 602 Lymphatic capillaries, 602 Lymphatic vessels and ducts, 603 Lymph nodes, 604 Ageing and the cardiovascular system, 604 563
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Introduction The function of the circulatory system is to deliver oxygen, nutrients and other substances to all the body’s cells and to remove the waste products of cellular metabolism such as carbon dioxide. Delivery and removal are achieved by a complex array of tubing (the blood vessels) connected to a pump (the heart). The heart pumps blood continuously through the blood vessels with cooperation from other systems, particularly the nervous and endocrine systems, which are intrinsic regulators of heart and blood vessel activity. Nutrients and oxygen are supplied by the digestive and respiratory systems; gaseous wastes of cellular metabolism are blown off by the lungs; and other wastes are removed by the liver and kidneys. Of critical importance to cardiovascular function is the vascular endothelium, the cells that line the blood vessels and facilitate homeostasis. As a multifunctional system, its health is essential to normal vascular physiology and its dysfunction is a critical factor in the development of vascular disease. The lymphatic system is also discussed briefly in this chapter, as the lymphatic circulation contributes to movement of fluid between tissues and the circulatory system.
The circulatory system The heart pumps blood through two separate circulatory systems: one to the lungs, and the other to all the other
tissues and organs of the body. Structures on the right side of the heart (or right heart) pump blood through the lungs. This system is known as the pulmonary circulation. The left side of the heart (or left heart) sends blood throughout the systemic circulation, which supplies all other body cells (see Fig. 22.1). The two systems are serially connected; thus, the output of one becomes the input of the other. Blood flow is always in one direction through the circulatory system, so that it moves from right heart to pulmonary circulation, then to left heart and systemic circulation. Arteries carry blood from the heart to all parts of the body, where they branch into increasingly smaller vessels and ultimately become a fine meshwork of capillaries (see Fig. 22.2). Capillaries allow the closest contact and exchange between the blood and the interstitial fluid (interstitium) — the environment in which the cells live. The plasma passes through the walls of the capillaries into the interstitial space. Veins channel blood from capillaries in all parts of the body back to the heart.
The structure of the heart The size and location of the heart
The heart weighs approximately 250–300 g in the adult and is about the size of an adult fist. It lies obliquely (diagonally) within the central compartment of the thoracic cavity, known as the mediastinum, an area above the diaphragm
FIGURE 22.1
Blood flow through the circulatory system. In the pulmonary circulation, blood is pumped from the right side of the heart to the gas-exchange tissues of the lungs. In the systemic circulation, blood is pumped from the left side of the heart to all other tissues of the body.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
HEART
HEART
Right atrium
Left atrium
Right AV valve
Left AV valve
Right ventricle
Left ventricle
Pulmonary SL valve
Aortic SL valve
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LUNGS Vena cava
Pulmonary artery
Arteries
Pulmonary veins
Aorta
Arterioles Veins of each organ
Capillaries
Arteries of each organ
Venules Venules of each organ
Veins
Arterioles of each organ
Capillaries of each organ
FIGURE 22.2
Diagram showing the serially connected pulmonary and systemic circulatory systems and how to trace the flow of blood. Right heart chambers propel unoxygenated blood through the pulmonary circulation, and the left heart chambers propel oxygenated blood through the systemic circulation. AV = atrioventricular; SL = semilunar.
and between the lungs, slightly to the left of the midline of the body (see Figs 22.3 and 22.4). The heart is protected by the bony structures of the thoracic cage, namely the thoracic vertebrae, the sternum and the ribs. Within the mediastinum, the heart is enclosed by a fibrous pericardium; a double-walled sac. This tough sac surrounds the heart and anchors it between the major blood vessels and the diaphragm (see Fig. 22.5). The apex or tip of the heart (inferior part) points towards the left hip and actually touches the chest wall between the fifth and the sixth ribs (fifth intercostal space).
The heart wall
The heart wall has three layers: the pericardium, the myocardium and the endocardium (see Fig. 22.6). The serous pericardium (or epicardium) is a double-walled membranous sac that encloses the heart and: (1) prevents displacement of the heart during gravitational acceleration or deceleration; (2) serves as a physical barrier that protects the heart against infection and inflammation from the lungs and pleural space; and (3) contains pain receptors (nociceptors) and mechanoreceptors to elicit reflex changes in blood pressure and heart rate. The two layers of the serous pericardium
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A
B
Right lung
Aorta
Superior vena cava
Left atrium Heart covered by visceral layer of serous pericardium (epicardium)
Left lung Right atrium Sternum Fibrous Heart pericardium Parietal layer of serous pericardium Diaphragm
C
Pulmonary trunk
Left ventricle Interventricular sulcus
Right ventricle Pericardial cavity
Sternum Fibrous pericardium Right atrium Internal thoracic vessels
Right ventricle Aortic valve Left ventricle
Pleural cavity Pericardial cavity
Oesophagus
Descending aorta Azygos vein
D Oesophagus Trachea Brachiocephalic artery Left brachiocephalic vein Azygos vein Right pulmonary artery Lung Aorta and aortic valve Left atrium Sternum Right ventricle Diaphragm
FIGURE 22.3
The location of the heart. A The heart in the mediastinum showing its relationship to the lungs and other structures. B Detail of the heart resting on the diaphragm with the pericardial sac opened. C Transverse section of a cadaver specimen and a drawing of the thoracic structures at the level of the sixth thoracic vertebra. D Midline sagittal section of a cadaver specimen and a line drawing showing thorax structures.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
*
FIGURE 22.4
Normal heart and aorta, gross. From this view can be seen the aortic root (■), aortic arch (❒) and thoracic aorta (+). The pulmonic trunk (★) is present. On the anterior surface of the heart is the anterior descending coronary artery (▲).
are the parietal (outermost layer) and the visceral (inner layer) pericardia (see Fig. 22.6). These are separated by a fluid-filled space called the pericardial cavity. The pericardial fluid (10–30 mL) is secreted by cells of the serous pericardium and lubricates the membranes that line the pericardial cavity, enabling the membranes to slide over one another with minimum friction as the heart beats. The thickest layer of the heart wall, the myocardium, is composed of cardiac muscle. The thickness of the myocardium is quite different in each heart chamber and is related to the amount of work the muscle must perform — the left side of the heart does more work and has a thicker myocardium than the right. The internal lining of the myocardium, the endocardium, consists of connective tissue (trabeculae) and simple squamous epithelial cells (see Fig. 22.6). This lining is continuous with the endothelium that lines all the arteries, veins and capillaries of the body, creating a continuous, closed circulatory system.
Heart chambers and great vessels
The heart is divided into four chambers: the right and left atria (atria = plural, atrium = singular), and the right and
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left ventricles. Blood passes from the right atrium to the right ventricle and then travels to the pulmonary circulation. After gas exchange in the lungs, oxygenated blood returns to the left side of the heart to the left atrium, then to the left ventricle and finally to the systemic circulation to reach all body cells. Blood flow through these chambers is illustrated in Fig. 22.7. The myocardial thickness of each cardiac chamber depends on the amount of pressure it must generate. The atria are smaller than the ventricles and have thinner walls because they are low-pressure chambers that serve as storage units for blood, which is emptied into the adjacent ventricles. The ventricles have a much thicker myocardial layer, constitute most of the bulk of the heart and provide the force to pump blood around the pulmonary and systemic circulations. Mean pulmonary arterial pressure is approximately 15 mmHg; by comparison, mean systemic arterial pressure is much higher at about 95 mmHg. For this reason, the myocardium of the left ventricle is several times thicker than that of the right ventricle. Blood moves in and out of the heart through several large vessels (see Fig. 22.7). Blood vessels that transport blood away from the heart are called arteries, while those returning blood to the heart are called veins. The right side of the heart receives deoxygenated blood from the systemic circulation and then forces it into the pulmonary circulation. Blood returning to the heart from the pulmonary circulation is oxygenated and enters the left side and is then pumped to the systemic circulation. The right atrium receives blood from the systemic circulation through the superior and inferior venae cavae (venae cavae = plural, vena cava = singular). The superior vena cava transports venous blood from the brain, head, neck, arms and thorax, while the inferior vena cava returns blood from the abdomen, pelvis and legs. Blood flows from the right atrium to the right ventricle. From here, blood exits the right heart via the pulmonary trunk (or artery), which divides into right and left pulmonary arteries to transport deoxygenated blood to the right and left lungs. These pulmonary arteries branch further into the pulmonary capillary bed, where oxygen and carbon dioxide exchange occurs. The four pulmonary veins, two from the right lung and two from the left lung, carry oxygenated blood from the lungs to the left atrium. Blood enters the left atrium and then fills the left ventricle. Approximately 70% of blood in the left ventricle is ejected out of the left side of the heart through the aorta (the largest artery of the body) to supply the systemic circulation. The remaining 30% contributes to the filling volume for ejection with the next contraction. The ascending aorta has a small branch that goes to the coronary arteries of the myocardium. The aorta then curves into the aortic arch, which has branches to the head, neck, brain and arms, before extending down to the descending aorta, which supplies the rest of the body. The relative shape of the ventricles reflects their functions. The right ventricle is shaped like a crescent or triangle, enabling a bellows-like action that efficiently ejects large
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A
Line of attachment of fibrous pericardium and reflection of serous pericardium
Fibrous pericardium
B
Right auricle
Left and right phrenic nerves
Ascending aorta
Pulmonary trunk
Serous pericardium: Visceral Parietal
Pericardial cavity
Pericardial space
Fibrous pericardium (cut)
Diaphragm Fibrous pericardium loosely attached to diaphragm
Visceral serous pericardium
Fibrous pericardium fused with diaphragm at central tendon
FIGURE 22.5
The heart and pericardium. A The pericardial sac cut and opened to expose the anterior surface of the heart. B Cadaver dissection showing many of the structures identified in the diagram.
Fatty connective tissue OUTSIDE OF HEART Coronary artery and vein Fibrous pericardium Serous pericardium (parietal layer)
Serous pericardium (visceral layer; epicardium)
INSIDE OF HEART
Pericardial space Myocardium Trabeculae Endocardium FIGURE 22.6
The wall of the heart. This section of the heart wall shows the fibrous pericardium, the parietal and visceral layers of the serous pericardium (with the pericardial space between them), the myocardium and the endocardium. Note the fatty connective tissue between the visceral layer of the serous pericardium (epicardium) and the myocardium. Note also that the endocardium covers beam-like projections of myocardial muscle tissue called trabeculae.
volumes of blood through a very small valve into the low-pressure pulmonary system. The left ventricle is larger and bullet-shaped, helping it to eject blood through a relatively large valve opening into the high-pressure systemic circulation. A septal membrane separates the right and left sides of the heart and prevents blood from crossing to the other side. The atria are separated by the interatrial septum (the membrane between two cavities) and the ventricles are separated by the interventricular septum. Indentations of the endocardium form valves that separate the atria from the ventricles and the ventricles from the aorta and pulmonary arteries.
Valves of the heart
One-way blood flow through the heart is facilitated by the four heart valves. During ventricular relaxation or filling, the two atrioventricular valves open and blood flows from the atria into the relaxed ventricles. With increasing ventricular pressure, these valves close and prevent backflow into the atria as the ventricles contract. The two atrioventricular valves are located in the wall between the atria and ventricles (see Fig. 22.8). They consist of flaps of tissue called leaflets or cusps, which are attached to the papillary muscles by the chordae tendineae — these
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
HEAD AND UPPER EXTREMITY OF THE SYSTEMIC CIRCULATION Aorta Pulmonary artery
Superior vena cava
Lungs (pulmonary circulation)
Right atrium Pulmonary semilunar valve Tricuspid valve
Pulmonary vein Left atrium Mitral valve Aortic semilunar Left valve ventricle Descending aorta
Right ventricle Inferior vena cava
TRUNK AND LOWER EXTREMITY OF THE SYSTEMIC CIRCULATION FIGURE 22.7
The course of blood flow through the heart chambers and heart valves. Deoxygenated blood from the superior and inferior vena cavae enter the right atrium, then the right ventricle, and travel through the pulmonary artery into the pulmonary circulation. Oxygenated blood from the pulmonary veins enters the left atrium, then the left ventricle, and travels through the aorta into the systemic circulation.
A
Left AV (mitral) valve
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are strong cords of connective tissue that prevent the valves from blowing out. The papillary muscles are extensions of the myocardium that pull the cusps together and downwards at the onset of ventricular contraction when the valves close, thus preventing their backward expulsion into the atria. The right atrioventricular valve is called the tricuspid valve because it has three cusps. The left atrioventricular valve is a bicuspid (two-cusp) valve called the mitral valve (as it resembles a bishop’s headwear known as a mitre). The tricuspid and mitral valves function as a unit because the atrium, fibrous rings, valvular tissue, chordae tendineae, papillary muscles and ventricular walls are connected. Collectively, these six structures are known as the mitral and tricuspid complex. Damage to any one of the complex’s six components can alter function significantly. The semilunar valves of the heart are located at the junction between the ventricle and its flow-on artery. They open when intraventricular pressure exceeds aortic and pulmonary pressure and blood flows out of the ventricles and into the systemic and pulmonary circulations, respectively. After ventricular contraction and ejection, intraventricular pressure falls and the pulmonary and aortic semilunar valves close, preventing backflow into the right and left ventricles. The fibrous skeleton of the heart consists of four rings of dense fibrous connective tissue. These surround each heart valve and provide strong sites for each valve to anchor. This fibrous skeleton also somewhat divides the atrium from the ventricles.
Heart sounds
Sounds are audible when listening to the heart using a stethoscope and are described as sounding like ‘lub-dub’.
Pulmonary SL valve Aortic SL valve
B
Right AV (tricuspid) valve
Skeleton of heart Left AV (mitral) valve Right AV (tricuspid) valve
FIGURE 22.8
The structure of the heart valves. A The heart valves in this drawing are depicted as viewed from above (looking down into the heart). Note that the semilunar (SL) valves are closed and the atrioventricular (AV) valves are open, as when the atria are contracting. B is similar to A except that the semilunar valves are open and the atrioventricular valves are closed, as when the ventricles are contracting.
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Base of heart Pulmonary semilunar valve Aortic semilunar valve Left AV (mitral) valve Apex of heart
Right AV (tricuspid) valve
FIGURE 22.9
Relationship of the heart to the anterior wall of the thorax. The location of the heart in relation to the ribs is shown here. AV = atrioventricular.
The sounds are generated by turbulence associated with closing of the heart valves and therefore are important clinically in indicating valve abnormalities. The first sound (‘lub’), known as S1, occurs during ventricular contraction and results from closure of the atrioventricular valves (left mitral valve, right tricuspid valve). This sound is audible in synchrony with the arterial pulse, best felt in the carotid area. The second sound (‘dub’), known as S2, results from closure of the semilunar valves (pulmonary and aortic) at the beginning of ventricular relaxation. Although we usually refer to two heart sounds, it is actually possible to ‘split’ each sound as the valves on the left side tend to close slightly before those on the right side. Such splitting of heart sounds, known as physiological splitting, is more easily audible during inspiration. Furthermore, the sounds from each valve project to specific locations on the anterior thoracic wall, which assists in hearing individual valves (see Fig. 22.9). Heart sounds are often difficult to auscultate (hear using a stethoscope) and require practice to distinguish differences, especially the individual valves. The valves are best heard by placing the stethoscope at the following locations (see Fig. 22.10): • aortic valve: second intercostal space on the right-hand side of the sternum
Aortic area (base)
Pulmonic area
Erb’s point Tricuspid area Mitral area (apex)
FIGURE 22.10
Cardiac auscultatory areas. The areas for location of heart sounds correspond to the ribs as landmarks.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
• pulmonary valve: second intercostal space on the left-hand side of the sternum • tricuspid valve: fourth intercostal space on the left-hand side of the sternum • mitral valve: fifth intercostal space in the midclavicular line (apex).
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FOCU S ON L EA RN IN G
1 Briefly describe the heart wall. 2 Outline the pathway of blood flow through the heart and circulatory system. Include names for the blood vessels and heart chambers and at each point indicate whether the blood is oxygenated or deoxygenated. 3 Name the heart valves and indicate their locations. 4 Discuss what causes the heart sounds and how to distinguish them.
The circulatory anatomy of the fetus is substantially different from that of a newborn. The differences reflect the presence of the umbilical cord and the functions performed by the mother. Umbilical cord The placenta is an organ that grows early in embryonic development and its function is to allow the exchange of nutrients, wastes and blood gases between the circulations of the mother and the fetus. Blood vessels travel between the placenta and the fetus via the umbilical cord and enter the fetus at the umbilicus (see Fig. 22.11). The umbilical cord contains one umbilical vein, which returns oxygenated nutrient-rich blood from the mother, via the placenta, towards the fetal heart. Two umbilical arteries, which arise from the fetal internal iliac arteries, transport deoxygenated blood and waste products towards the placenta, to be eliminated by the mother. It is important to note that although extensive exchange between maternal and fetal blood components occurs, the two blood supplies do not actually mix. Fetal circulatory features The anatomical and physiological features of the fetal circulation are required because the placenta undertakes
Blood flow during the cardiac cycle The pumping action of the heart consists of contraction and relaxation of the myocardial layer of the heart wall. Each contraction and the relaxation that follows it constitutes one cardiac cycle. Blood flow through the heart during a single cardiac cycle is illustrated in Fig. 22.13. During diastole (relaxation), blood fills the ventricles. The ventricles fill rapidly in early diastole and again in late diastole when the atrium contracts, known as atrial kick. The ventricular contraction that follows, termed systole, propels the blood out of the ventricles and into the circulation. Contraction
the functions of the lungs, digestive system, waste removal and immune function of the fetus. Accordingly, the fetal liver and lungs require only minimal blood flow and three vascular shunts bypass blood from these organs. The features that are unique to the fetus are: • Ductus venosus: a continuation of the umbilical vein, which allows blood to bypass the fetal liver. The amount of blood bypassing the liver through the ductus venosus changes throughout the gestation period, reflecting hepatic development. This vessel closes after birth (and becomes the ligamentum venosum). • Foramen ovale: an opening between the right and left atria in the septum, which allows most fetal blood to pass directly from the right atrium to the left atrium, thereby bypassing the fetal lungs. This opening closes shortly after birth (and becomes the fossa ovalis). • Ductus arteriosis: a vessel that connects the pulmonary artery directly with the aorta, further bypassing the fetal lungs. This vessel closes after birth (becoming the ligamentum arteriosum). These fetal shunts usually close shortly after birth to allow adequate perfusion of the lungs and liver (see Fig. 22.12).
of the left ventricle is slightly earlier than contraction of the right ventricle to ensure left-sided emptying before blood is ejected from the right (see Fig. 22.14). The phases of the cardiac cycle can be identified on initiation of ventricular myocardial contraction (see Fig. 22.15): Ventricular systole (contraction) 1a Isovolumetric ventricular contraction: characterised by unchanging ventricular volume (as both sets of heart valves are closed), as the pressure increases rapidly. 1b Ventricular ejection: the pressure in the ventricle reaches a peak, and the aortic valve opens causing a rush of blood out of the ventricle and into the aorta. This
PAEDIATRICS
Paediatrics and fetal circulation
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Ductus arteriosus Pulmonary trunk
Aortic arch
Ascending aorta Superior vena cava
Left lung
Foramen ovale Right lung
Liver
Abdominal aorta
Inferior vena cava Ductus venosus Maternal side of placenta Fetal side of placenta
Hepatic portal vein
Umbilical vein
Common iliac artery
Fetal umbilicus Umbilical arteries
Internal iliac arteries
Umbilical cord
FIGURE 22.11
Plan of fetal circulation. Before birth, the human circulatory system has several special features that adapt the body to life in the womb. These features (labelled in red type) include two umbilical arteries, one umbilical vein, ductus venosus, foramen ovale, ductus arteriosus and umbilical cord.
phase is completed by the closing of the aortic valve and corresponds to the second heart sound as described earlier. Ventricular diastole (relaxation) 2a Isovolumetric ventricular relaxation: ventricular volume remains the same, as the pressure drops. 2b Ventricular filling: this includes passive filling, which is followed by ventricular filling during atrial contraction.
The coronary circulation Blood within the heart chambers does not supply oxygen and other nutrients to the cells of the heart, as blood travels through these chambers too quickly for oxygen and other nutrients to diffuse through the thick myocardium. Like all organs (including the lungs), the heart structures are nourished by vessels of the systemic circulation. The branch
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
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Superior vena cava Aortic arch
Ascending aorta Foramen ovale becomes fossa ovalis
Ductus arteriosus becomes ligamentum arteriosum
Inferior vena cava Liver Pulmonary trunk
Ductus venosus becomes ligamentum venosum
Abdominal aorta
Hepatic portal vein Umbilical vein becomes round ligament
Kidney Umbilicus
Umbilical arteries become umbilical ligaments
Common iliac artery Internal iliac arteries
FIGURE 22.12
Changes in circulation after birth. After birth the foramen ovale closes to become the fossa ovalis, the ductus arteriosus closes to become the ligamentum arteriosum and the ductus venosus becomes the ligamentum venosum.
of the systemic circulation that supplies the heart is termed the coronary circulation and consists of coronary arteries, which receive blood, during ventricular diastole through openings in the aorta called the coronary ostia. The coronary veins carry blood away from the cells and empty into the right atrium through the opening of a large vein called the coronary sinus (see Fig. 22.16).
Coronary arteries
The right coronary artery and the left coronary artery (see Fig. 22.16) traverse the epicardium, myocardium and endocardium, and branch to become arterioles and then capillaries. Their main branches are outlined in Box 22.1.
Collateral arteries
The collateral arteries are really connections, or anastomoses, between two branches of the same or the opposite coronary artery. The epicardium contains more collateral vessels than the endocardium. It may surprise you to learn that we are capable of growing new blood vessels — this process of angiogenesis may be initiated by increasing amounts of tissue (such as during weight gain or the growth of cancers) or when existing vessels are not delivering sufficient oxygen. In this case, gradual coronary occlusion results in the growth of coronary collaterals. The collateral circulation is responsible for supplying blood and oxygen to the myocardium, which has been deprived of oxygen following severe narrowing and reduced vasoelastic function (how
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Systole
B
Diastole
A
Semilunar valves open L. atrium
L. atrium R. atrium
Semilunar valves closed
L. ventricle
R. ve nt ric le
R. atrium
L. ventricle
R. ve nt ric le
Atrioventricular valves closed
Atrioventricular valves open
FIGURE 22.13
Blood flow through the heart during a single cardiac cycle. A During diastole, blood flows into atria, atrioventricular valves are pushed open and blood begins to fill ventricles. Atrial systole squeezes any blood remaining in atria out into the ventricles. B During ventricular systole, the ventricles contract, pushing blood out through the semilunar valves into the pulmonary artery (right ventricle) and aorta (left ventricle).
BOX 22.1
Main branches of the coronary arteries
• Left coronary artery. Arises from a single ostium behind the left cusp of the aortic semilunar valve; ranges from a few millimetres to a few centimetres long; passes between the left arterial appendage and the pulmonary artery and generally divides into two branches: the left anterior descending artery and the circumflex artery; other branches are distributed diagonally across the free wall of the left ventricle. • Left anterior descending artery (or anterior interventricular artery). Delivers blood to portions of the left and right ventricles and much of the interventricular septum; travels down the anterior surface of the interventricular septum towards the apex of the heart. • Circumflex artery. Travels in a groove (coronary sulcus) that separates the left atrium from the left ventricle and extends to the left border of the heart; supplies blood to the left atrium and lateral wall of the left ventricle; often branches to the posterior surfaces of the left atrium and left ventricle. • Right coronary artery. Originates from an ostium behind the right aortic cusp, travels from behind the pulmonary artery and extends around the right heart to the heart’s posterior surface, where it branches to the atrium and ventricle; three major branches are the conus (supplies blood to the upper right ventricle), right marginal branch (travels along the right ventricle to the apex), and posterior descending branch (lies in posterior interventricular sulcus and supplies smaller branches to both ventricles).
far the blood vessel stretches) of a major coronary artery. New collateral vessels are formed through angiogenesis, which is stimulated by hypoxia and vascular endothelial growth factor. In response to flow, stress and pressure, collateral vessels are restructured and remodelled through the production (synthesis) and degradation of extracellular matrix components in the vessel wall.
Coronary capillaries
The heart has an extensive capillary network. Blood travels from the arteries to the arterioles and then into the capillaries, where exchange of oxygen and other nutrients takes place. At rest, the heart extracts on average 70–80% of the oxygen delivered to it and coronary blood flow is directly related to myocardial oxygen consumption. Therefore, as myocardial oxygen requirements increase,
Cardiac cycle
4 Isovolumetric ventricular relaxation
3
Pressure (mmHg)
100 80
20
After passing through the extensive capillary network, blood from the coronary arteries drains into the cardiac veins, which travel alongside the arteries. Most of the venous drainage of the heart occurs through veins in the visceral pericardium. The veins then feed into the great cardiac vein (see Fig. 22.16) and coronary sinus (a cavity that acts like a vein) on the posterior surface of the heart, between the atria and ventricles, in the coronary sulcus. The deoxygenated blood of the coronary sinus empties directly into the right atrium, along with deoxygenated blood returning from the remaining systemic circulation. The myocardium has an extensive system of lymphatic vessels. With cardiac contraction, the lymphatic vessels drain fluid to lymph nodes in the anterior mediastinum that eventually empty into the superior vena cava. The lymphatics are important for protecting the myocardium against injury (see ‘The lymphatic system’ below).
Ventricular volume (mL)
Coronary veins and lymphatic vessels
Aortic blood flow (L/min)
FIGURE 22.14
such as during exercise, so too must coronary blood flow increase.
2b Ventricular filling
Aortic valve closes
Aortic pressure
Left ventricular pressure
Mitral valve closes
Mitral valve opens
0
The phases of the cardiac cycle. 1 Atrial systole. 2 Isovolumetric ventricular contraction. Ventricular volume remains constant as pressure increases rapidly. 3 Ejection. 4 Isovolumetric ventricular relaxation. Both sets of valves are closed, and the ventricles are relaxing. 5 Passive ventricular filling. The atrioventricular (AV) valves are forced open and the blood rushes into the relaxing ventricles.
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60 40
Ejection
Aortic valve opens
2a Isovolumetric relaxation
120
2 Ventricular diastole (relaxation)
Isovolumetric ventricular contraction
1b Ventricular ejection
2
1a Isovolumetric contraction
Passive ventricular filling
Atrial systole
1 Ventricular systole (contraction)
1
5
Cardiac pumping cycle
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
Left atrial pressure
5 4 3 2 1 0
125 100 75 50 0
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Time (sec)
FIGURE 22.15
Composite chart of heart function. This chart is a composite of several diagrams of heart function (cardiac pumping cycle, blood pressure, blood flow and volume), all adjusted to the same timescale.
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A
B
Superior vena cava
Pulmonary trunk
Aorta
Left coronary artery
Aortic semilunar valve
Left atrium
Right atrium
Pulmonary trunk Left atrium
Right atrium
Coronary sinus
Circumflex artery
Right coronary artery Right marginal artery
Aorta
Superior vena cava
Left anterior descending artery Left ventricle Right ventricle
Posterior interventricular artery
Middle cardiac vein Great cardiac vein
Great cardiac vein Small cardiac vein
Left ventricle
Right ventricle
C Aorta Superior vena cava
Pulmonary trunk Left pulmonary arteries
Right pulmonary arteries Right pulmonary veins Right atrium Right coronary artery Right ventricle
Left pulmonary veins Left atrium Left coronary artery
Left anterior descending artery Left ventricle
Inferior vena cava
FIGURE 22.16
Coronary circulation. A Arteries. B Veins. Both A and B are anterior views of the heart. Vessels near the anterior surface are more darkly coloured than vessels of the posterior surface seen through the heart. C View of the anterior (sternocostal) surface.
FOCUS O N L E ARN IN G
1 Discuss the anatomical differences between the fetal circulation and the adult circulation. Explain why each of the 3 features unique to the fetus is of benefit to the fetus. 2 Describe the phases of the cardiac cycle. 3 Explain the function of the coronary circulation.
Structures that control heart function Myocardial cells
The cells of the myocardium are referred to as cardiac myocytes (muscle cells); they are composed of long, narrow fibres that contain bundles of longitudinally arranged
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
myofibrils. The cardiac muscle is striated and shares many features with skeletal muscle (see Chapter 20). In this section, we compare skeletal and cardiac muscle and explore the features that are unique to the cells of our hearts. There are two types of cells within the heart: myocardiocytes and pacemaker cells. Myocardiocytes make up the atria and ventricles cells and are made up of two types: contractile (cells that can shorten and lengthen their fibres) and autorhythmic/conductile (those that create and transmit impulses fibres). Although both cardiac muscle cells and skeletal muscle cells are striated (i.e. have repeating sarcomeres), cardiac muscle cells are short and branched, whereas skeletal muscle cells are long without branching. Skeletal muscle cells are multinucleated due to their length; however, cardiac muscle cells being much shorter have only one (or two) nuclei. The differences between cardiac and skeletal muscle reflect heart function and enable cardiac fibres to (1) transmit action potentials quickly from cell to cell, (2) maintain high levels of energy production and (3) gain access to more ions, particularly sodium and potassium, in the extracellular environment. First, electrical impulses are transmitted rapidly from one cardiac fibre to another because the network of fibres is connected with intercalated discs, which are thickened portions of the sarcolemma (cell membrane). The intercalated discs contain two junctions: desmosomes, which attach one cell to another, and gap junctions (see Fig. 22.17), which allow the electrical impulse to spread from cell to cell. Together, these junctions provide a low-resistance pathway for impulse transmission. As the gap junctions allow the electrical impulses to spread between cells immediately, it allows the cardiac muscles to contract in unison. Second, unlike skeletal muscle, the heart cannot rest and is in constant need of energy compounds such as adenosine triphosphate (ATP). Therefore, the cytoplasm surrounding the bundles of myofibrils in each cardiac muscle cell contains a superabundance of mitochondria (25% of the cellular volume is mitochondria compared to 2% for skeletal muscle cells). Cardiac muscle cells have more mitochondria than do skeletal muscle cells to provide the necessary respiratory enzymes for aerobic metabolism and to supply quantities of ATP sufficient for the constant action of the myocardium. Third, cardiac fibres contain more transverse tubules (T tubules) than do skeletal muscle fibres. Because the T tubule system is continuous with the extracellular space and the interstitial fluid, it facilitates the rapid transmission of electrical impulses from the surface of the sarcolemma to the myofibrils inside the fibre. This activates all the myofibrils of one fibre simultaneously. When an action potential is transmitted through the T tubules, it induces the sarcoplasmic reticulum to release its stored calcium, which is necessary to allow, and prolong muscle contraction.
Intercalated disc
Myosin
Actin
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Branched structure of cardiac muscle
Microfibril
Desmosome
Intercalated disc
Mitochondrion
Gap junction FIGURE 22.17
Electrical coupling of cardiac myocytes. The heart muscle cells are electrically synchronised through gap junctions at the intercalated discs, allowing the electrical signal to quickly spread throughout an entire chamber very quickly.
Myocardial excitation–contraction coupling
Excitation-contraction coupling is the process by which an action potential in the plasma membrane of the muscle fibre triggers the cycle, leading to cross-bridge activity and contraction. Activation of this cycle depends on the availability of calcium; calcium binds with troponin to allow actin–myosin cross-bridge formation (refer to Chapter 20). Cell membrane pumps create concentration gradients across the cell membrane during diastole to create a resting electrical potential of −80 to −90 mV. Normally, extracellular fluid contains approximately 140 mmol/L sodium and 4.0 mmol/L potassium. In intracellular fluid these concentrations are reversed, a process dependent on the sodium potassium ATP pump. At rest cell membranes are more permeable to potassium and consequently potassium moves slowly and passively down its concentration gradient from intracellular to extracellular fluid. There are five key phases to the cardiac action potential: 0 depolarisation 1 early rapid repolarisation 2 plateau phase
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3
final rapid repolarisation 4 resting membrane phase. Phase 0, the phase of rapid depolarisation, results in a rapid upstroke in the action potential caused by the rapid ion movement of sodium flowing into the cell altering the charge from −90 mV to +30 mV. This inward rapid flow of sodium is the result of sodium channels opening. Phase 1 is the brief beginning of repolarisation, the result of abrupt closure of sodium channels and the initiation of a transient outward flow of potassium resulting in the curve returning to approximately 0 on the action potential curve (Fig. 22.18). Phase 2, known as the plateau phase of the action potential curve, is the result of influx of calcium via the fast channels and then more via the slower channel, the time of which determines stroke volume due to its influence on the contractile strength of muscle fibres. Calcium is stored in the T tubule system and the sarcoplasmic reticulum (located around the myofibrils). After electrical excitation, calcium enters the myocardial cell from the extracellular fluid, due to the opening of calcium channels (L-type, T-type) in cardiac tissues. The L-type, or long-lasting, channels predominate and are the channels blocked by commonly used calcium channel-blocking drugs (verapamil, nifedipine, diltiazem). These drugs lessen the strength of cardiac contraction, thereby decreasing the heart’s requirements for oxygen, and treat angina pectoris (refer to Chapter 23). During phase 3, the potassium channel opens, increasing potassium exodus for the cell. This process, coupled with the sodium potassium pump restores the cell to its maximal diastolic negativity before the next depolarisation occurs (phase 4) and the cycle repeats.
+40 +30
Phase 1
+20 +10
Phase 2
Voltage (mV)
0 –10 –20 –30 –40 –50 –60
Phase 3 Phase 0
–70 –80 –90
Phase 4
Cardiac muscle action potential stages FIGURE 22.18
Phases of a cardiac action potential. Phase 0: rapid depolarisation, Phase 1: brief beginning of repolarisation, Phase 2: the plateau phase of the action potential curve, Phase 3: rapid repolarisation phase, and Phase 4: resting membrane potential.
A refractory period, during which no new cardiac action potential can be initiated by a stimulus, follows depolarisation. The absolute refractory period corresponds to the time needed for the reopening of channels that permit sodium and calcium influx (beginning of phase 0 to almost the end of phase 3). A relative refractory period occurs near the end of repolarisation, following the effective refractory period (remainder of phase 3 from −60 mV to −85 mV). Importantly, the refractory period in cardiac myocytes is quite long — much longer than for skeletal muscle. This is particularly important in the cardiac myocyte, as it prevents additional contractions from occurring immediately, thereby allowing time for filling.
Myocardial relaxation
Adequate relaxation is just as vital to optimal cardiac function as contraction, as relaxation allows for the filling of chambers with blood. After contraction, free calcium ions are actively pumped out of the cell cytoplasm back into the interstitial fluid or are reaccumulated in the sarcoplasmic reticulum and stored. Troponin releases its bound calcium. The tropomyosin complex blocks the active sites on the actin molecule, preventing cross-bridges with the myosin heads. Relaxation of the myocardium then permits filling of the heart chambers.
Myocardial metabolism
Cardiac muscle depends on the constant production of ATP for energy. ATP is produced within the mitochondria mainly from glucose, fatty acids and lactate. If the myocardium is inadequately perfused (has inadequate blood flow), such as during coronary heart disease, anaerobic metabolism becomes an essential source of energy. The energy produced by metabolic processes is used for muscle contraction and relaxation, electrical excitation, membrane transport and production of large molecules. Normally, the amount of ATP produced supplies sufficient energy to pump blood throughout the system. The oxygen supply to the myocardium is delivered exclusively by the coronary arteries. Approximately 70–75% of the oxygen from the coronary arteries is used immediately by cardiac muscle, leaving little oxygen in reserve. Any increased energy needs can be met by increasing coronary blood flow. When oxygen content decreases, the local concentration of metabolic factors increases. One of these, adenosine, dilates coronary arterioles, thereby increasing coronary blood flow, providing more oxygen and restoring homeostasis. The oxygen content of the blood cannot be increased under normal atmospheric conditions, nor can the amount of oxygen extracted from the blood be appreciably increased from the resting level. However, myocardial oxygen consumption can increase several-fold with exercise and decrease moderately under conditions such as hypotension and hypothermia. As such, the cardiac muscle cells are susceptible to damage from oxygen deficiency.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
F O CUS O N L E A R N IN G
1 Describe the structural features of the cardiac muscle cells that are specialised to cardiac function. 2 Explain the process of excitation–contraction coupling in the myocardium. 3 Briefly list features of myocardial relaxation and the metabolism of the myocardium.
The cardiac conduction system
The continuous, rhythmic repetition of the cardiac cycle (systole and diastole) depends on the transmission of electrical impulses, termed cardiac action potentials, through the myocardium. (Action potentials are described in Chapter 6.) Because the muscle fibres of the myocardium are uniquely joined by intercalated discs, action potentials pass from cell to cell rapidly and efficiently. This allows cells to contract synchronously, thereby allowing coordination of cells and coordination of heart function. The myocardium contains its own conduction system — specialised cells that enable it to generate and transmit action potentials without stimulation from the nervous system. These cells are concentrated at certain sites in the myocardium called nodes. Normally, electrical impulses arise in the sinoatrial node (SA node), which is often called the pacemaker of the heart. The SA node is located at the junction of the right atrium and superior vena cava, just above the tricuspid valve (see Fig. 22.19). The SA node is heavily innervated by both
Sinus node
Internodal pathways
AV node AV bundle Left bundle branch Right bundle branch
FIGURE 22.19
The cardiac conduction system. Sinoatrial node, intermodal pathways, atrioventricular node, ventricular bundle branches (bundle of His), and the Purkinje system of the heart. AV = atrioventricular.
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sympathetic and parasympathetic nerve fibres. In the resting adult, the SA node generates about 75 action potentials per minute. Each one travels rapidly from cell to cell and through special pathways in the atrial myocardium (left and right), causing both atria to contract, thus beginning systole. The SA node is responsible for setting the regular rhythm of the heart — this regular rhythm is referred to as the sinus rhythm. Ventricular contraction is delayed because the fibrous skeleton of the heart interrupts cell-to-cell transmission of the electrical impulses. In this manner, the atria can contract first (often called atrial kick), which has the important role of ‘topping up’ the blood volume of the ventricles (prior to their contraction). The action potential is transmitted from the atrial to the ventricular myocardium through fibres of the conduction system, travelling first to the atrioventricular node (AV node), then to the bundle of His (atrioventricular bundle) and finally through the bundle branches of the interventricular septum to Purkinje fibres in the heart wall (see Fig. 22.19). The AV node is well situated for controlling conduction between the atria and ventricles. It is located in the right atrial wall above the tricuspid valve. Behind it are numerous autonomic parasympathetic ganglia. These ganglia serve as receptors for the vagus nerve (of the parasympathetic nervous system) and cause slowing of impulse conduction through the AV node. Conducting fibres from the AV node converge to form the bundle of His, which travels a short distance inferiorly before splitting into the right and left bundles. The right bundle branch is thin and travels without much branching to the right ventricular apex. Because of its thinness and relative lack of branches, the right bundle branch is susceptible to interruption by damage to the endocardium. The left bundle branch arises perpendicularly from the bundle of His and, in some hearts, divides into two branches, or fascicles — a left anterior bundle branch and a left posterior bundle branch. Blood flow through the posterior of the left ventricle is relatively non-turbulent, so the left bundle branch is somewhat protected from injury caused by wear and tear. The Purkinje fibres are the terminal branches of the right and left bundle branches. They extend from the ventricular apices to the fibrous rings and penetrate the heart wall to the outer myocardium. From the SA node the impulse that begins contraction spreads throughout the right atrium at a conduction velocity of about 1 metre per second. Intermodal conducting pathways conduct the impulse from the SA node to the left atrium and also from the SA node to the AV node. From the AV node, the impulse travels from the atrioventricular bundle and through the bundle branches to the Purkinje fibres. The first areas of the ventricles to be excited are portions of the interventricular septum. The septum is activated from both the right bundle branch and the left bundle branch. The extensive network of Purkinje fibres promotes the rapid spread of the impulse to the
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ventricular apices. The basal and posterior portions of the ventricles are the last to be activated.
Action potentials of the cardiac conduction system
Automaticity, or the property of generating spontaneous depolarisation to threshold, enables the SA and AV nodes to generate cardiac action potentials without any stimulus. Cells capable of spontaneous depolarisation are called autorhythmic cells. These cells of the cardiac conduction system can stimulate the heart to beat even when it is removed from the body. The membrane potential of autorhythmic cells does not actually have a stable membrane potential at ‘rest’. Instead, it slowly creeps towards threshold during the diastolic phase of the cardiac cycle. During this time, slow depolarisation occurs due to the opening of slow sodium channels, which allows a gradual influx of sodium ions, causing the membrane potential to approach threshold (see Fig. 22.20). Once the threshold of –40 mV has been reached, calcium channels open, allowing for rapid calcium influx from the extracellular fluid. This causes the main depolarisation (upwards) spike in the graph on Fig. 22.20. This contrasts with the action potentials of other excitable tissues (neurons and muscles), whereby in those cells the depolarisation is due to sodium entry. Finally, the calcium channels close and the potassium channels open, allowing potassium to exit the cell, resulting in repolarisation, which returns the autorhythmic cells to ‘rest’. This is instantly followed by slow depolarisation, which allows the next action potential to commence. Rhythmicity is the regular generation of an action potential by the heart’s conduction system. The electrical impulse begins in the SA node and it sets the pace because it has the fastest rate of depolarisation (compared with other
Potassium exit
Calcium entry
Millivolts charge
SA NODE 0
Slow depolarisation: sodium entry
–80 0
200
400
600
800
Time (milliseconds) FIGURE 22.20
Cardiac action potentials in the SA node. The cardiacexcitatory centre increases blood pressure and heart rate via the sympathetic nervous system. The cardioinhibitory centre decreases heart rate via the parasympathetic nervous system.
components of the conduction system). The SA node depolarises spontaneously between 60 and 100 times per minute — average is approximately 75 times per minute, which results in a heart rate of 75 beats per minute. If the SA node is damaged, the AV node will become the heart’s pacemaker at a rate of about 40–60 spontaneous depolarisations per minute. Purkinje fibres are capable of spontaneous depolarisation, but at a rate of only 30–40 beats per minute (see Fig. 22.20).
RESEARCH IN F CUS Aerobic exercise, heart rate and arterial stiffness Resting heart rate and arterial stiffness are associated with a high risk for cardiovascular disease. As little as 12 weeks’ aerobic exercise has been shown to decrease resting heart rate and arterial stiffness (measured using a technique that measures brachial-ankle pulse velocity) as well as lower systolic and diastolic blood pressure, resulting in reducing future cardiovascular risk. Additionally, in this study of women with known metabolic syndrome, exercise resulted in significant reductions in other measures of metabolic syndrome including body weight, waist circumference and fasting blood sugar.
Cardiac innervation
Although the cardiac cells are autorhythmic, the rate of SA node depolarisation is usually controlled by the sympathetic and parasympathetic fibres of the autonomic nervous system. Thus, the heart will beat in the absence of any nervous connection. Stimulation of the SA node by the sympathetic nervous system rapidly increases heart rate. Furthermore, noradrenaline and adrenaline interact with β1 (beta1)adrenergic receptors on the cardiac muscle cell membranes. The overall effect is an increased influx of calcium, which increases the contractile strength of the heart and increases the speed of electrical impulses through the heart muscle and the nodes (see Fig. 22.21). The parasympathetic nervous system affects the heart through the vagus nerve, which releases acetylcholine. Acetylcholine causes decreased heart rate and slows conduction through the AV node and prolongs intranodal conduction time. In addition to the autonomic nervous system, the heart action is also influenced by substances delivered to the myocardium in coronary blood. Nutrients and oxygen are needed for cellular survival and normal function, whereas hormones and other substances affect the strength and duration of myocardial contraction and the degree and duration of myocardial relaxation. Normal or appropriate function depends on the availability of these substances, which is why coronary heart disease can seriously disrupt heart function.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
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Cardioexcitatory centre
Cardioinhibitory centre
via sympathetic nervous system
via sympathetic nervous system
via parasympathetic nervous system
• SA node
CONCEPT MAP
Cardiac control centres in medulla
Blood vessels Vasoconstriction
Increased heart rate
Decreased heart rate
FIGURE 22.21
Autonomic innervation of the cardiovascular system. The sympathetic nervous system increases both heart rate and vasoconstriction, while the parasympathetic nervous system decreases heart rate.
The electrocardiogram The amount of electrical activity of the heart is substantial when you consider the large number of cells that are depolarising and repolarising in unison. In fact, the amount of activity is so great that this current is conducted through body fluids and can be recorded from the body surface — by electrocardiogram (ECG). ECG is performed using a number of electrodes that are placed in specific locations on the body surface; these electrodes reflect different aspects of the heart. The standard position for recording an ECG is to have the patient supine (lying down on their back), although other positions may be used too (such as while the patient exercises during a stress test). The position of the electrodes for the standard limb leads (leads I, II and III) is shown in Fig. 22.22. The recording electrodes are attached to both arms and the left leg, in positions that essentially form a triangle around the body (Einthoven’s triangle). Importantly, only two electrodes are active at any one time. Each electrode pair (one positive, one negative) is referred to as a lead and recordings from each lead give different traces from the ECG trace. In addition to the standard leads, augmented limb leads (aVR, aVL, aVF) provide further traces, which are made by comparisons between the existing limb leads. The use of the chest (precordial) leads requires six more leads being placed at specific locations around the chest (see Fig. 22.23): • V1: fourth intercostal space, right sternal border • V2: fourth intercostal space, left sternal border
• • • •
V3: midway between V2 and V4 V4: fifth intercostal space, midclavicular line V5: anterior axillary line, same level with V4 V6: midaxillary line, same level with V4 and V5. By combining the standard limb leads, the augmented limb leads and the chest lead recordings, a comprehensive view of heart function can be obtained using a 12-lead ECG (see Fig. 22.24). Although the ECG recording appears different for each of the 12-lead recordings, some underlying principles common to all traces are: • action potentials of cardiac conduction cells cause voltage changes • a wave that is travelling towards the positive lead will have an upward deflection • a wave that is travelling away from the positive lead will have a downward deflection • waves that are travelling at a 90° angle to a particular lead will create no deflection, and this is called an isoelectric signal. On an ECG recording (see Fig. 22.25), the waves or segments and their corresponding cardiac events are: • P wave: this represents right and left atrial depolarisation. • PR interval: this is a measure of time from the onset of atrial activation (P wave) to the onset of ventricular activation (beginning of QRS), normally 0.12–0.20 seconds. It is the time necessary for electrical activity to travel from the SA node through the atria, AV node, bundle of His and Purkinje fibres to activate ventricular myocardial cells.
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Right arm RA _ _
Left arm LA + _
I
II
LL RA
III Einthoven’s triangle
LA
+
+ Left leg LL
I +
RA
_ aVF
LA
+ II
_ aVL aVR _ III LL + Electrocardiograph FIGURE 22.22
Electrocardiogram limb leads. Electrodes are placed on the right arm (RA) or wrist, on the left arm (LA) or wrist and on the left leg (LL) or ankle. Einthoven’s triangle shows the ‘electrical angle’ of each of the three standard limb leads: I, II and III. The inset shows the electrical angle of the augmented limb leads (aVR, aVL, aVF), which combine limb leads to form virtual leads given different angles of electrical voltage measurement.
• QRS complex: this represents ventricular depolarisation. The QRS complex represents the sum of all ventricular muscle cell depolarisations (Q wave = first negative wave after P wave representing septal depolarisation; R wave = first positive wave representing ventricular depolarisation; and S wave = return to isoelectrical line). The configuration and amplitude of the QRS complex vary considerably between individuals. The duration is normally between 0.06 and 0.10 seconds. Atrial repolarisation is also occurring at this time.
• ST segment: during the ST interval, the entire ventricular myocardium is depolarised, so the ventricles are contracting. • QT interval: this is sometimes called the ‘electrical systole’ of the ventricles. It lasts about 0.4 seconds but varies inversely with the heart rate. • T wave: this represents ventricular repolarisation. • TP segment: this represents ventricular relaxation and filling.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
Electrical depolarisation refers to the spread of action potentials through the cardiac muscle. The action potential initiates events that cause the interaction of actin and myosin, thereby causing muscle contraction. If we consider how this relates to an ECG (see Fig. 22.26), the atrial depolarisation of the P wave causes contraction of the atria (Fig. 22.26B and C), followed by atrial repolarisation (relaxation; see Fig. 22.26D). Next, the QRS complex corresponds to ventricular depolarisation, reflected in the contraction of the ventricles (see Fig. 22.26D and E). The ventricles then repolarise (relax; see Fig. 22.26F) and the heart cycle is fully relaxed and the cycle is ready to commence again (see Fig. 22.26G).
V6
LV
RV
V5
V 1 V2 V1
V2
V3
V4
V5
V3
V4
V6
FOCU S ON L EA RN IN G
1 Describe the components of the cardiac conduction system. 2 Discuss how electrical impulses travel through the cardiac conduction system. 3 Describe the action potentials of the cardiac conduction cells, and explain how the cells are able to generate action potentials without any input from the nervous system. 4 Explain how the autonomic nervous system influences heart activity. 5 Briefly outline how to position electrodes for an ECG and explain how to interpret an ECG recording.
Factors affecting cardiac performance Cardiac performance can be quantified by measuring the cardiac output. Cardiac output is the volume of blood that is pumped out of the heart and flows through the systemic (or pulmonary) circuit over 1 minute; it is expressed in litres per minute. To determine cardiac output, heart rate is multiplied by stroke volume (the volume of blood pumped out of one ventricle with each contraction). Normal cardiac output is approximately 5 litres per minute for a resting adult. Cardiac output = heart rate × stroke volume = 75 beats min × 70 mL beat = 5.25 L min
FIGURE 22.23
Electrocardiogram chest leads. Electrodes are placed at specific locations across the chest. Each of these is compared with a single virtual lead formed by the combination of all three limb electrodes and electrically positioned approximately over the spine.
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Although the ventricular contraction is powerful, it does not eject all the blood it contains. The maximum amount of
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
II
FIGURE 22.24
12-lead electrocardiogram recording. This brief recording of a typical 12-lead ECG shows information recorded from all six limb leads and all six chest leads. Note that they are all printed above a continuous recording of lead II, which becomes a point of reference. Health professionals can usually get more information from 12 different ECG leads than from any one ECG lead.
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A R ECG deflections
stroke volume end-diastolic volume 70 mL beat = 120 mL beat = 58%
Ejection fraction =
T
Voltage
P
Thus, an average of 70 mL of blood is pumped out of each ventricle during ventricular contraction. An alternative measure of the amount of blood leaving the ventricle with contraction is the ejection fraction, which indicates the percentage of blood that has filled the ventricle and that is then ejected with ventricular contraction. It is calculated as follows:
Ventricular Q S Atrial repolarisation depolarisation Ventricular depolarisation (and atrial repolarisation) Time
B R ECG intervals
ST segment
T
Voltage
P
PR interval 0.12–0.20 sec
QRS under 0.10 sec QT interval under 0.38 sec
Time FIGURE 22.25
Electrocardiogram and cardiac electrical activity. A Normal ECG: depolarisation and repolarisation. B ECG intervals among P, QRS and T waves.
blood that fills the ventricle during diastole (relaxation) is defined as the end-diastolic volume, while the volume that remains in the ventricle at the end of systole (contraction) is known as the end-systolic volume. It is the difference between these two values which gives us the stroke volume: Stroke volume = end-diastolic volume − end-systolic volume = 120 mL beat − 50 mL beat = 70 mL beat
The normal ejection fraction of the resting heart is in the range of 55–75%. The ejection fraction is increased by factors that increase contractility (e.g. sympathetic nervous system activity). A decrease in the ejection fraction is a hallmark of ventricular failure and is used clinically to assist with diagnosis of ventricular performance. The ejection fraction can be measured clinically using echocardiography or injection of a dye during cardiac ventriculography (such as during a coronary angiogram; refer to Chapter 23). The factors that determine cardiac output are (1) preload, (2) afterload, (3) myocardial contractility and (4) heart rate. Preload, afterload and contractility all affect stroke volume.
Preload
Preload is influenced by the factors just prior to ventricular contraction and is determined by the end-diastolic volume (and the associated end-diastolic pressure). The first factor is the amount of venous return to the ventricle, which relates directly to the end-diastolic volume — the amount of blood returning to the heart and filling the ventricle. More filling of blood leads to a greater volume of blood available to leave the heart as stroke volume. Also, muscle fibres have an optimal resting length from which to generate the maximum amount of contractile strength (the length–tension relationship; refer to Chapter 20). The Frank-Starling law of the heart describes the length–tension relationship between the end-diastolic volume (amount of filling) and the stroke volume. Within a normal range of muscle stretching, increased preload increases cardiac output (see Fig. 22.27). However, excessive stretching causes actin and myosin to become completely disengaged and causes the developed tension (force of contraction) to drop to zero. The relationship between stretch and contraction can be compared with the actions of a rubber band. To a certain point, the more the rubber band is stretched, the further it will fly when one end is released. Beyond that amount of stretching, the rubber band will break. Factors that increase contractility cause the heart to operate on a higher length–tension curve. Heart failure is characterised by a lower length–tension curve. Fig. 22.28 demonstrates the relationship between end-diastolic volume and cardiac output.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
A
585
B P
C
D P
P Q S
E
F
R P
QRS complex P wave
T wave
Q
S
G
QRS complex P wave
T wave
Depolarisation Repolarisation
FIGURE 22.26
Events represented by electrocardiogram. A The heart wall is completely relaxed, with no change in electrical activity, so the ECG remains constant. B The P wave occurs when the AV node and atrial walls depolarise. C The atrial walls are completely depolarised, and thus no change is recorded on the ECG. D The QRS complex occurs as the atria repolarise and the ventricular walls depolarise. E The atrial walls are now completely repolarised, the ventricular walls are now completely depolarised and thus no change is seen on the ECG. F The T wave appears on the ECG when the ventricular walls repolarise. G Once the ventricles are completely repolarised, we are back at the baseline of the ECG.
Afterload
Left ventricular afterload refers to the resistance ‘downstream’ to the ejection of blood from the left ventricle. It is the load the ventricular muscle must move as it contracts. Aortic diastolic pressure is a good index of afterload. Pressure in the ventricle must exceed the pressure within the aorta before blood can be pumped out during systole. Low aortic
pressures (decreased afterload) enable the heart to contract more rapidly, whereas high aortic pressures (increased afterload) slow contraction and cause higher workloads against which the heart must function so that it can eject less blood. This is common in those with increased blood pressure (hypertension), as there is increased pressure in the aorta (refer to Chapter 23). In some individuals, changes in afterload are the result of aortic valvular disease.
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Part 4 Alterations to body maintenance
Myocardial contractility
Cardiac output or stroke volume or stroke work or systolic muscle tension
Stroke volume (the volume of blood ejected per beat) depends on the force of contraction, which is determined by myocardial contractility, or the degree of myocardial fibre shortening. Three major factors determine the force of contraction: (1) changes in the stretching of the ventricular myocardium caused by changes in ventricular filling volume (preload); (2) alterations in the sympathetic activation of
200 Normal contractility
100
0 Ventricular end-diastolic volume (mL)
FIGURE 22.27
The Frank-Starling law of the heart. The relationship between length and tension in the heart. Enddiastolic volume determines the end-diastolic length of the ventricular muscle fibres and is proportional to the tension generated during systole, as well as to cardiac output, stroke volume and stroke work.
the ventricles; and (3) adequacy of myocardial oxygen supply. As discussed previously, increased blood flow from the vena cavae into the heart distends (stretches) the ventricle by increasing preload, which increases the stroke volume and, subsequently, cardiac output. Chemicals affecting contractility are called inotropes. The most important positive inotropes, those that increase contractility, are adrenaline and noradrenaline released from the sympathetic nervous system and adrenal glands. Other positive inotropes include thyroid hormone and dopamine. The most important of the negative inotropes, those that decrease contractility, is acetylcholine released from the parasympathetic nervous system (via the vagus nerve). Many drugs have positive or negative inotropic properties that can have profound effects on cardiac function. Myocardial contractility is also affected by oxygen and carbon dioxide levels in the coronary blood. With severe hypoxaemia (arterial oxygen saturation less than 50% compared with a normal value of approximately 98%), contractility is decreased. On the other hand, with less severe hypoxaemia (oxygen saturation in range of 50–90%), contractility is stimulated, as there may be an increased myocardial response to circulating catecholamines. Preload, afterload and contractility all interact with one another to determine stroke volume and cardiac output.
Heart rate
The average heart rate in adults is about 75 beats per minute, which lowers on average by 10–20 beats/minute during
CONCEPT MAP
Cardiac output
×
Stroke volume Preload
Venous return Enddiastolic volume
Afterload
Aortic pressure Aortic valvular function
Contractility
Enddiastolic volume Sympathetic stimulation Myocardial oxygen supply
Heart rate Central nervous system Autonomic nervous system Neural reflexes Atrial receptors Hormones
FIGURE 22.28
Factors affecting cardiac performance. Cardiac output, which is the amount of blood (in litres) ejected by the heart per minute, depends on the heart rate (beats per minute) and stroke volume (millilitres of blood ejected during ventricular systole).
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
sleep. Substantial slowing of the heart rate to below 60 beats per minute is referred to as bradycardia. In highly trained athletes, the resting heart rate can be below 50 beats/minute, as training produces hypertrophy of the cardiac muscle, leading to a lower resting heart rate and greater stroke volume than before training. In addition, training lowers peripheral resistance in blood vessels by vasodilation in active muscles, which lowers afterload. In effect, each contraction is more powerful than prior to athletic training, so fewer contractions are required. The heart rate can also accelerate to a state of tachycardia of more than 100 beats/ minute during muscular activity, emotional excitement or pathophysiological conditions. The control of heart rate includes activity of the central nervous system, such as excitement, autonomic nervous system (fight–flight stimulation), neural reflexes, atrial receptors and hormones (see Fig. 22.28).
587
Carotid artery
Brachial artery
Pulse
With each ventricular contraction, the pressure entering the arterial system corresponds to a wave of pressure that spreads throughout the major arteries. Hence the pulse is a reflection of the heart rate. The pulse can be palpated at various sites throughout the body, where the artery is located near to the body surface with a bone or other firm tissue behind it. Sites where the pulse points are most easily felt are shown in Fig. 22.29.
RESEARCH IN F CUS Heart rate and cardiovascular mortality Higher heart rate is associated with increased risk of cardiovascular mortality. A linear relationship exists between resting heart rate (RHR) and risk of mortality with metaanalysis of prospective studies to date reporting a 6% increase mortality risk for each 10 bpm increase in RHR.
Radial artery Femoral artery
Popliteal (posterior to knee)
Posterior tibial Dorsalis pedis
FIGURE 22.29
Pulse points. Each pulse point is named after the artery with which it is associated.
F O CUS O N L E A R N IN G
1 Explain how to calculate cardiac output, including the normal values. 2
Briefly explain what the ejection fraction is.
3 Define the term preload and list the factors that determine preload. 4
Explain what afterload is and how it is influenced.
5 Discuss the factors that influence myocardial contractility, including why this is important clinically. 6 List the main factors that alter heart rate.
The physiology of cardiovascular control Cardiovascular control centres in the brain
The cardiovascular control centres are in the medulla oblongata of the brainstem, along with other vital centres such as the respiratory control centre. The neurons from the cardiovascular control centres communicate with the
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Part 4 Alterations to body maintenance
heart via the autonomic nervous system. Because parasympathetic activation generally depresses cardiac function (slows down the SA node rate of depolarisation and decreases the heart rate), this area of the medulla oblongata is referred to as the cardioinhibitory centre. The resting heart rate in healthy individuals is primarily under the control of parasympathetic stimulation, which slows down the rate of the SA node from its inherent (or inbuilt) rate of depolarisation of 100 times per minute to the actual average resting rate of 75 per minute. Excitation or increased heart activity occurs with sympathetic stimulation, which arises from the cardioexcitatory centre in the medulla oblongata. Sympathetic activation increases the rate of depolarisation of the SA node, causing an increase in heart rate. Parasympathetic effects from the vagus nerves override sympathetic effects in the SA node. Secondary brain regions involved in control of cardiovascular function are located in the hypothalamus, cerebral cortex and thalamus, as well as complex networks of exciting or inhibiting interneurons (connecting neurons) throughout the brain. The hypothalamic centres regulate cardiovascular responses to changes in temperature; the cerebral cortex centres adjust cardiac reaction to a variety of emotional states; and the medullary control centre regulates heart rate and blood pressure.
Neural reflexes
The Bainbridge reflex causes the heart rate to increase with increased venous return or after intravenous infusion of fluid (see Fig. 22.30), whereby increased pressure in the right atrium stimulates atrial stretch receptors, leading to a rise in the heart rate. The magnitude of the change in the heart rate depends on the initial heart rate. The baroreceptor reflex facilitates blood pressure changes and heart rate changes. It is mediated by receptors known as baroreceptors, which are stimulated by the amount of stretch in the blood vessel wall due to blood pressure; these are located in the walls of the aortic arch and carotid arteries. These baroreceptors increase their rate of
Intravenous infusion
Increased right atrial pressure
firing, sending neural impulses over the glossopharyngeal nerve (ninth cranial nerve) and through the vagus nerve (tenth cranial nerve) to the cardiovascular control centres in the medulla oblongata. In response to a rise in blood pressure, these centres increase parasympathetic activity and decrease sympathetic activity, causing blood vessels to dilate and the heart rate to decrease. Responses to the baroreceptor reflex return the blood pressure to its previous level, which may or may not be normal. The higher the blood pressure, the greater the reflexive decrease in the heart rate. If blood pressure is decreased, the baroreceptor reflex accelerates the heart rate and causes vessels to constrict, raising blood pressure back towards normal (see Fig. 22.30). Baroreceptor function is discussed in more detail later under ‘Regulation of blood pressure’. Neural receptors in the lungs cause the heart rate to increase during inspiration and decrease during expiration. This is a normal effect of the cardiac cycle and is referred to as sinus arrhythmia. The vagal fibres are stretched in inspiration and inhibit the cardioinhibitory centre of the medulla. This allows unopposed sympathetic acceleration of the heart rate. It is likely that changes in the pressures of the abdominal and thoracic cavities during respiration contribute to sinus arrhythmia. During inspiration, the diaphragm pushes down into the abdominal cavity, thereby increasing the pressure within the cavity. This assists venous return to the heart from the abdominal veins, which results in an increase in the heart rate.
Atrial receptors
Receptors that influence heart rate exist in both atria. They are located in the right atrium at its junctions with the venae cavae and in the left atrium at its junctions with the pulmonary veins. Stimulation of these atrial receptors also increases urine volume, presumably because of a neurally mediated reduction in antidiuretic hormone (ADH). In addition, in response to the increases in blood volume and stretch on cardiac chambers, atrial natriuretic peptide (ANP)
Stimulate atrial receptors
Bainbridge reflex
+ Heart rate
Increased cardiac output
Increased arterial pressure
Baroreceptor reflex
–
FIGURE 22.30
The heart rate and intravenous infusions. Intravenous infusions of blood or electrolyte solutions tend to increase the heart rate through the Bainbridge reflex and to decrease the heart rate through the baroreceptor reflex. The actual change in heart rate induced by such infusions is the result of these two opposing effects.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
is released from atrial tissue and brain natriuretic peptide released primarily from ventricular tissues. BNP and ANP belong to a grouping of protein hormones called natriuretic peptides. These natriuretic peptides have an important role in regulating the circulation. Both ANP and BNP act on blood vessels, causing them to dilate, or widen and also have powerful diuretic and natriuretic (sodium excretion) properties by acting on the kidneys resulting in decreased blood volume and pressure.
Hormones and biochemicals
Hormones and biochemicals affect the arteries, arterioles, venules and capillaries and the contractility of the myocardium. Noradrenaline increases the heart rate, enhances myocardial contractility and constricts blood vessels. Adrenaline dilates vessels of the liver and skeletal muscle, increases heart rate and also causes an increase in myocardial contractility. Some adrenocortical hormones, such as cortisol, potentiate the effects of these catecholamines. Thyroid hormones enhance sympathetic activity, promoting increased cardiac output. A decrease in growth hormone, as well as in thyroid and adrenal hormones, results in bradycardia, reduced cardiac output and low blood pressure. Therefore, overall there are many influences on cardiovascular function.
The systemic circulation The arteries and veins of the systemic circulation are illustrated in Fig. 22.31. Blood from the left side of the heart flows through the aorta and into the systemic arteries. The arteries branch into small arterioles, which branch further into the smallest vessels, the capillaries, where nutrient exchange occurs between the blood and cells. Blood from the capillaries then enters tiny venules that join to form the larger veins, which return venous blood to the right heart. The peripheral vascular system is an imprecise term used to describe the part of the systemic circulation that supplies the skin and the extremities, particularly the legs and feet. Most organs receive an arterial supply of oxygenated blood with venous drainage of deoxygenated blood. However, some organs have a more unusual blood vessel system: • Lungs. In addition to receiving oxygenated blood through the bronchial arteries (which provide nutrient-rich blood to most respiratory tissues), the lungs also receive deoxygenated blood from the pulmonary artery and, after gas exchange, oxygenated blood is drained from the lungs in the pulmonary vein. This pulmonary circulation was discussed earlier in the chapter. • Liver. In addition to receiving oxygenated blood through the hepatic artery (which provides nutrient-rich blood), an additional supply of blood enters through the hepatic portal vein — this blood contains the substances that have been absorbed from the digestive system. This is discussed in Chapter 26 as part of the digestive system.
589
• Brain. The cerebral arterial circle contains anastomoses (connections) of arteries with arteries, which ensures that alternative routes are available for blood to enter the brain. This was discussed in Chapter 6 as part of the neurological system.
Blood vessels
Blood vessel walls are composed of three layers: 1 tunica intima (innermost, or intimal, layer), which lines the vessel lumen or internal cavity 2 tunica media (middle, or medial, layer) 3 tunica externa or adventitia (outermost, or external, layer). These structures are illustrated in Fig. 22.32. Blood vessel walls vary in thickness depending on the thickness or absence of one or more of these three layers. Cells of the larger vessels are nourished by the vasa vasorum, small vessels located in the tunica externa.
Arteries
Arterial walls are composed of elastic connective tissue, fibrous connective tissue and smooth muscle. Elastic arteries have a thick tunica media with more elastic fibres than smooth muscle fibres. They are located nearest to the heart and include the aorta, its major branches and the pulmonary trunk. Elasticity allows the vessels to stretch as blood is ejected from the heart during systole. During diastole, elasticity promotes recoil of the arteries, maintaining blood pressure within the vessels. Muscular arteries are medium-sized and small arteries are further from the heart than the elastic arteries. By the time blood reaches the muscular arteries, the major fluctuations in blood pressure have decreased substantially. Muscular arteries have more muscle fibres than the elastic arteries because they require less stretch and recoil. Muscular arteries distribute blood to arterioles throughout the body and help control blood flow because their smooth muscle can be stimulated to contract or relax. Contraction narrows the vessel lumen — vasoconstriction — which diminishes flow through the vessel. Conversely, when the smooth muscle layer relaxes — vasodilation — more blood flows through the vessel lumen. An artery becomes an arteriole where the diameter of its lumen narrows to less than 0.5 mm. The arterioles are composed almost exclusively of smooth muscle and regulate the flow of blood into the capillaries in two ways: (1) arteriole vasoconstriction, which limits the flow of blood into the capillaries; and (2) arteriole vasodilation, which permits blood to enter the capillaries freely. The thick smooth muscle layer of the arterioles is a major determinant of the resistance blood encounters as it flows through the systemic circulation.
Capillaries
The capillaries are the smallest blood vessels; they are the sites of actual exchange of substances between the blood
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A Occipital Facial
Right common carotid
Internal carotid External carotid Left common carotid Left subclavian
Brachiocephalic
Arch of aorta
Lateral thoracic Right coronary
Pulmonary Left coronary
Axillary
Aorta Celiac
Brachial
Splenic
Superior mesenteric
Renal
Abdominal aorta
Inferior mesenteric Radial
Common iliac
Ulnar
Internal iliac (hypogastric)
Palmar arch: Deep Superficial
External iliac
Digital Deep medial circum ex femoral Deep femoral Femoral Popliteal
Anterior tibial Peroneal Posterior tibial Arcuate Dorsal metatarsal FIGURE 22.31
The circulatory system. A Principal arteries of the body.
Dorsal pedis
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
B
Inferior sagittal sinus
Superior sagittal sinus Straight sinus Transverse sinus Cervical plexus External jugular Internal jugular Left brachiocephalic
Angular Facial Right brachiocephalic Right subclavian
Left subclavian
Superior vena cava
Cephalic Axillary
Right pulmonary
Great cardiac
Small cardiac Inferior vena cava
Basilic
Hepatic
Median basilic
Hepatic portal
Splenic
Median cubital
Inferior mesenteric Common iliac
Superior mesenteric Gastroepiploic Common iliac
Internal iliac
Digital
External iliac
Femoral
Femoral
Great saphenous Popliteal
Small saphenous
Fibular (peroneal) Anterior tibial Posterior tibial
Digital Dorsal venous arch FIGURE 22.31 (continued)
The circulatory system. B Principal veins of the body.
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A
Tunica intima Endothelium Basement membrane Tunica media Smooth muscle Tunica externa
B
Tunica intima Endothelium Basement membrane Tunica media Smooth muscle Tunica externa
Elastic artery
Large vein
C
FIGURE 22.32
Schematic drawing and micrograph of an artery and a vein. Blood vessel walls of A artery and B vein, showing the layers of the vessels and the comparative thicknesses of tissue layers. C Seen here in cross-section is a normal artery (■) with a thick, smooth muscle wall alongside a normal vein (❒) with a thin, smooth muscle wall, running in connective tissue in a fascial plane between muscle bundles of the lower leg.
and the cells (see Fig. 22.33). The capillary network is composed of connective channels, or thoroughfares, called metarterioles and ‘true’ capillaries (see Fig. 22.34). The capillaries branch from the metarterioles, meeting at a ring of smooth muscle called the precapillary sphincter. As the sphincters contract and relax, they regulate blood flow through the capillaries. Appropriately stimulated, the precapillary sphincters help maintain arterial pressure and regulate selective flow to vascular beds. The capillary walls are very thin, making possible the rapid exchange of substances including nutrients and hormones between the blood and the interstitial fluid, from which they are taken up by the cells. A single endothelial cell may form the entire vessel wall if the capillary has no tunica media or tunica externa. In continuous capillaries, very few spaces are available for substances to cross the vessel wall (such as in the brain; see Fig. 22.35A). In fenestrated capillaries, the endothelial cells contain pores termed fenestrations (see Fig. 22.35B), whereas sinusoids have large openings that facilitate exit of substances from the capillary (see Fig. 22.35C). Substances pass between the capillary lumen and the interstitial fluid: (1) through junctions between
endothelial cells; (2) through fenestrations in endothelial cells; (3) in vesicles moved by active transport across the endothelial cell membrane; or (4) by diffusion through the endothelial cell membrane. A single capillary may be only 0.5 to 1 mm in length and 0.01 mm in diameter — this is just large enough for red blood cells to flow through in single file, remembering that the diameter of an erythrocyte is approximately 8 micrometres, or 0.008 mm (refer to Chapter 16 and Fig. 22.33B). The capillaries are so numerous that their total surface area may be more than 600 m2 — larger than 100 football fields.
Endothelium
All tissues depend on a blood supply and the blood supply depends on endothelial cells, which form the lining of the blood vessel. This blood vessel lining is referred to as the endothelium. Endothelial cells are really quite remarkable in that they can adjust their number and arrangement to accommodate local requirements. Thus, they are a life-support tissue extending and remodelling the network of blood vessels to enable tissue growth, motion and repair.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
A
593
B Capillary
Arteriole
Precapillary sphincters
FIGURE 22.33
Capillary wall. A Capillaries have a wall composed of only a single layer of flattened cells, whereas the walls of the larger vessels also have smooth muscle. B Capillary with red blood cells in single file (× 500).
A
B
From heart
From heart
Arteriole
Arteriole Endothelium
Endothelium Metarteriole
Smooth muscle fibre
Precapillary sphincters (relaxed) True capillary
Smooth muscle fibre
Capillary bed
Thoroughfare channel
Smooth muscle fibre
Smooth muscle fibre Metarteriole Precapillary sphincters (contracted)
Thoroughfare channel Endothelium
Endothelium Venule
Venule To heart
To heart FIGURE 22.34
Microcirculation. Control of blood flow through a capillary network is regulated by the relative contraction of precapillary sphincters surrounding arterioles and metarterioles. A Sphincters are relaxed, permitting blood flow to enter the capillary bed. B With sphincters contracted blood flows from the metarteriole directly into the thoroughfare channel, bypassing the capillary bed.
The endothelium provides a smooth, continuous lining throughout the vascular system and an intact endothelium facilitates good blood flow. An intact endothelium also prevents unnecessary blood clotting and platelet activation (refer to Chapter 16).
Veins
Approximately two-thirds of the total blood volume is in the veins of the systemic circulation. Despite the large volume of blood, veins are low-pressure vessels. The smallest venules closest to the capillaries have an inner lining,
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Part 4 Alterations to body maintenance
C
A
B
CONTINUOUS CAPILLARY
FENESTRATED CAPILLARY
Intercellular cleft Lumen
SINUSOID Nucleus of endothelial cell
Intercellular cleft Fenestration (pore) Lumen
Pinocytic vesicles
Intercellular cleft Lumen
Nucleus of endothelial cell Basement membrane
Pinocytic vesicles Basement membrane
Incomplete basement membrane
FIGURE 22.35
Types of capillaries. A Note the presence of clefts only between adjacent endothelial cells. B In addition to intercellular clefts, fenestrations (pores) exist in the plasma membranes of endothelial cells. C In addition to large intercellular clefts and cellular fenestrations, the basement membrane is incomplete or absent.
Valves open
Blood reservoir
tunica intima and resemble the semilunar valves of the heart. When a person stands up, contraction of the skeletal muscles of the legs compresses the deep veins of the legs and assists the flow of blood towards the heart. This important mechanism of venous return is called the skeletal muscle pump (see Fig. 22.37).
FOCU S ON L EA RN IN G Valves closed FIGURE 22.36
Valves of vein. Pooled blood is moved towards the heart as valves are forced open by pressure from the volume of blood downstream.
composed of the endothelium of the tunica intima and surrounded by fibrous tissue. The largest venules are surrounded by smooth muscle fibres constituting a thin tunica media. Compared with arteries, veins are thin-walled and fibrous and have a larger diameter (see Fig. 22.32). Veins are also more numerous than arteries. In veins, the tunica externa has less elastic tissue than in arteries, so veins do not recoil after distension as quickly as do arteries (Fig. 22.31). Like arteries, veins receive nourishment from the tiny vasa vasorum. Some veins, most commonly in the lower limbs, contain valves to regulate the one-way flow of blood towards the heart (see Fig. 22.36). These valves are folds of the
1 Describe how the cardiovascular control centres in the brain influence heart activity. Relate this to the earlier discussion on autorhythmic cells of the heart conduction system. 2 Describe the baroreceptor reflex. 3 Relate heart rate to the respiratory cycle. 4 Describe the structure of blood vessels throughout the circulation. 5 Explain the skeletal muscle pump.
Blood pressure and blood flow Normal pressures within cardiac chambers and the vessels of the systemic and pulmonary circulations are shown in Table 22.1. In both the systemic and the pulmonary circulations, blood pressures decline as the blood travels from the ventricle through the circulation and returns to the heart (see Fig. 22.38).
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
595
B
A
Muscles relaxed
Muscles contracted
FIGURE 22.37
The skeletal muscle pump. A When the skeletal muscle is relaxed, the blood flow through the vein is largely unaffected. B During contraction of the skeletal muscle, the compression of the vein forces the blood to be returned towards the heart. Note: the closure of the venous valves prevents backflow of blood.
TABLE 22.1 The range of pressures of the systemic and pulmonary circulations LOCATION
RANGE (mmHG)
Left side of heart Left atrium Left ventricle: systolic Left ventricle: end-diastolic
4–12 90–140 4–12
Systemic circulation Aorta, large arteries
120–80
Arterioles
60
Capillaries
15–35
Venules
15
Veins, venae cavae
3–15
Right side of heart Right atrium Right ventricle: systolic Right ventricle: end-diastolic
0–8 15–28 0–8
Pulmonary circulation Pulmonary artery
15
Capillaries
10
Pulmonary veins
Factors affecting blood flow
5
Blood flow is the amount of fluid moved per unit of time and is usually expressed as litres or millilitres per minute (mL/min). Flow is regulated by the same physical properties that govern the movement of simple fluids in a closed, rigid
system — that is, pressure, resistance, velocity, turbulent versus laminar flow and compliance.
Pressure and resistance
Pressure in a liquid system is the force exerted on the liquid per unit area and is expressed as millimetres of mercury (mmHg) when referring to the body. Blood flow throughout the entire vascular system depends partly on the difference between pressures in the arterial and venous vessels supplying the organ. Fluid moves from the arterial end of the capillaries, a region of greater pressure, to the venous end, a region of lesser pressure. Resistance is the opposite to force. In the cardiovascular system, most opposition to blood flow is provided by the diameter and length of the blood vessels themselves. Therefore, changes in blood flow through an organ result from changes in the vascular resistance within the organ. Resistance in a vessel is inversely related to blood flow — that is, increased resistance leads to decreased blood flow. Poiseuille’s law shows the relationship among blood flow, pressure and resistance: Blood flow through the vessel = blood pressure difference at either end of the vessel resistance within the vessel or Q = δ P R where Q = blood flow, δ P = the pressure difference ( P1 − P2 ) and R = resistance.
Resistance to flow cannot be measured directly, but it can be calculated if the pressure difference and flow volumes are known. Resistance to blood flow is proportional to the viscosity of the blood and the length of the vessel (as well as a constant 8/π) and it is inversely proportional to the fourth power of the lumen’s radius (radius4).
Part 4 Alterations to body maintenance
BLOOD VESSEL RADIUS
120
Vena cava, R. atrium
Venules, veins
Capillaries
L. ventricle
130
Arterioles
SYSTEMIC CIRCULATION
A
Aorta, arteries
596
Systole
80 Pressure (mmHg)
Diastole
BLOOD VESSEL LENGTH
Another important factor is the length of the vessel. Generally, resistance to flow is greater in longer tubes because resistance increases with length. Clearly, blood vessel length does not change in the short term and therefore this is not used to alter blood flow rate in the short term.
40
VISCOSITY
0
Pulm. veins, L. atrium
Small veins
Capillaries
Arterioles
R. ventricle
Pulm. artery, arteries
PULMONARY CIRCULATION
B
130
The most important factor determining resistance within a blood vessel is the radius or diameter of the vessel lumen, expressed in Poiseuille’s formula as its radius (see Fig. 22.39). Small changes in the lumen radius lead to quite substantial changes in vascular resistance. The calculations from Fig. 22.39 demonstrate that by halving the blood vessel radius from 4 to 2, the resulting increase in resistance decreases the flow rate tremendously, from 256 mL/min to a mere 16 mL/min. This clearly shows that vessel radius is a powerful influence on resistance and blood flow rate. It is important to learn that changes in radius are used to facilitate immediate changes in blood flow, as this is undertaken regularly throughout the day in different parts of the body.
120
Blood flow rate decreases with increasing viscosity of the fluid, which provides greater resistance to flow than thin fluids. Blood that contains a high percentage of red cells is more viscous. This relationship is expressed as the haematocrit — the ratio of the volume of red blood cells to the volume of whole blood. A high haematocrit reduces flow through the blood vessels, particularly the microcirculation (arterioles, capillaries, venules). Conditions in which the haematocrit is elevated — for example, dehydration, cyanotic congenital heart disease or polycythaemia — can lead to increased cardiac work as a result of increased vascular resistance. radius = 1 1 mL/min
80
radius = 2
Pressure (mmHg)
1 min 16 mL/min
radius = 4
40
1 min 256 mL/min
0 1 min FIGURE 22.38
Pressure profiles along the systemic and pulmonary circulations. The oscillations represent variations in time, not distance. Pulm = pulmonary; L = left; R = right.
FIGURE 22.39
Lumen diameter, blood flow and resistance. The effect of lumen radius on blood flow rate through a vessel. Note that the flow rate changes substantially with small changes in radius. The calculations were performed using the formula, blood flow rate = radius4 (i.e. radius × radius × radius × radius).
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
TOTAL RESISTANCE
Resistance to flow through a system of vessels, or total resistance, depends not only on characteristics of individual vessels but also on whether the vessels are arranged in series or in parallel (see Fig. 22.40). Resistance is lessened where the blood flow can travel through a parallel arrangement. This represents the blood flow through a capillary bed, where capillaries are in parallel.
Neural control of total peripheral resistance
Total resistance in the systemic circulation, sometimes called total peripheral resistance, is determined primarily by change in the radius of the arterioles. As described in the previous section, radius has the main influence on blood flow. Reflex control of total cardiac output and peripheral resistance includes: (1) sympathetic stimulation of heart, arterioles and veins; and (2) parasympathetic stimulation of the heart. The autonomic nervous system is monitored by the cardiovascular control centre in the brain (see Fig. 22.41). The hypothalamic centres regulate vascular (and cardiac) responses to changes in temperature. When the body’s core temperature exceeds normal, the hypothalamus initiates reflex dilation of arterioles and veins in the skin. Skin blood flow increases and heat is lost in the form of sweat and convective heat loss. When body core temperature decreases below normal, surface vessels constrict, shunting blood to the vital organs. Vasoconstriction is regulated by an area of the brainstem that maintains a constant (tonic) output of noradrenaline from sympathetic fibres in the peripheral arterioles. This tonic activity is essential for maintenance of blood pressure.
Laminar versus turbulent flow
Normally, blood flow through the vessels is laminar (laminar flow), meaning that concentric layers of molecules move ‘straight ahead’. Each concentric layer flows at a different velocity (see Fig. 22.42). The cohesive attraction between the fluid and the vessel wall prevents the molecules of blood
597
that are in contact with the wall from moving. The next thin layer of blood is able to slide slowly past the stationary layer and so on until, at the centre, the blood velocity is greatest. Large vessels have room for a large centre layer; therefore, they have less resistance to flow and greater flow and velocity than smaller vessels. Where flow is obstructed, the vessel turns or blood flows over rough surfaces, the flow becomes turbulent (turbulent flow), with whorls or eddy currents that produce noise, causing a murmur to be heard on auscultation. Resistance increases with turbulence (see Fig. 22.42).
Vascular compliance
Vascular compliance is the increase in volume a vessel can accommodate for a given increase in pressure. Compliance depends on the ratio of elastic fibres to muscle fibres in the vessel wall. The elastic arteries are more compliant than the muscular arteries and the veins are more compliant than either type of artery and can serve as storage areas for the circulatory system. Compliance determines a vessel’s response to pressure changes. For example, with a small increase in pressure, a large volume of blood can be accommodated by the venous system. In the less-compliant arterial system, where smaller volumes and higher pressures are normal, small variations in pressure cause little or no change in the volume of blood within the arterial vessels.
Regulation of blood pressure Arterial pressure
Arterial pressure is constantly regulated to maintain tissue perfusion or blood supply to the capillary beds, during a wide range of physiological conditions, including changes in body position, muscular activity and circulating blood volume. The mean arterial pressure (MAP), which is the average pressure in the arteries throughout the cardiac cycle, depends on the elastic properties of the arterial walls and the mean volume of blood in the arterial system. Mean arterial pressure can be approximated from the measured values of the systolic and diastolic pressures, as follows: SBP − DBP MAP = DBP + 3 120 mmHg − 80 mmHg = 80 mmHg + 3 = 93 mmHg Where DBP = diastolic blood pressure SBP = systolic blood pressure
FIGURE 22.40
Arrangement of blood vessels in series and in parallel. A For vessels arranged in series, resistance occurs as the blood must all travel through the same pathway. B For vessels arranged in parallel, resistance is lessened, as there are alternative routes for the blood flow.
An alternative method of assessing arterial blood pressure is by calculating the pulse pressure. This is the difference between systolic and diastolic blood pressures, and using normal values is as follows: Pulse pressure = systolic pressure − diastolic pressure = 120 mmHg − 80 mmHg = 40 mmHg
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Part 4 Alterations to body maintenance
A
Carotid sinus baroreceptors
ln
gea
Cardioregulatory and vasomotor centres in the medulla oblongata
Aortic arch baroreceptors
p
sso
Glo
yn har
e er v
ner ve Vagus
Vagus nerve (parasympathetic)
Sympathetic nerve fibres Sympathetic chain
Circulatory system
Chemoreceptors in the medulla oblongata: CO2, pH (H+)
Vasomotor centre
G lo
B
Vagus ne
al ynge ar e h v op er ss n e Vagus nerv
Chemoreceptors in the carotid and aortic bodies: O2, CO2, pH (H+)
etic) path sym a r a r ve (p
Cardioregulatory centre Sympathetic nerve fibres Sympathetic chain
Circulator y system
FIGURE 22.41
Baroreceptor and chemoreceptor reflex control of blood pressure. A Baroreceptors located in the carotid sinuses and aortic arch detect changes in blood pressure. Action potentials are conducted to the cardioregulatory and vasomotor centres. The heart rate can be decreased by the parasympathetic system; the heart rate and stroke volume can be increased by the sympathetic system. The sympathetic system can also constrict or dilate blood vessels. B Chemoreceptors located in the medulla oblongata and in the carotid and aortic bodies detect changes in blood oxygen, carbon dioxide or pH. Action potentials are conducted to the medulla oblongata. In response, the vasomotor centre can cause vasoconstriction or dilation of blood vessels by the sympathetic system, and the cardioregulatory centre can cause changes in the pumping activity of the heart through the parasympathetic and sympathetic systems.
The mean arterial pressure can now be rewritten as: MAP =
diastolic pressure + pulse pressure 3
Pulse pressure is proportional to stroke volume (SV) and therefore useful in management of critically ill patients with altered haemodynamic states. Additionally, higher pulse pressure has been associated with adverse events in patients with coronary heart disease.1 The major factors and relationships that regulate arterial blood pressure are
summarised in Fig. 22.43. In Table 22.2 the factors that affect both mean arterial pressure and capillary flow are summarised. BARORECEPTORS
Major stretch receptors (baroreceptors) are located in the aorta and in the carotid sinus (see Fig. 22.44, also Fig. 22.41). They respond to changes in smooth muscle fibre length by altering their rate of discharge and supply sensory information to the cardiovascular centre that regulates blood
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
pressure. The net effect of this major blood pressure-regulating reflex is to reduce blood pressure to normal by decreasing cardiac output (heart rate and stroke volume) and peripheral resistance. ARTERIAL CHEMORECEPTORS
Specialised areas within the aortic and carotid arteries are sensitive to concentrations of oxygen, carbon dioxide and Vessel wall
A
599
hydrogen ions (pH) in the blood. These chemoreceptors are most important for the control of respiration but also transmit impulses to the medullary cardiovascular centres that regulate blood pressure. If arterial oxygen concentration or pH falls, a reflexive increase in blood pressure occurs, whereas an increase in carbon dioxide causes a slight increase in blood pressure. The major chemoreceptive reflex is the result of alterations in arterial oxygen concentration, with only minor effects resulting from altered pH or carbon dioxide levels. HORMONES
Blood flow
Blood pressure can be influenced by factors that change the total volume of blood in the circulatory system. Antidiuretic hormone (ADH) is released by the posterior pituitary and
TABLE 22.2 Factors that affect mean arterial pressure and capillary flow MEAN ARTERIAL PRESSURE
B
Vessel wall
Peripheral resistance*
Constriction
FIGURE 22.42
Laminar and turbulent blood flow. A Laminar flow. Fluid flows in long, smooth-walled tubes as if it is composed of a large number of concentric layers. B Turbulent flow. Turbulent flow is caused by numerous small currents flowing crosswise or oblique to the long axis of the vessel, resulting in flowing whorls and eddy currents.
Increased
Decreased
Decreased
Decreased
Increased
Increased
Increased
Increased
Decreased
Decreased
Decreased
Stroke volume‡ Increased
Increased
Increased
Decreased
Decreased
Decreased
†
*Cardiac output constant; peripheral resistance and stroke volume constant; peripheral resistance and heart rate constant.
‡
Increased blood viscosity
leads to Increased peripheral resistance
leads to
Increased cardiac output causes
causes
Increased volume of blood entering arteries per minute results in
Decreased diameter of arterioles
Decreased volume of blood leaving arteries per minute, the ‘arteriole runoff’ Increased arterial blood volume
results in
manifest as Increased arterial blood pressure FIGURE 22.43
The relationship between arterial blood volume and blood pressure. Increased cardiac output and increased peripheral resistance contribute to increased arterial blood pressure.
leads to
CONCEPT MAP
leads to
Increased heart rate
Increased
Heart rate†
Blood flow
Increased stroke volume
CAPILLARY FLOW
600
Part 4 Alterations to body maintenance
CONCEPT MAP
Homeostasis of blood pressure restored
Decreased heart rate
↑ Mean arterial pressure
Vasodilation
detected by Baroreceptors
to blood vessels to sinoatrial node
afferent impulses to Medulla
FIGURE 22.44
Baroreceptor control of arterial pressure. Increased arterial blood pressure is detected by the baroreceptors, and these send signals to the cardiac control centres in the brainstem. In response, decreased heart rate and vasodilation lower blood pressure back to normal.
causes reabsorption of water by the kidney (refer to Chapter 10). With reabsorption, the blood plasma volume increases, thereby increasing blood pressure (see Fig. 22.45). Renin is an enzyme produced and secreted by the juxtaglomerular cells of the kidneys. Factors that increase renin release include the following: • a drop in blood pressure (detected as decreased blood flow in the renal artery) • a drop in blood volume (also detected as decreased blood flow in the renal artery) • a decrease in the amount of sodium chloride delivered to the kidneys • low potassium concentrations in the plasma • β-adrenergic stimuli (whereas β-adrenergic inhibitors decrease renin release). Once in the circulation, renin splits off a polypeptide from angiotensinogen to generate angiotensin I. This is converted by an enzyme, angiotensin-converting enzyme (ACE), to angiotensin II, a powerful vasoconstrictor that stimulates the secretion of aldosterone from the adrenal gland (see Fig. 22.45). Full details of this important renin-angiotensin-aldosterone system are discussed in Chapter 28 (see also Fig. 28.15). This kidney-based renin-angiotensin system serves as an important regulatory loop. For example, decreases in blood pressure or sodium delivery to the kidneys (specifically, the macula densa), as might occur after haemorrhage or extracellular fluid volume deficits (dehydration), stimulate secretion of renin, which leads to formation of angiotensin II to restore blood pressure. Angiotensin II stimulates aldosterone release, resulting in sodium and water retention by the kidneys. Overall, the renin-angiotensin system is activated after volume depletion or hypotension, or both, and is suppressed after volume repletion.
Posterior pituitary
ADH
(Vasoconstriction)
Natriuretic peptides
Adrenal cortex
Angiotensin II
(ACE) Aldosterone Angiotensin I Renin Angiotensinogen Kidney Fluid and Na+ loss FIGURE 22.45
Three mechanisms that influence total plasma volume. The antidiuretic hormone (ADH) mechanism and renin-angiotensin and aldosterone mechanisms increase water retention and thus increase total plasma volume. The natriuretic peptides antagonise these mechanisms by promoting water loss and sodium (Na+) loss, thus promoting a decrease in total plasma volume. ACE = angiotensin-converting enzyme.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
In addition, BNP is also secreted from cardiac cells and it too increases sodium loss from the body through the kidneys. It is used both as an indicator and as a treatment for acute heart failure.
Angiotensin I ACE
ACE inhibitors
601
Venous pressure AT1 antagonist drugs
Angiotensin II
AT1
AT2
Signalling pathways Influence genes
?
• Vascular diseases • Cardiac diseases • Renal diseases FIGURE 22.46
Angiotensin II and receptors, AT1 and AT2. Blocking the angiotensin-converting enzyme (ACE) with ACE inhibitors decreases the amount of angiotensin II. Blocking the receptor AT1 with drugs (AT1 antagonists) blocks the attachment of angiotensin II to the cell, preventing the cellular effects and decreasing the vascular, cardiac and renal effects.
Angiotensin II has two subtypes of receptors — AT1 and AT2 (see Fig. 22.46) — both of which are expressed in human hearts. AT1 is also found on vascular smooth muscle and endothelial cells, nerve endings and conduction tissues, adrenal cortex, liver, kidneys and brain. AT2 receptors are found in the adrenal medulla, uterus and ovarian follicles, renal tubules and vasculature. The majority of actions of angiotensin II occur through the AT1 receptor, including vasoconstriction, stimulation of aldosterone release, inflammatory myocyte hypertrophy, fibroblast proliferation, collagen production, smooth muscle cell growth, endothelial adhesion molecule expression and catecholamine production. Angiotensin II has been implicated in the progression of heart failure (see Chapter 23). Therefore, treatments such as ACE inhibitors and angiotensin-receptor antagonists that inhibit mostly AT1 receptors are frequently prescribed to patients with cardiovascular diseases. Another mechanism that can change blood plasma volume and therefore blood pressure is the natriuretic peptides (see Fig. 22.45). Atrial natriuretic peptide is a hormone secreted from cells in the right atrium when blood pressure increases within this chamber. Atrial natriuretic peptide inhibits antidiuretic hormone by increasing urine sodium loss, leading to the formation of a large volume of dilute urine that decreases blood volume and blood pressure.
The main determinants of venous blood pressure are: (1) the volume of fluid within the veins; and (2) the compliance (distensibility, or stretchiness) of the vessel walls. The venous system accommodates approximately two-thirds of the total blood volume at any given moment, with venous pressure averaging less than 10 mmHg. In contrast, the arteries accommodate about 15% of the total blood volume, with an average arterial pressure (blood pressure) of about 100 mmHg. The sympathetic nervous system controls compliance. The walls of the veins are highly innervated by sympathetic fibres that, when stimulated, cause venous smooth muscle to contract and increase muscle tone. This stiffens the wall of the vein, which reduces distensibility and increases blood pressure, forcing more blood through the veins and into the right heart. Two other mechanisms that increase venous pressure and venous return to the heart are: (1) the skeletal muscle pump; and (2) the respiratory pump. During skeletal muscle contraction, the veins within the muscles are partially compressed, causing decreased venous capacity and increased return to the heart (see Fig. 22.37). The respiratory pump acts during inspiration, when the veins of the abdomen are partially compressed by the downward movement of the diaphragm. Thus increased abdominal pressure will increase venous pressure and move blood towards the heart (increased venous return).
Regulation of the coronary circulation
Flow of blood in the coronary circulation is directly proportional to the perfusion pressure and inversely proportional to the vascular resistance of the bed. Coronary perfusion pressure is the difference between pressure in the aorta and pressure in the venous coronary vessels of the right atrium. Aortic pressure is the driving pressure that perfuses vessels of the myocardium. Vasodilation and vasoconstriction normally maintain coronary blood flow despite stresses imposed by the constant contraction and relaxation of the heart muscle and despite shifts (within a physiological range) of coronary perfusion pressure. Several anatomical factors influence coronary blood flow. The aortic valve cusps obstruct coronary blood flow by pushing against the openings of the coronary arteries during systole. Also during systole, the coronary arteries are compressed by ventricular contraction. The resulting systolic compressive effect is particularly evident in the subendocardial layers of the left ventricular wall and can greatly decrease coronary blood flow. Therefore, most coronary blood flow in the left ventricle occurs during diastole. During the period of systolic compression, when flow is slowed or stopped, oxygen is supplied by myoglobin,
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Part 4 Alterations to body maintenance
a protein present in heart muscle that binds oxygen during diastole and then releases it when blood levels of oxygen fall during systole.
Autoregulation
Autoregulation (automatic self-regulation) enables individual vessels to regulate blood flow by altering their own arteriolar resistances. Autoregulation in the coronary circulation maintains constant blood flow at perfusion pressures (mean arterial pressure) between 60 and 180 mmHg, provided that other influencing factors are held constant. Thus, autoregulation ensures constant coronary blood flow despite shifts in the perfusion pressure within the stated range. The mechanism of autoregulation is not known, but two explanations have been proposed: • The myogenic hypothesis proposes that autoregulation originates in vascular smooth muscle, responding to changes in arterial pressure. With an increase in arterial pressure, vasoconstriction occurs due to contraction of smooth muscle. Conversely, vasodilation is stimulated by decreased arterial pressure. • The metabolic hypothesis of autoregulation proposes that autoregulation of coronary vessels originates in the myocardium. Myocardial cells release chemicals in response to oxygen requirements when arterial pressure is low. This causes vasodilation and an increase in blood flow. When arterial pressure is high, the chemicals are washed out and vasoconstriction occurs and blood flow returns to normal.
Fig. 22.47). Normally, fluid is forced out of the blood at the arterial end of the blood capillary bed and is reabsorbed into the bloodstream at the venous end. However, capillary outflow exceeds venous reabsorption by about 3 litres per day, so some fluid lags behind in the interstitium. To maintain sufficient blood volume in the cardiovascular system, this fluid must eventually rejoin the bloodstream; this is the function of the lymphatic system. Fluid flow from the blood capillary to the extracellular fluid is an important part of maintaining hydration of body cells. The amount of fluid flow is dependent on two main pressures (referred to as Starling’s law of the capillaries): • Capillary hydrostatic pressure: this is the actual blood pressure within the capillary and it tends to force fluids out of the blood vessel. The hydrostatic pressure is higher at the arterial end (35 mmHg) than at the venous end (17 mmHg) of the capillary, as fluid loss causes a lower pressure at the end of the capillary. • Capillary oncotic pressure: this relates to the presence of proteins within the capillary, as proteins tend to attract water. This pressure tends to draw fluids into the blood vessel. As proteins do not leave the capillary, the oncotic pressure (25 mmHg) remains essentially the same from the arterial to the venous end (see Fig. 22.48). Arteriole (from heart)
Blood capillary
Venule (from heart)
FOCUS O N L E ARN IN G
1 Briefly explain each of the factors that contribute to blood pressure and blood flow. Indicate the main factor that is used to alter blood flow in the short term.
Tissue cells
2 Discuss what is meant by peripheral resistance and how the autonomic nervous system controls peripheral resistance. 3 Outline the difference between laminar and turbulent flow in blood vessels. 4 Explain the arterial blood pressure. 5 Discuss the baroreceptor reflex and arterial chemoreceptors in controlling blood pressure. 6 Describe how the renin-angiotensin-aldosterone system influences blood pressure.
Interstitial fluid
7 Briefly discuss the venous blood pressure and how it is altered. 8 Indicate the importance of autoregulation.
The lymphatic system Lymphatic capillaries
The lymphatic system is a special vascular system that picks up excess tissue fluid and returns it to the bloodstream (see
Lymphatic capillary
Lymph fluid (to veins)
FIGURE 22.47
The role of the lymphatic system in fluid balance. Fluid from plasma flowing through the capillaries moves into interstitial spaces. Although much of this interstitial fluid is either absorbed by tissue cells or reabsorbed by capillaries, some of the fluid tends to accumulate in the interstitial spaces. As this fluid builds up, it tends to drain into lymphatic vessels that eventually return the fluid to the venous blood.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
Capillary (fluid movement by net filtration) pressures
Cell (fluid movement by osmosis)
Capillary hydrostatic pressure
Filtrati
Tonsils Cervical lymph node
Intracellular osmotic pressure
Arteriole
Right lymphatic duct
Interstitial osmotic pressure
on
Peyer’s patches in intestinal wall
Net pressure: 10 mmHg outwards
603
Entrance of thoracic duct into subclavian vein Thymus gland Axillary lymph node Thoracic duct Spleen
Interstitial hydrostatic pressure
Red bone marrow
Capillary oncotic pressure
n tio orb s b Rea Net pressure: 8 mmHg inwards Venule
Inguinal lymph node
Lymphatics
FIGURE 22.48
Fluid movement between the plasma and interstitial spaces. The movement of fluid between the vascular interstitial spaces and the lymphatics is the result of net filtration of fluid across the capillary membrane. Capillary hydrostatic pressure is the primary force for fluid movement out of the arteriolar end of the capillary and into the interstitial spaces. At the venous end, capillary oncotic pressure (from plasma proteins) attracts water back into the vascular space. Fluid that does not return in the venous end of the capillary is drained by the lymphatic system.
The overall effect of fluid flow is that fluid leaves the capillary at the arterial end and not all of this is returned to the bloodstream. This remaining excess fluid is drained by the lymphatic capillaries, through the lymphatic vessels. It is worth briefly mentioning that both hydrostatic and oncotic pressures also exist in the extracellular fluid, due to the presence of both fluid (hydrostatic pressure) and proteins (oncotic pressure). However, both of these pressures are quite small (0–1 mmHg) due to constant drainage by the lymphatic system (see Chapter 29).
Lymphatic vessels and ducts
The components of the lymphatic system are the lymphatic vessels and the lymph nodes (see Fig. 22.49). In this pumpless system, a series of valves ensures one-way flow of the excess interstitial fluid (now called lymph) towards the heart. The
FIGURE 22.49
Principal organs of the lymphatic system. The inset shows the areas drained by the right lymphatic duct (green) and the thoracic duct (blue).
lymphatic capillaries are closed at the ends, as shown in Fig. 22.50. Lymph consists primarily of water and small amounts of dissolved proteins (mostly albumin) that are too large to be reabsorbed into the less permeable blood capillaries. Once within the lymphatic system, lymph travels through larger vessels called lymphatic venules and lymphatic veins. The lymphatic vessels run alongside the arteries and veins and eventually drain into one of two large ducts in the thorax: the right lymphatic duct or the thoracic duct. The right lymphatic duct drains lymph from the right arm and the right side of the head and thorax, whereas the larger thoracic duct receives lymph from the rest of the body (see Fig. 22.49). The right lymphatic duct and the thoracic duct drain lymph into the right and left subclavian veins, respectively. The lymphatic veins are thin-walled like the veins of the cardiovascular system. In the larger lymphatic veins,
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A From heart
To heart
To venous system
Lymph vessel Arteriole
B
Lymph nodes
Venule
Venous capillaries
Arterial capillaries
endothelial flaps form valves similar to those in the circulatory veins (see Fig. 22.36). The valves permit lymph to flow in only one direction because lymphatic vessels are compressed intermittently by contraction of skeletal muscles, pulsatile expansion of an adjacent artery and contraction of the smooth muscles in the walls of the lymphatic vessel.
As lymph is transported towards the heart, it is filtered through thousands of bean-shaped lymph nodes clustered along the lymphatic vessels (see Fig. 22.49). Lymph enters the node through several afferent lymphatic vessels, filters through the sinuses in the node and leaves by way of efferent lymphatic vessels. Lymph flows slowly through the node, which facilitates the phagocytosis of foreign substances within the node and prevents them from re-entering the bloodstream. (Phagocytosis is described in Chapter 12.)
Lymphatic capillaries Fluid exchange
Anchoring filament
FOCU S ON L EA RN IN G
1 Explain how the lymphatic system is involved in fluid movements. 2 Outline the pathway of lymph flow, from entering the lymphatic system to entering the cardiovascular system.
Lymph
Blood capillary
FIGURE 22.50
Lymphatic capillaries. A Schematic representation of the lymphatic capillaries. B Anatomic components of microcirculation.
Ageing and the cardiovascular system Blood vessels become less compliant (or stretchable) with age, due to a number of factors including fibrosis and calcification, which can substantially limit changes in vessel diameter in response to increased blood flow and/ or vasodilator molecules. In addition, there is a narrowing of vessel lumen due to the development of atherosclerosis (described in Chapter 23). This hardening of the arteries with increasing age increases the risk of developing raised blood pressure (see Fig. 22.51). Increased blood pressure (hypertension) and atherosclerosis are major causes of cardiovascular pathophysiology, which are discussed in more detail in Chapter 23.
AGEING
A range of normal anatomical and physiological changes are seen in the ageing heart. In most cases, these changes do not lead to the development of cardiovascular diseases, but reflect general physiological body trends leading to decline in performance towards the later state of our life span. The physiological changes that occur affect all parts of the heart, with the myocardium showing increased fibrosis and a decrease in myocyte numbers, the valves becoming calcified and hypertrophy of the left ventricle reducing lumen size. The effects of ageing on cardiovascular function are summarised in Table 22.3.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
TABLE 22.3 Cardiovascular function in the elderly RESTING CARDIAC PERFORMANCE
Cardiac output
Unchanged or slightly decreased in women only
Heart rate
Slight decrease
Stroke volume
Slight increase
Ejection fraction
Unchanged
Afterload
Increased
End-diastolic volume
Unchanged
End-systolic volume
Unchanged
Contraction
Increased because of prolonged relaxation
Cardiac dilation
No change
200 Pressure (mmHg)
DETERMINANT
605
Systolic
150
Mean
100
Diastolic
50 0
0
20
40 Age (years)
60
80
FIGURE 22.51
Changes in systolic, diastolic and mean arterial pressures with age. The shaded areas show the approximate normal ranges.
FOCU S ON L EA RN IN G
1 Discuss features seen on the heart and blood vessels during ageing.
Chapter SUMMARY The circulatory system • The circulatory system is the body’s transport system. It delivers oxygen, nutrients and other valuable substances throughout the body and carries metabolic wastes to the liver, kidneys and lungs for excretion. • The circulatory system consists of the heart and blood vessels and is made up of two separate, serially connected systems: the pulmonary circulation and the systemic circulation. • The pulmonary circulation is driven by the right side of the heart; its function is to deliver blood to the lungs for oxygenation. • The systemic circulation is driven by the left side of the heart; its function is to move oxygenated blood throughout the body.
The structure of the heart • The heart consists of four chambers (two atria and two ventricles), four valves (two atrioventricular valves and two semilunar valves), a muscular wall, a fibrous skeleton, a conduction system, nerve fibres, systemic vessels (the coronary circulation) and openings where the great vessels enter the atria and ventricles.
• The heart wall, which encloses the heart and divides it into chambers, is made up of three layers: the pericardium (outer layer), the myocardium (muscular layer) and the endocardium (inner lining). • The myocardial layer of the two atria, which receive blood entering the heart, is thinner than the myocardial layer of the ventricles, which have to be stronger to squeeze blood out of the heart. • Deoxygenated (venous) blood from the systemic circulation enters the right atrium through the superior and inferior venae cavae. From the atrium, the blood passes through the right atrioventricular (tricuspid) valve into the right ventricle. In the ventricle, the blood flows from the inflow tract to the outflow tract and then through the pulmonary semilunar valve (pulmonary valve) into the pulmonary artery, which delivers it to the lungs for oxygenation. • Oxygenated blood from the lungs enters the left atrium through the four pulmonary veins (two from the left lung and two from the right lung). From the left atrium, the blood passes through the left atrioventricular valve (mitral valve) into the left ventricle. In the ventricle, the blood flows from the inflow tract to the outflow tract and then through the aortic semilunar valve (aortic Continued
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valve) into the aorta, which delivers it to systemic arteries of the entire body. • The heart valves ensure the one-way flow of blood from atrium to ventricle and from ventricle to artery. Heart sounds are due to closing of the valves at slightly different times.
Paediatrics: fetal circulation • The fetal circulation is structurally different to that of the adult, due to the umbilical cord, ductus venosus, foramen ovale and ductus arteriosis. These structures become modified to the adult circulation shortly after birth.
Blood flow during the cardiac cycle • The pumping action of the heart consists of two phases: diastole, during which the myocardium relaxes and the ventricles fill with blood; and systole, during which the myocardium contracts, forcing blood out of the ventricles. A cardiac cycle consists of one systolic contraction and the diastolic relaxation that follows it. Each cardiac cycle constitutes one ‘heartbeat’.
The coronary circulation • The coronary circulation consists of arteries and veins that supply blood to the cells of the myocardium. Oxygenated blood enters the coronary arteries through an opening in the aorta and unoxygenated blood from the coronary veins enters the right atrium through the coronary sinus. The ability of the coronary vessels to form anastomoses is an important feature that ensures that oxygen supply to the myocardium remains adequate.
Structures that control heart function • Unique features that distinguish myocardial cells from skeletal cells enable myocardial cells to transmit action potentials faster (through intercalated discs), produce more ATP (because of a large number of mitochondria) and have readier access to ions in the interstitium (because of an abundance of transverse tubules). These combined differences enable the myocardium to work constantly, which skeletal muscle is not required to do. • Cardiac myocyte action potentials differ from those of skeletal muscle. One important difference is the role of calcium in the action potential, particularly through the L-type channels. Calcium influx gives a unique shape to the action potential. • The conduction system of the heart generates and transmits electrical impulses (cardiac action potentials) that stimulate systolic contractions. The autonomic nerves (sympathetic and para-sympathetic fibres) can adjust heart rate and systolic force, but they do not stimulate the heart to beat. • Cells of the cardiac conduction system possess the properties of automaticity and rhythmicity. Automatic cells return to threshold and depolarise rhythmically without outside stimulus. The cells of the sinoatrial (SA) node depolarise faster than other automatic cells, making it the natural pacemaker of the heart. If the SA node is disabled, the next fastest pacemaker, the atrioventricular (AV) node, takes over.
• Cardiac action potentials are generated by the SA node at the rate of about 75 impulses per minute. The impulses can travel through the conduction system of the heart, stimulating myocardial contraction as they go. • Each cardiac action potential travels from the SA node to the AV node to the bundle of His (atrioventricular bundle), through the bundle branches and finally to the Purkinje fibres. There the impulse is stopped. It is prevented from reversing its path by the refractory period of cells that have just been polarised. The refractory period ensures that diastole (relaxation) occurs, thereby completing the cardiac cycle.
The electrocardiogram • The normal electrocardiogram is the sum of all action potentials. The P wave represents atrial depolarisation; and the QRS complex is the sum of all ventricular cell depolarisations. The ST interval occurs when the entire ventricular myocardium is depolarised.
Factors affecting cardiac performance • Cardiac performance is affected by preload, afterload, myocardial contractility and heart rate. • Preload, or pressure generated in the ventricles at the end of diastole, depends on the amount of blood in the ventricle. Afterload is the resistance to ejection of the blood from the ventricle. Afterload depends on pressure in the aorta. • The Frank-Starling law of the heart states that the myocardial stretch determines the force of myocardial contraction (the greater the stretch, the stronger the contraction). • Contractility is the potential for myocardial fibre shortening during systole. It is determined by the amount of stretch during diastole (i.e. preload) and by sympathetic stimulation of the ventricles. • The heart rate is determined by the SA node and by components of the autonomic nervous system, including cardiovascular control centres in the brain, neuroreceptors in the atria and aorta, hormones and catecholamines (adrenaline and noradrenaline).
The physiology of cardiovascular control • Cardiovascular control centres in the medulla are the cardioacceleratory centre, which increases the heart rate via the sympathetic nervous system, and the cardioinhibitory centre, which slows the heart rate via the parasympathetic nervous system. • The baroreceptor reflex detects changes in stretch in major blood vessels and controls the heart rate to restore homeostasis.
The systemic circulation • Vessel walls consist of three layers: the tunica intima (inner layer), the tunica media (middle layer) and the tunica externa (outer layer). • Layers of the vessel wall differ in thickness and composition from vessel to vessel, depending on the vessel’s size and location within the circulatory system. In general, the tunica media of arteries close to the heart contains a greater proportion of elastic fibres because
•
•
•
•
•
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
these arteries must be able to distend during systole and recoil during diastole. Distributing arteries further from the heart contain a greater proportion of smooth muscle fibres because these arteries must be able to constrict and dilate to control blood pressure and volume within specific capillary beds. Blood flows from the left ventricle into the aorta and then into arteries that eventually branch into arterioles and capillaries, the smallest of the arterial vessels. Oxygen, nutrients and other substances needed for cellular metabolism pass from the capillaries into the extracellular fluid where they are available for uptake by the cells. Capillaries also absorb products of cellular metabolism from the cells in venous blood. Venules, the smallest veins, receive capillary blood. From the venules, the venous blood flows into larger and larger veins until it reaches the venae cavae, through which it enters the right atrium. Blood flow into the capillary beds is controlled by the contraction and relaxation of smooth muscle bands (precapillary sphincters) at junctions between metarterioles and capillaries. Endothelial cells form the lining, or endothelium, of blood vessels. The endothelium is a life-support tissue and functions as a filter, altering permeability and changes in vasomotion (constriction and dilation), and is involved in clotting and inflammation. Blood flow through the veins is assisted by the contraction of skeletal muscles (the muscle pump), and one-way valves prevent backflow in the lower body, particularly in the deep veins of the legs.
Blood pressure and blood flow • Blood flow is affected by blood pressure, resistance to flow within the vessels, blood consistency (which affects velocity), anatomic features that may cause turbulent or laminar flow and compliance (distensibility) of the vessels. • Poiseuille’s law describes the relationship of blood flow, pressure and resistance as the difference between pressure at the inflow end of the vessel and pressure at the outflow end, divided by resistance within the vessel. According to this law, resistance depends on the vessel’s length and radius and on the viscosity of the blood. The greater the vessel’s length and the blood’s viscosity and the narrower the radius of the vessel’s lumen, the greater the resistance within the vessel. • Total peripheral resistance, or the resistance to flow within the entire systemic circulatory system, depends on the combined length and radius of all the vessels within the system.
607
• Arterial blood pressure is influenced and regulated by factors that affect cardiac output (heart rate, stroke volume), total resistance within the system and blood volume. • Antidiuretic hormone, the renin-angiotensin system and natriuretic peptides can all alter blood volume and thus blood pressure. • The tissue renin-angiotensin system is activated in response to tissue injury. This system is gaining importance in the maladaptive alterations, such as ventricular and vascular remodelling, alterations in renal function and atherosclerosis. • Venous blood pressure is influenced by blood volume within the venous system and compliance of the venous walls. • Blood flow through the coronary circulation is governed not only by the same principles as flow through other vascular beds but also by adaptations dictated by cardiac dynamics. First, blood flows into the coronary arteries during diastole rather than systole, because during systole, the cusps of the aortic semilunar valve block the openings of the coronary arteries. Second, systolic contraction inhibits coronary artery flow by compressing the coronary arteries. • Autoregulation enables the coronary vessels to maintain optimal perfusion pressure despite systolic effects, and myoglobin in heart muscle stores oxygen for use during the systolic phase of the cardiac cycle.
The lymphatic system • The lymphatic vessels collect fluids from the interstitium and return the fluids to the circulatory system. The vessels of the lymphatic system run in the same sheaths with the arteries and veins. • Lymph (interstitial fluid) is absorbed by lymphatic venules in the capillary beds and travels through ever larger lymphatic veins until it is emptied through the right or left thoracic duct into the right or left subclavian vein. • As lymph travels towards the thoracic ducts, it is filtered by thousands of lymph nodes clustered around the lymphatic veins. The lymph nodes are sites of immune function.
Ageing and the cardiovascular system • With increasing age, there is a tendency towards replacement of normal structures with collagen and fibrous tissue. Both the myocardium and heart valves are affected. • With age, blood vessels lose their compliance, which can increase the tendency to develop high blood pressure (hypertension).
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CASE STUDY
A DU LT Liam is a 36-year-old engineer who started a job at a new company 2 years ago. When he started his new job, Liam realised that after being employed with his previous company for 10 years, he had allowed himself to become complacent with many aspects of his life, including his health. He decided to get fit again and slowly worked up to a comprehensive exercise regime. He now exercises for 1 to 2 hours per day and has a healthy diet. He does not smoke, but he does enjoy regular partying and drinks alcohol on weekends. His height and weight are normal. Liam recently volunteered for a research project on exercise physiology and has been able to see a range of data on his cardiac performance. During the exercise phase of the project, Liam was required to undertake vigorous cycling for 30 minutes while he was attached to various monitors that assess his ventilation and heart performance. He was unable to drink fluid during the period of cycling.
1
2
3
4
5
Liam’s cardiac output at rest was estimated to be 5.8 litres/minute. How does this value compare with the average value? Discuss what processes have led to his cardiac output being 5.8 litres/minute. Liam’s cardiac output during vigorous exercise was 28 litres/minute. How does this value compare with the values discussed in question 1? What would the circulating levels of antidiuretic hormone (ADH) be in Liam’s blood by the end of the 30 minutes of exercise? Discuss how secretion of renin would be altered at the end of 30 minutes of exercise. What are the effects of renin secretion? Explain how the autonomic nervous system coordinates blood flow to different organs during exercise. How would this be different 1 hour after completing exercise?
CASE STUDY
A GEING Natalie is an 84-year-old who attends her general practitioner (GP) for her routine health check. She is a retired registered nurse who also served in the army overseas in the Vietnam War (did not sustain any injuries). Natalie currently lives at home with her husband of 54 years and is self-caring in activities of daily living. She has two grown-up children who live nearby. Natalie has a history of hypertension (currently taking the angiotensin-converting-enzyme inhibitor lisinopril). On assessment, her blood pressure was 152/92 mmHg and resting pulse 86 bpm. Additionally, the GP observed that Natalie appeared breathless upon entering the GPs office and noted on examination that she had slight oedema in her lower legs.
1
2 3
4 5
How does Natalie’s blood pressure compare with expected values for her age? Discuss the changes that occur in age that result in blood pressure changes. What is the role of angiotensin in the body? Describe the actions of angiotensin-converting-enzyme inhibitors. How does Natalie’s pulse rate compare with expected normal values for her age? Discuss the changes in heart rate with ageing (both resting and maximal heart rate). Explain the physiological changes that occur to result in lower leg extremity oedema. Discuss possible reasons for Natalie’s breathlessness on exertion.
CHAPTER 22 The structure and function of the cardiovascular and lymphatic systems
609
REVIEW QUESTIONS 1 Draw the heart and systemic and pulmonary circulations. Label the great vessels, heart chambers, heart valves and whether blood is oxygenated or deoxygenated. 2 Discuss why it is so beneficial for the fetus to have structural specialisations to the cardiovascular system. (Think about what the effects might be on the mother if these specialisations were not in place.) 3 Explain the phases of the cardiac cycle, ensuring that you include pressure and volume changes within the chambers. 4 Discuss why the coronary circulation is necessary and how this circulation can be modified in order to maintain adequate blood flow. 5 Outline the specialisations of the myocardium that are unique to allow the function of the heart.
6 Explain how action potentials generated in the sinoatrial node lead to the coordinated contraction of the whole heart. 7 Outline how the autonomic nervous system modifies the functions of the cardiovascular system. 8 Explain what might be achieved from being able to alter preload, afterload, myocardial contractility and heart rate. 9 Describe the effect that the renin-angiotensin-aldosterone system has on blood pressure. 10 Outline the role that the lymphatic system has in working with the cardiovascular system. Predict what might happen if a lymphatic vessel were blocked.
Key terms
CHAPTER
23
Alterations of cardiovascular function across the life span Thomas Buckley
Chapter outline Introduction, 611 Alterations of blood flow and pressure, 611 Hypertension, 611 Orthostatic hypotension, 616 Arteriosclerosis, 617 Atherosclerosis, 618 Coronary heart disease, 621 Myocardial ischaemia, 623 The acute coronary syndromes, 627 Aneurysm, 634 Embolism, 637 Peripheral artery disease, 637 Alterations to veins, 638 Alterations of the heart wall, 643 Disorders of the pericardium, 643
Disorders of the myocardium: the cardiomyopathies, 644 Disorders of the endocardium, 644 Alterations of cardiac conduction, 652 Arrhythmias, 653 Heart failure, 657 Left heart failure, 657 Right heart failure, 661 Shock, 661 Impairment of cellular metabolism, 662 Types of shock, 664 Multiple organ dysfunction syndrome, 673
tricuspid regurgitation, 648 unstable angina, 628 valvular regurgitation, 645 valvular stenosis, 645 varicose vein, 639 venous thromboembolus, 638 ventricular septal defect (VSD), 640 610
acute coronary syndromes, 627 acute myocardial infarction (AMI), 628 acute onset of systolic left heart failure, 658 anaphylactic shock, 666 aneurysm, 634 angina pectoris, 625 angiotensin-converting enzyme (ACE) inhibitors, 616 aortic regurgitation, 646 aortic stenosis, 645 arrhythmias, 653 arteriosclerosis, 617 atherosclerosis, 618 atrial septal defect (ASD), 641 cardiogenic shock, 664 cardiomyopathies, 644 chronic left heart failure, 661 congenital heart disease, 640 congestive heart failure, 657 coronary angiography, 626 coronary artery bypass graft, 627 coronary heart disease, 621 cyanosis, 640 diastolic heart failure, 661 dyslipidaemia, 622 embolism, 637 embolus, 637 hibernating myocardium, 630 high-density lipoproteins (HDL), 622 hypertension, 611 hypovolaemic shock, 665 infective endocarditis, 650 left heart failure, 657 low-density lipoproteins (LDL), 622 mitral regurgitation, 648 mitral stenosis, 646 mitral valve prolapse, 648 multiple organ dysfunction syndrome (MODS), 661 myocardial ischaemia, 623 myocardial remodelling, 630 myocardial stunning, 630 neurogenic shock, 666 non-ST elevation MI (non-STEMI), 628 patent ductus arteriosus, 642 percutaneous transluminal coronary angioplasty (PTCA), 627 pericardial effusion, 644 peripheral artery disease, 637 Prinzmetal’s angina, 625 pulmonary stenosis, 642 rheumatic heart disease, 648 right heart failure, 661 septic shock, 668 shock, 661 silent ischaemia, 625 ST elevation MI (STEMI), 628 stable angina, 625 systemic inflammatory response syndrome (SIRS), 668 systolic heart failure, 657 tetralogy of Fallot, 642
CHAPTER 23 Alterations of cardiovascular function across the life span
Introduction Cardiovascular diseases are conditions and diseases that affect the heart and vasculature (blood vessels). There are variations in the definition of cardiovascular diseases, with some classifications including heart disease, vascular disease, stroke and circulatory disease. The most common forms of cardiovascular diseases are hypertension, coronary heart disease, heart failure and cerebrovascular disease. Cerebrovascular disease arises from pathological processes in blood vessels of the brain, with stroke being the most frequent manifestation of cerebrovascular disease. Although stroke is classified as a cardiovascular disease, it is discussed in Chapter 9 to consider the effects on the brain. In Western countries, cardiovascular disease is an epidemic and major health problem. Approximately 18% of Australians (3.5 million people) are reported to have a long-term cardiovascular condition, with the prevalence of disease increasing with age (see Fig. 23.1). In addition, cardiovascular disease remains a major contributor to mortality, accounting for 34% and 40% of all deaths in Australia and New Zealand, respectively. In more recent years, there has been a reduction in the mortality rate attributable to cardiovascular disease due to improvements in cardiovascular disease management and a lowering of some risk factors (such as smoking).1 Unfortunately, these reductions are somewhat offset by the increased prevalence of cardiovascular disease in the elderly, combined with increasing rates of obesity and diabetes mellitus in the population (see Chapter 35 and 36). In addition, most people are afflicted with more than one cardiovascular condition and many have multiple cardiovascular risk factors. Furthermore, in both Australia and New Zealand cardiovascular disease is more prevalent in the Indigenous population than in the non-Indigenous population.2,3
Per cent Men
80
Women
60 40 20 0
18–44
45–54
55–64
65–74
75+
Age group (years) FIGURE 23.1
Prevalence of cardiovascular disease, among Australian adults in 2014–15 The number of Australians with cardiovascular disease, shown as a percentage of the adult population.
611
It is vital that you have a comprehensive understanding of the pathophysiology of cardiovascular conditions, due to the high prevalence of cardiovascular disease in the community. Nurses are more actively involved than they have been previously in the management of cardiovascular conditions such as hypertension and heart failure, and your comprehension of the pathophysiology will aid your ability to care for individuals with cardiovascular conditions.
Alterations of blood flow and pressure Pathophysiological alterations to arteries and veins include hypertension, atherosclerosis and peripheral vascular disease, and all of these conditions can lead to other cardiovascular diseases. The damage to the arteries in particular can lead to coronary heart disease, cerebrovascular disease or heart failure — the top three causes of death due to cardiovascular disease in Australia and New Zealand.1 This section details the formation of arterial and venous alterations, which will aid your understanding of the primary cardiovascular diseases. We start with the most common cardiovascular condition worldwide, hypertension.
Hypertension
Hypertension, or high blood pressure, is consistent elevation of systemic arterial blood pressure. It considerably increases the individual’s risk of developing coronary heart disease, heart failure and strokes. It is the most prevalent cardiovascular condition and is estimated to afflict about 1 billion people worldwide — just over one-quarter of the world’s adult population.4 Approximately 3.7 million Australians over the age of 25 years (30% of adults) have high blood pressure or are on medication to treat high blood pressure.1 Unfortunately, evidence suggests that a large number of adults and children have undiagnosed hypertension.5,6 The prevalence of hypertension increases in the elderly and in Aboriginal and Torres Strait Islander peoples and Māori and Pacific Islander peoples compared to the non-Indigenous population.1,3 The diagnosis of hypertension is based on repeated blood pressure (BP) measurements at different times, when systolic blood pressure is equal to or greater than 140 mmHg or diastolic pressure is 90 mmHg or greater (see Table 23.1).7 Normal blood pressure is associated with the lowest cardiovascular risk, whereas those who fall in the ‘high–normal’ range are at risk for developing hypertension unless they institute lifestyle modifications.8 A patient whose blood pressure is above normal, but not meeting the cut-off values for hypertension, may be diagnosed with pre-hypertension. All categories of hypertension are associated with an increased risk of myocardial infarction, kidney disease and stroke. Systolic hypertension, even when not accompanied by an increase in diastolic pressure, is the most significant factor in causing organ damage (heart,
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kidney and brain). Table 23.1 also indicates the grades of hypertension, which reflect the severity of increased blood pressure. Individuals may have combined systolic and diastolic hypertension or isolated systolic hypertension. Most cases of combined systolic and diastolic hypertension are diagnosed as primary hypertension (also called essential or idiopathic hypertension) and account for approximately 90–95% of cases of hypertension. Secondary hypertension is caused by an underlying disease process such as kidney disease, hormone imbalances and drugs, and accounts for approximately 5–10% of cases. Ultimately, hypertension results from a sustained increase in peripheral resistance (vasoconstriction of the arterioles) or an increase in circulating blood volume (cardiac output), or both.
Factors associated with primary hypertension
A specific cause for primary hypertension has not been identified, but a combination of genetic and environmental factors is thought to be responsible for its development. Genetic predisposition to hypertension is thought to be polygenic; that is, there is more than one gene involved (see Chapter 38). A range of environmental factors are associated with primary hypertension — see Box 23.1 ‘Risk factors for primary hypertension’. Many of these factors are also risk factors for other cardiovascular disorders; this is a recurring feature of cardiovascular disease. Although populations with a high dietary sodium intake have long been shown to have an increased incidence of hypertension, studies indicate that low dietary potassium, calcium and magnesium intakes are also risk factors, because,
TABLE 23.1 Classification of clinical blood pressure levels in adults DIAGNOSTIC CATEGORY*
SYSTOLIC (mmHg)
AND/OR
DIASTOLIC (mmHg)
Optimal
males after 55 years) High dietary sodium intake Low dietary intake of potassium, calcium, magnesium Glucose intolerance Chronic stress, anxiety
CHAPTER 23 Alterations of cardiovascular function across the life span
↑ Sympathetic nervous system activity ↑ Reninangiotensinaldosterone system activity
Decreased dietary potassium, magnesium and calcium
Decreased renal sodium excretion (shift in pressure– natriuresis relationship)
Increased dietary sodium intake Insulin resistance Obesity
Endothelial dysfunction Dysfunction of the natriuretic hormones
Renal glomerular and tubular inflammation
CONCEPT MAP
Genetics
613
FIGURE 23.2
Factors that cause a shift in the pressure–natriuresis relationship. Numerous factors have been implicated in the pathogenesis of sodium retention in individuals with hypertension. These factors cause less renal excretion of sodium than would normally occur with increased blood pressure.
↑Heart rate and peripheral resistance leads to
↑ Sympathetic nervous system activity leads to
results in
↑ Insulin resistance causes (over time)
Vascular remodelling affects
Endothelial dysfunction
results in
causes
contributes to Procoagulant effects affects Narrowing of vessels and vasospasm
Hypertension
CONCEPT MAP
causes
FIGURE 23.3
The role of the sympathetic nervous system in the pathogenesis of hypertension. Increased activity of the sympathetic nervous system causes increases in heart rate, peripheral resistance and vascular remodelling, with narrowing and spasm of the arteries. The sympathetic nervous system contributes to insulin resistance, which is associated with endothelial dysfunction and decreased production of vasodilators. The sympathetic nervous system has procoagulant (tendency to clot) properties, making vascular spasm and thrombosis more likely.
renin and angiotensin levels and procoagulant effects are all induced by the sympathetic nervous system (see Fig. 23.3).11 The renin-angiotensin-aldosterone system plays an important role in blood pressure regulation by moderating vascular tone and influencing sodium and water retention by the kidneys. Furthermore, angiotensin II mediates arteriolar remodelling and is associated with end-stage organ effects of hypertension, including renal disease and cardiac hypertrophy.
Natriuretic hormones promote the excretion of sodium in the urine. They include atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide and urodilatin. The function of these hormones can be affected by excessive sodium intake; inadequate dietary intake of potassium, magnesium and calcium; and obesity.12 Dysfunction of these hormones, along with alterations in the renin-angiotensin-aldosterone system and the sympathetic nervous system, cause an increase in vascular tone and a change in the pressure–natriuresis
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relationship. Sodium retention leads to water retention, causing an increase in blood volume, which contributes to elevations in blood pressure. Subtle renal injury results, with renal vasoconstriction and tissue ischaemia. Tissue ischaemia causes inflammation of the kidneys, and contributes to dysfunction of the internal structure of the kidneys, namely the glomeruli and tubules, which actually promotes additional sodium retention. This vicious cycle leads to increases in blood pressure at rest and eventually hypertension. Inflammation plays a role in the pathogenesis of hypertension. Endothelial injury and tissue ischaemia result in the release of vasoactive inflammatory cytokines (see Chapter 13). Although many of these cytokines (for instance, histamine) have vasodilatory actions in acute inflammatory injury, chronic inflammation contributes to vascular remodelling and smooth muscle contraction. Endothelial injury and dysfunction in primary hypertension are further characterised by a decreased production of vasodilators, such as nitric oxide, and increased production of vasoconstrictors, such as endothelin. Insulin resistance (see Chapter 36) is common in hypertension, even in individuals without diabetes mellitus.13 Insulin resistance is associated with decreased endothelial release of nitric oxide and other vasodilators. It also affects renal function and causes the kidneys to retain sodium
CONCEPT MAP
Genetic influences Defects in renal sodium haemostasis
and water. Insulin resistance is associated with overactivity of the sympathetic nervous system and the renin-angiotensinaldosterone system. The pathophysiology of primary hypertension is summarised in Fig. 23.4.
Secondary hypertension
Secondary hypertension is caused by an underlying disease process or medication that raises peripheral vascular resistance or cardiac output. The condition is more prevalent in younger people (< 30 years of age) and those over 50 years of age.14,15 If the cause is identified and removed before permanent structural changes occur, blood pressure returns to normal. Examples include kidney disease due to the retention of sodium and water (see Chapter 30), adrenocortical hormonal imbalances such as primary hyperaldosteronism (see Chapter 11), and drugs (oral contraceptives, corticosteroids, antihistamines).
Isolated systolic hypertension
Isolated systolic hypertension is typically defined as a sustained systolic BP > 140 mmHg and diastolic BP below 90 mmHg. Isolated systolic hypertension accounts for a substantial proportion of hypertension in individuals older than 65 years of age and is strongly associated with cardiovascular and cerebrovascular events.
Environmental factors
Functional, vasoconstriction
Defects in vascular smooth muscle growth and structure
Vascular reactivity
Vascular wall thickness
Inadequate sodium excretion Sodium and water retention Plasma and ECF volume
Natriuretic hormone
Cardiac output (autoregulation)
Total peripheral resistance Hypertension
FIGURE 23.4
The pathophysiology of primary hypertension. A hypothetical scheme for the pathogenesis of essential hypertension, implicating genetic defects in renal excretion of sodium, functional regulation of vascular tone and structural regulation of vascular calibre. Environmental factors, especially increased sodium intake, may potentiate the effects of genetic factors. The resultant increases in cardiac output and peripheral resistance contribute to hypertension. ECF = extracellular fluid.
CHAPTER 23 Alterations of cardiovascular function across the life span
An increased pulse pressure (systolic minus diastolic pressure) indicates reduced vascular compliance of large arteries. Pulse pressure is increased in isolated systolic hypertension and is related to either an increase in cardiac output (heart valve disease) or peripheral resistance (caused by atherosclerosis). Pharmacological management of isolated systolic hypertension is required because the systolic blood pressure is greater than 140 mmHg.
TABLE 23.2 The pathological effects of sustained primary hypertension
MECHANISM OF INJURY
POTENTIAL PATHOLOGICAL EFFECTS
Myocardium
Increased workload combined with diminished blood flow through coronary arteries
Left ventricular hypertrophy, myocardial ischaemia, left heart failure
Coronary arteries
Accelerated atherosclerosis (coronary artery disease)
Myocardial ischaemia, myocardial infarction, sudden death
Kidneys
Renin and aldosterone secretion stimulated by reduced blood flow
Retention of sodium and water, leading to increased blood volume and continuation of hypertension
Reduced oxygen supply
Tissue damage that compromises filtration
High pressures in renal arterioles
Renal failure
Brain
Reduced blood flow and oxygen supply; weakened vessel walls, accelerated atherosclerosis
Transient ischaemic attacks, cerebral thrombosis, aneurysm, haemorrhage, acute brain infarction
Eyes (retinas)
Reduced blood flow
Retinal vascular sclerosis
High arteriolar pressure
Exudation, haemorrhage
Aorta
Weakened vessel wall
Dissecting aneurysm
Arteries of lower extremities
Reduced blood flow and high pressures in arterioles, accelerated atherosclerosis
Intermittent claudication, gangrene
SITE OF INJURY
Heart
Complicated hypertension
Cardiovascular complications of sustained hypertension include left ventricular hypertrophy, angina pectoris, heart failure, coronary heart disease, myocardial infarction and sudden death. Myocardial hypertrophy in response to hypertension is mediated by several neurohormonal substances, including catecholamines from the sympathetic nervous system (adrenaline and noradrenaline) and angiotensin II.16 In addition, the increased size of the heart muscle increases demand for oxygen delivery over time, contractility of the heart is impaired, and the individual is at increased risk for heart failure. Vascular complications include the formation, dissection and rupture of aneurysms (outpouchings in vessel walls) and atherosclerosis leading to vessel occlusion. Microalbuminuria (small amounts of protein in the urine) occurs in 10–25% of individuals with essential hypertension and is now recognised as an early sign of impending renal dysfunction and significantly increased risk for cardiovascular events. The pathological effects of sustained primary hypertension are summarised in Table 23.2. CLINICAL MANIFESTATIONS
The early stages of hypertension have no clinical manifestations other than elevated blood pressure. Most importantly, there are usually no signs and symptoms; thus, hypertension is often called a silent disease. Some hypertensive individuals never have signs, symptoms or complications, whereas others become very ill. Still other individuals have anatomical and physiological damage caused by past hypertensive disease, despite current blood pressures being within normal ranges. The chance of developing primary hypertension increases with age. Although hypertension is usually thought to be an adult health problem, it is important to remember that hypertension does occur in children and is being diagnosed with increasing frequency.17 Usually, however, increased peripheral resistance and early hypertension develop in the second, third and fourth decades of life. If elevated blood pressure is not detected and treated, it becomes established and may begin to accelerate its effects on tissues when the individual is 30–50 years of age. This sets the stage for the complications of hypertension that begin to appear during the fourth, fifth and sixth decades of life. Most clinical manifestations of hypertensive disease are caused by complications that damage organs and tissues outside the vascular system. Besides elevated blood pressure, the signs and symptoms therefore tend to be specific for
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the organs or tissues affected. Evidence of heart disease, renal insufficiency, central nervous system dysfunction, impaired vision, impaired mobility, vascular occlusion or oedema can all be caused by sustained hypertension. EVALUATION AND TREATMENT
A single elevated blood pressure reading does not indicate hypertension. Diagnosis requires the measurement of blood pressure on at least two separate occasions. The individual should be seated and relaxed, preferably in a quiet room prior to measurement, the arm supported at heart level
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and free of clothing that could impede blood flow. After 30 seconds, repeat the procedure on the same arm and average the readings if the systolic blood pressure difference is less than 10 mmHg and the diastolic blood pressure difference is less than 6 mmHg. In addition, the person should have a physical examination, with investigations such as 24-hour blood pressure monitoring in selected individuals, blood analysis (testing for sodium, potassium, chloride, bicarbonate, urea, creatinine, uric acid, haemoglobin, fasting glucose, total cholesterol, LDL cholesterol (see ‘Dyslipidaemia and atherosclerosis-promoting diet’ below), HDL cholesterol, triglycerides, liver function), urinalysis (testing for blood and protein) and an electrocardiogram.7 Individuals who have elevated blood pressure are assumed to have primary hypertension unless their history, physical examination or investigations indicates secondary hypertension. Treatment of primary hypertension depends on its severity. Lifestyle modification is important for preventing hypertension in those individuals who fall into the high–normal category (see Table 23.1) and for treating hypertension. Important lifestyle modifications include increasing exercise levels, making dietary modifications, ceasing smoking, limiting alcohol intake and losing weight. Pharmacological interventions are required when lifestyle modifications and systolic or diastolic blood pressure is not controlled (see Fig. 23.5). The decision to commence antihypertensive drugs should be based on the severity of the hypertension and the extent of end-organ damage. A variety of drugs are used to manage high blood pressure and these drugs are grouped in Table 23.3. An understanding of how these drugs work can be derived from reviewing the location of (alpha)- and (beta)-adrenergic receptors (refer to Chapter 6). Also, Chapter 28 provides an explanation of how aldosterone is released and its functions. This will explain why angiotensin-converting enzyme (ACE) inhibitors may be useful: they decrease the formation of angiotensin II and the release of aldosterone.
Orthostatic hypotension
Orthostatic hypotension, or postural hypotension, refers to a decrease in both systolic and diastolic arterial blood pressure on standing. Normally when an individual stands up, the gravitational changes on the circulation are compensated by mechanisms such as reflex arteriolar and venous constriction controlled by the baroreceptors and increased heart rate. Furthermore, mechanical factors such as the closure of valves in the venous system, pumping of the leg muscles and a decrease in intrathoracic pressure assist in increasing venous return in the heart. Collectively, these maintain blood pressure. Orthostatic hypotension is often accompanied by dizziness, blurring or loss of vision and syncope (fainting) caused by insufficient vasomotor compensation and reduction of blood flow through the brain. This occurs because the normal or compensatory vasoconstrictor response to standing is absent so that there is blood pooling
TABLE 23.3 Drug classifications used to treat hypertension and the variables they affect REDUCE STROKE VOLUME
REDUCE SYSTEMIC VASCULAR RESISTANCE
DECREASE HEART RATE
Thiazide diuretics
Combined α, βadrenergic blockers
β-blockers
Chlorthalidone Hydrochlorothiazide Loop diuretics Frusemide Potassium-sparing diuretics Amiloride Spironolactone Angiotensinconverting enzyme (ACE) inhibitors Captopril Enalapril Angiotensin II receptor blockers Irbesartan Losartan
Carvedilol Labetalol Angiotensinconverting enzyme (ACE) inhibitors Captopril Enalapril
Atenolol Metoprolol Combined α, β-adrenergic blockers Carvedilol Labetalol
Angiotensin II receptor blockers Irbesartan Losartan Calcium channel blockers Diltiazem Verapamil α-blockers Prazosin Centrally acting αblockers Clonidine Methyldopa Direct-acting vasodilators Hydralazine Minoxidil
α = alpha; β = beta.
in the muscle vasculature, as well as in the splanchnic and renal beds. Orthostatic hypotension may be acute and temporary or chronic: • Acute orthostatic hypotension is caused when the normal regulatory mechanisms are sluggish as a result of (1) altered body chemistry, (2) drug action (e.g. antihypertensives, antidepressants), (3) prolonged immobility caused by illness, (4) starvation, (5) physical exhaustion, (6) any condition that produces volume depletion (e.g. dehydration, diuresis, potassium or sodium depletion) or (7) venous pooling (e.g. pregnancy, extensive varicosities of the lower extremities). The elderly are particularly susceptible to this type of orthostatic hypotension. • Chronic orthostatic hypotension may be (1) secondary to a specific disease or (2) idiopathic or primary. The diseases that cause secondary orthostatic hypotension are endocrine disorders (e.g. adrenal insufficiency,
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FIGURE 23.5
Treatment strategy for patients with newly diagnosed hypertension. The treatment for hypertension commences with determining cardiovascular risk, and then lifestyle modifications and pharmacological management are used as appropriate. Source: Reproduced with permission from Guideline for the diagnosis and management of hypertension in adults 2016. © 2016 National Heart Foundation of Australia.
diabetes mellitus), metabolic disorders (e.g. porphyria) or diseases of the central or peripheral nervous systems (e.g. intracranial tumours, cerebral infarcts, Wernicke’s encephalopathy, peripheral neuropathies). It is more prevalent in the aged population and may be attributable to an increase in mortality due to secondary effects of orthostatic hypotension, such as falls.18 In addition to cardiovascular symptoms, associated impotence and bowel and bladder dysfunction are common.
Although no curative treatment is available for orthostatic hypotension, often it can be managed adequately with a combination of non-pharmacological and pharmacological therapies. For both acute and chronic forms, hypotension resolves when the underlying disorder is corrected.
Arteriosclerosis
Arteriosclerosis is a chronic disease of the arterial system characterised by abnormal thickening and hardening of
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F OC US O N L E ARN IN G
1 Describe the major risk factors for hypertension. 2 Summarise the pathophysiology of primary hypertension. 3 Discuss the causes of orthostatic hypotension.
the vessel walls. Smooth muscle cells and collagen fibres migrate into the tunica intima (internal layer of the arterial wall), causing it to stiffen and thicken, gradually narrowing the arterial lumen (see Fig. 23.6). Changes in lipid, cholesterol and phospholipid metabolism within the tunica intima also contribute to arteriosclerosis. Although these changes may be part of normal ageing, pathophysiological conditions such as hypertension, insufficient perfusion (blood flow) of tissues or weakening and outpouching of arterial walls can be exacerbated by the changes to the arterial walls brought about by arteriosclerosis.
Atherosclerosis
Atherosclerosis is the most common form of arteriosclerosis. It is characterised by soft deposits of intra-arterial fat and fibrin in the vessels walls that harden over time. Atherosclerosis is not a single disease entity but rather a pathological process that can affect vascular systems throughout the body, resulting in ischaemic syndromes that can vary widely in their severity and clinical manifestations. It is the leading cause of coronary heart and cerebrovascular disease. (Atherosclerosis of the coronary arteries is described later in this chapter, and atherosclerosis of the cerebral arteries leading to cerebrovascular disease is described in Chapter 9.) PATHOPHYSIOLOGY
Inflammation plays a fundamental role in mediating all of the steps in the initiation and progression of atherosclerosis
FIGURE 23.6
Arteriosclerosis. Cross-section of a normal artery and an artery altered by disease. Note the substantial decrease in the diameter of the lumen in the occluded artery compared with the normal artery.
formation.19–21 Atherosclerosis begins with injury to the endothelial cells that line the artery walls. Possible causes of endothelial injury include the common risk factors for atherosclerosis, such as smoking, hypertension, diabetes mellitus, increased levels of low-density lipoprotein (LDL) cholesterol and decreased levels of high-density lipoprotein (HDL) cholesterol. Other possible causes of endothelial injury include elevated C-reactive protein (CRP), increased serum fibrinogen, insulin resistance, oxidative stress, infection and periodontal disease. Injured endothelial cells become inflamed and cannot make normal amounts of antithrombic and vasodilating substances. When the endothelium is injured, it loses the ability both to prevent clotting and to vasodilate. This results in platelets aggregating when thromboxane A2 increases (refer to Chapter 16), and the release of serotonin and endothelin combines to cause vasoconstriction. This leads to a decrease in blood flow and, ultimately, ischaemia. At the same time, sympathetic nervous system activation causes vasoconstriction when noradrenaline is released. The enzyme ACE in the endothelium also converts angiotensin I to angiotensin II (Fig. 23.7 summarises these events). Collectively, this leads to vasoconstriction and increased clotting. The next step in the formation of atherosclerosis occurs when inflamed endothelial cells express adhesion molecules that bind monocytes and other inflammatory and immune cells. Monocytes adhere to the injured endothelium and release numerous inflammatory cytokines (e.g. tumour necrosis factor-alpha [TNF-α], interferons, interleukins and C-reactive protein) and enzymes that further injure the vessel wall.22 Toxic oxygen radicals generated by the inflammatory process cause oxidation (i.e. addition of oxygen) of LDL. Oxidised LDL is engulfed by macrophages, which then penetrate into the intima of the vessel. These lipid-laden macrophages are called foam cells and when they accumulate in significant amounts, they form a lesion called a fatty streak (see Figs 23.8 and 23.9). Even small-sized lesions can be found in the walls of arteries of most people, including young children. Once formed, fatty streaks produce more toxic oxygen radicals and cause immunological and inflammatory changes resulting in progressive damage to the vessel wall. Macrophages also release growth factors that stimulate smooth muscle cell proliferation. Smooth muscle cells in the region of endothelial injury proliferate, produce collagen and migrate over the fatty streak forming a fibrous plaque (see Fig. 23.9). The fibrous plaque may calcify, protrude into the vessel lumen and obstruct blood flow to distal tissues (especially during exercise), which may cause symptoms such as angina or intermittent claudication (leg pain with exercise) due to poor blood circulation. Many plaques, however, are ‘unstable’, meaning they are prone to rupture even before they affect blood flow significantly and are clinically silent until they rupture. Plaques that have ruptured are called complicated plaques. Once rupture occurs, exposure of underlying tissue results in platelet adhesion, initiation of the coagulation (or clotting)
CHAPTER 23 Alterations of cardiovascular function across the life span
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FIGURE 23.7
Endothelium regulation of vasoconstriction, vasodilation and platelet aggregation. Endothelial cell damage, such as that associated with atherosclerosis formation, causes vasoconstriction and platelet aggregation to dominate over vasodilation.
1
Monocyte
LDL
Lumen of artery Endothelium
Lipid pool
3 Oxidised LDL
Foam cell 4
2
1 LDL enters intima through intact endothelium 5
2 Intimal LDL is oxidised into proinflammatory lipids 3 Oxidised LDL causes adhesion and entry of monocytes and T lymphocytes across endothelium
Smooth muscle
Cytokines
4 Monocytes differentiate into macrophages and then consume large amounts of LDL, transforming into foam cells 5 Foam cells release growth factors (cytokines) that encourage atherosclerosis
FIGURE 23.8
Low-density lipoprotein (LDL) oxidation. After the LDL enters the subendothelium, it becomes oxided. Oxided LDL promotes macrophage entry into the subendothelium, and as these consume the oxidised LDL they become foam cells. Foam cells further promote atherosclerosis.
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A A Damaged endothelium: chronic endothelial injury _ Hypertension _ Smoking _ Hyperlipidaemia _ Haemodynamic factors _ Toxins _ Viruses _ Immune reactions
Endothelium Tunica intima Tunic media Adventitia
Monocyte Damaged endothelium
Platelets Macrophage
Response to injury
B B
Fatty streak
C C
Fibrous plaque
D D
Lipids Platelets adhere to damaged endothelium Foamy macrophage (foam cells) ingesting lipids Migration of smooth muscle into the intima Lipid accumulation Fibroblast (connective tissue cell) Collagen cap (fibrous tissue) Fibroblast (connective tissue cell) Fissure in plaque Lipid pool
Thrombus (forms due to endothelial damage) Thinning collagen cap Lipid pool
Complicated lesion
FIGURE 23.9
The progression of atherosclerosis. A Damaged endothelium. B Diagram of fatty streak and lipid core formation. C Diagram of fibrous plaque. Raised plaques are visible: some are yellow; others are white. D Diagram of complicated lesion; thrombus is red; collagen is blue. Plaque is complicated by red thrombus deposition.
CHAPTER 23 Alterations of cardiovascular function across the life span
cascade and rapid thrombus formation. The thrombus may suddenly occlude the affected vessel, resulting in ischaemia and infarction. Aspirin or other antithrombotic agents are used to prevent this complication of atherosclerotic disease. CLINICAL MANIFESTATIONS
Atherosclerosis presents with symptoms and signs that result from inadequate perfusion of tissues because of obstruction of the vessels that supply them. Partial vessel obstruction may lead to transient ischaemic events, often associated with exercise or stress. As the lesion becomes complicated, increasing obstruction with superimposed thrombosis may result in tissue infarction. Obstruction of peripheral arteries can cause significant pain and disability. Coronary heart disease caused by atherosclerosis (see Fig. 23.10) is the major cause of myocardial ischaemia and is one of the most important health issues in Western countries, including Australia and New Zealand. Atherosclerotic obstruction of the vessels supplying the brain is the major cause of strokes. EVALUATION AND TREATMENT
In evaluating individuals for the presence of atherosclerosis, a complete history (including risk factors), physical examination and laboratory data are considered. The use of x-rays, electrocardiography, ultrasonography, nuclear scanning and angiography may be necessary to identify affected vessels, particularly coronary vessels. The primary goal in the management of atherosclerosis is to restore adequate blood flow to the affected tissues. If
A
B
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an individual presents with acute ischaemia, interventions are specific to the diseased area (e.g. acute myocardial infarction due to occlusion of the coronary vessel). In situations where the disease process does not require immediate intervention, management focuses on removing the initial causes of vessel damage and preventing lesion progression. This includes lifestyle modifications, such as increasing exercise levels, ceasing smoking and controlling hypertension and diabetes mellitus where appropriate, and reducing LDL levels by diet or medications, or both.
Coronary heart disease
Coronary heart disease refers to conditions that affect the coronary blood vessels that supply the heart with nutrients and oxygen (see Chapter 22). We have chosen to use the term coronary heart disease to align with the terminology used by the Australian Institute of Health and Welfare, the New Zealand Ministry of Health and the peak cardiac bodies in both countries, the National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. In clinical practice you may see a variety of terms used for coronary heart disease, such as ischaemic heart disease, coronary artery disease and heart disease. These terms are essentially synonymous and are often used interchangeably. However, one of the most important aspects to remember is that more than 90% of all cases of myocardial ischaemia (a local state in which the cardiac cells are temporarily deprived of blood supply) result from obstruction of the coronary arteries due to atherosclerosis. Persistent ischaemia or complete occlusion of a coronary artery causes the acute coronary syndromes including infarction or irreversible myocardial damage. Acute myocardial infarction constitutes the often fatal event known within the community as a heart attack.
The development of coronary heart disease
*
* *
FIGURE 23.10
Coronary artery atherosclerosis. A A coronary artery with 60–70% occlusion (black outline and arrow demonstrate narrowing of lumen) due to atherosclerosis. This degree of occlusion may lead to angina. B Severe coronary artery disease and evidence of past thrombus (black arrow), with only three small lumens (*) providing blood flow to the myocardium.
Approximately 3.0% of Australians (more than 685 000 people) have coronary heart disease. It is associated with the elderly, as the prevalence of coronary heart disease increases with age (see Fig. 23.1).1 Numerous types of genetic susceptibilities to coronary heart disease have been identified in individuals with a family history of heart disease. Risk factors can be categorised as conventional (major) versus non-traditional (novel) and modifiable versus non-modifiable. Much new information has been obtained about the conventional risk factors, which have markedly improved prevention and management of the disease. Conventional risk factors for coronary heart disease that are non-modifiable include: • advanced age • male or female after menopause • family history. Modifiable risk factors include: • dyslipidaemia and atherosclerosis-promoting diet • hypertension • cigarette smoking
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• diabetes mellitus and insulin resistance • obesity and a sedentary lifestyle. We now focus our attention on discussing these modifiable risk factors. DYSLIPIDAEMIA AND ATHEROSCLEROSIS-PROMOTING DIET
The term lipoprotein refers to lipids, phospholipids, cholesterol and triglycerides bound to carrier proteins. These carrier molecules assist in transporting lipid-based molecules through the water-based environment of the blood. Lipids (cholesterol in particular) are required by most cells for the manufacture and repair of plasma membranes. Cholesterol is also a necessary component for the production of such essential substances as bile acids and steroid hormones. Although cholesterol can easily be obtained from dietary fat intake, most body cells can also produce cholesterol. The cycle of lipid metabolism is complex. Dietary fat is packaged into particles known as chylomicrons in the small intestine. Chylomicrons are required for absorption of fat; they function by transporting lipid from the small intestine to the liver and peripheral cells. Chylomicrons are the least dense of the lipoproteins and primarily contain triglyceride. Some of the triglyceride may be removed from the blood and either stored by adipose tissue or used by muscle as an energy source. The chylomicron remnants, composed mainly of cholesterol, are taken up by the liver. A series of chemical reactions in the liver results in the production of several lipoproteins that vary in density and function. These include very-low-density lipoproteins (VLDL), primarily triglyceride and protein; low-density lipoproteins (LDL), mostly cholesterol and protein; and high-density lipoproteins (HDL), mainly phospholipids and protein. Dyslipidaemia refers to abnormal concentrations of serum lipoproteins. The National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand (2005) have classified the recommended target levels of lipoproteins in the blood (see Table 23.4). An increased serum concentration of LDL is considered a strong indicator of coronary risk. Serum levels of LDL are normally controlled by hepatic receptors that bind LDL and limit liver production of this lipoprotein. High dietary intake of cholesterol and fats, often in combination with a genetic predisposition to accumulations of LDL, results in
TABLE 23.4 Recommended target levels of lipids LIPOPROTEIN
mmol/L
• Low-density lipoprotein cholesterol (LDL-C)
< 1.8
• High-density lipoprotein cholesterol (HDL-C)
> 1.0
• Triglyceride (TG)
< 2.0
• Non–high-density lipoprotein cholesterol (NHDL-C)
< 2.5
Source: Reproduced with permission from Reducing risk in heart disease: an expert guide to clinical practice for secondary prevention of coronary heart disease Updated 2012 © 2012 National Heart Foundation of Australia.
high levels of LDL in the bloodstream. Oxidation of LDL, its migration into the vessel wall and phagocytosis by macrophages are key steps in the pathogenesis of atherosclerosis (see Fig. 23.10). LDL cholesterol also plays a role in endothelial injury, inflammation and immune responses that have been identified as being important in atherosclerosis formation.23 Aggressive reduction of LDL with diet and cholesterol-lowering drugs, such as HMG-CoA reductase inhibitors, more commonly referred to as statins, is associated with a dramatic decrease in risk for coronary heart disease.24 Low levels of HDL are also a strong indicator of coronary risk and high levels of HDL may be more protective for the development of atherosclerosis than low levels of LDL.25 HDL is responsible for ‘reverse cholesterol transport’, which returns excess cholesterol from the tissues to the liver for metabolism. HDL also participates in endothelial repair and decreases thrombosis.26 Exercise, weight loss, fish oil consumption and moderate alcohol use can result in modest increases in HDL. LDL is often referred to as ‘bad’ cholesterol (atherogenic — promoting development of atherosclerosis), while HDL is referred to as ‘good’ cholesterol (for protection from atherosclerosis). Other lipoproteins associated with increased cardiovascular risk include elevated serum VLDL (triglycerides) and increased lipoprotein (a). Triglycerides are associated with an increased risk for coronary heart disease, especially in combination with other risk factors such as diabetes mellitus. Lipoprotein (a) is a genetically determined molecular complex between LDL and a serum glycoprotein called apolipoprotein A and has been shown to be an important risk factor for atherosclerosis, especially in women. HYPERTENSION
Hypertension is responsible for a twofold to threefold increased risk of atherosclerosis. It contributes to endothelial injury and can lead to myocardial hypertrophy, which increases myocardial demand for coronary flow. This risk factor was discussed fully at the start of this chapter. CIGARETTE SMOKING
Both direct and passive (environmental) smoking increase the risk of coronary heart disease. Nicotine stimulates the release of catecholamines (adrenaline and noradrenaline), which increase heart rate and peripheral vasoconstriction. As a result, blood pressure increases, as do cardiac workload and oxygen demand. Cigarette smoking is also associated with an increase in LDL and a decrease in HDL, and contributes to damage of the blood vessel endothelial lining, blood vessel inflammation and thrombosis. It is likely that additional mechanisms by which smoking increases atherosclerosis also occur. DIABETES MELLITUS AND INSULIN RESISTANCE
Diabetes mellitus is an extremely important risk factor for coronary heart disease. Insulin resistance and diabetes have
CHAPTER 23 Alterations of cardiovascular function across the life span
multiple effects on the cardiovascular system, including endothelial damage, thickening of the vessel wall, increased inflammation, increased thrombosis and decreased production of endothelial-derived vasodilators such as nitric oxide.27 Diabetes mellitus is also associated with dyslipidaemia. Diabetes mellitus is discussed in Chapter 36. OBESITY AND SEDENTARY LIFESTYLE
The prevalence of people who are overweight or obese is increasing steadily in Western countries, and Australia and New Zealand are following this trend. In 2014–16, 63.4% of Australians aged 18 years and over were overweight or obese. The prevalence of overweight and obesity has increased in Australia over time, from 61.2% in 2007–8 and 56.3% in 1995. In both countries the incidence of overweight and obesity is higher in the Indigenous than non-Indigenous population.1 Metabolic syndrome is a combination of central (abdominal) obesity, abnormal glucose tolerance or impaired glucose tolerance, raised triglycerides, decreased HDL, elevated blood pressure and insulin resistance (see Chapter 36). It is estimated that almost 30% of Australian adults have metabolic syndrome. The combination of these risk factors considerably increases the development of cardiovascular disease and confers an even higher risk for coronary heart disease.28 Abdominal obesity has the strongest link with increased coronary heart disease risk and is related to insulin resistance, decreased HDL, increased blood pressure and decreased levels of adiponectin.29 Physical activity and weight loss offer substantial reductions in risk factors for coronary heart disease. Moreover, for a non-cardiac patient, exercise provides protection if there is a cardiovascular event.30 Exercise training improves major cardioprotection mechanisms including increased nitric oxide generation, decreased cytokine production and increased antioxidant defences. Similarly, research suggests that some foods or food components can decrease cardiovascular risk, and/or improve existent coronary heart disease. Beneficial nutrients include those found in fruits and vegetables and omega-3 polyunsaturated fatty acids.31,32 Coronary heart disease, myocardial ischaemia and acute myocardial infarction form a pathophysiological continuum that impairs the pumping ability of the heart by depriving the heart muscle of blood-borne oxygen and nutrients. We now explore how coronary heart disease results in myocardial dysfunction and possible cardiac cell death.
Myocardial ischaemia PATHOPHYSIOLOGY
The coronary arteries supply blood flow sufficient to meet the demands of the myocardium during normal levels of cardiac activity, as well as when the heart is working harder (such as during exercise). Oxygen is extracted from these vessels with maximal efficiency. If demand increases, healthy coronary arteries dilate to increase the flow of oxygenated blood to the myocardium. Various pathological mechanisms
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RESEARCH IN F CUS Inflammatory markers for cardiovascular risk It is well recognised that inflammation underlies the pathophysiology of atherosclerosis and transduces the effects of many known risk factors for the disease. Although controversial, biomarkers of inflammatory status, such as tumour necrosis factor-α, interferon-γ and C-reactive protein (CRP), have lent clinical credence to the connection between inflammation biology and human atherosclerosis. Statins effectively lower LDL and CRP levels in humans. Analyses of several large studies of statins in primary- and secondaryprevention populations suggest that some of their clinical benefit accrues from an anti-inflammatory action distinct from LDL lowering, although that anti-inflammatory intervention can reduce cardiovascular events independent of lipoprotein effects still requires testing. Several are under way or in the planning stage. For example, the Cardiovascular Inflammation Reduction Trial (CIRT) is currently testing whether treatment with weekly low dose methotrexate, a regimen used successfully in the management of rheumatoid arthritis, can reduce recurrent cardiovascular events. Meanwhile, biomarkers can be used to help treat people with, or at risk of, atherosclerosis by improving prognostication, by assessing the need for and intensity of treatment, by individualising the use of specific treatments and by helping to develop new therapeutics. For example, including CRP with conventional risk factors improves risk prediction for atherosclerotic events, both in people with and without established disease. Moreover, evidence accumulated demonstrates that small increases in biomarkers of inflammatory (such as CRP) can predict future cardiovascular events in apparently healthy people.
can interfere with blood flow through the coronary arteries, giving rise to myocardial ischaemia. Narrowing of a major coronary artery by more than 50% impairs blood flow enough to interfere with cellular metabolism (see Fig. 23.11). Myocardial ischaemia develops if blood flow or oxygen content of coronary blood is insufficient to meet the metabolic demands of myocardial cells. Imbalances between coronary blood supply and myocardial demand can result from a number of conditions. The most common cause of decreased coronary blood flow and myocardial ischaemia is the formation of atherosclerotic plaques in the coronary circulation. As the plaque increases in size, it may partially occlude the vessel, thus limiting coronary flow and causing ischaemia (see Fig. 23.12). This is common when metabolic demand increases, such as during exercise. Some plaques are ‘unstable’, meaning they are prone to ulceration or rupture. When this occurs, underlying tissues of the vessel wall are exposed, resulting in platelet adhesion and thrombus formation. This can suddenly cut off blood supply to the heart muscle, resulting in acute myocardial ischaemia and, if the vessel obstruction cannot be reversed rapidly, ischaemia
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CONCEPT MAP
Imbalance between coronary supply and myocardial demand Sudden death leads to
Heart failure
resulting in Myocardial O2 deficit
may result in
if Less than 20 min: ischaemic episode
Impaired/altered cardiac pumping
Altered response to electrical impulses
Arrhythmias
Failure to contract (mechanical)
if Greater than 20 min: myocardial infarction Myocyte death
Lack of response to electrical impulses
FIGURE 23.11
Ischaemic events that may lead to heart failure or sudden death. Insufficient oxygen for the heart’s requirements leads to myocardial oxygen deficit. If the oxygen is restored within 20 minutes, this may lead to electrical alterations that cause heart failure or become fatal. If the oxygen is restored after 20 minutes, the inability to contract may lead to heart failure.
A
B
FIGURE 23.12
Angiogram of coronary artery disease. A Normal left coronary artery angiogram. B Left coronary artery angiogram with decreased blood flow due to atherosclerosis. Note the position of the arrow in B; atherosclerosis significantly decreases blood flow from that point.
will progress to infarction (death of the cells). Myocardial ischaemia can also result from other causes of decreased blood and oxygen delivery to the myocardium, such as coronary spasm, hypotension, arrhythmias and decreased oxygen-carrying capacity of the blood, such as anaemia. Common causes of increased myocardial demand for blood include tachycardia, exercise and valvular disease.
In coronary heart disease, ischaemia can develop within 10 seconds of coronary occlusion. Myocytes (cardiac muscle cells) do not have the capacity to store a large amount of adenosine triphosphate (ATP). Therefore, myocytes need a constant supply of blood that carries oxygen and nutrients, so that ATP can be manufactured continually. If coronary artery blood flow is impeded, after several minutes, the
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heart cells lose the ability to contract, thus hampering pump function and depriving the myocardium of a glucose source necessary for aerobic metabolism. Anaerobic processes take over and lactic acid accumulates. Cardiac muscle cells remain viable for approximately 20 minutes under ischaemic conditions. If blood flow is restored, aerobic metabolism resumes, contractility is restored and cellular repair begins. If perfusion is not restored, then myocardial infarction occurs (see Fig. 23.11), which causes death to those deprived cardiac cells. These cells do not regenerate and remain as non-contractile scar tissue, no longer able to contribute to cardiac function. CLINICAL MANIFESTATIONS
Individuals with reversible myocardial ischaemia can present clinically in several ways. Chronic coronary obstruction results in recurrent predictable chest pain called angina pectoris (commonly referred to as angina). Abnormal vasospasm of coronary vessels results in unpredictable chest pain called Prinzmetal’s angina (also known as variant angina). Myocardial ischaemia that does not cause obvious and detectable symptoms is called silent ischaemia. ANGINA
Angina is chest pain caused by myocardial ischaemia. The discomfort is usually transient, lasting approximately 3–5 minutes. If blood flow is restored, no permanent change or damage results. Angina is typically experienced as substernal chest discomfort, ranging from a sensation of heaviness or pressure to moderately severe pain. Individuals often describe the sensation by clenching a fist over the left sternal border. Discomfort may radiate to the neck, lower jaw, left arm and left shoulder or, occasionally, to the back or down the right arm. Discomfort is commonly mistaken for indigestion. The pain is presumably caused by the build-up of lactic acid or abnormal stretching of the ischaemic myocardium that irritates myocardial nerve fibres. These afferent sympathetic fibres enter the spinal cord from levels C3 to T4, accounting for the variety of locations and radiation patterns of angina. Pallor, diaphoresis (excessive sweating) and dyspnoea may be associated with the pain. Stable angina is caused by gradual luminal narrowing and hardening of the arterial walls, so that affected vessels cannot dilate in response to increased myocardial demand associated with physical exertion or emotional stress. Prinzmetal’s angina is chest pain attributable to transient ischaemia of the myocardium that occurs unpredictably and often at rest. Pain is caused by vasospasm of one or more major coronary arteries, with or without associated atherosclerosis. The pain often occurs at night during rapid eye movement sleep and may have a cyclic pattern of occurrence. The angina may result from hyperactivity of the sympathetic nervous system, increased calcium flux in arterial smooth muscle or endothelial dysfunction with impaired production or release of prostaglandin or thromboxane and abnormal responses to acetylcholine.33 Myocardial ischaemia may not cause detectable symptoms such as angina. Ischaemia may be totally asymptomatic,
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referred to as silent ischaemia. Individuals may complain only of fatigue, dyspnoea or a feeling of unease. Silent ischaemia and atypical symptoms are more common in women (see ‘Research in Focus: Women and coronary heart disease’). In addition, individuals who experience angina often have additional silent episodes of myocardial ischaemia.
RESEARCH IN F CUS Women and coronary heart disease Coronary heart disease is an important cause of death among both men and women. In women, the disease develops 7 to 10 years later than in men, potentially because of a protective effect of oestrogens. However, coronary heart disease is the main cause of death among women and the survival advantage over men is lost in elderly women. In several countries more women die from cardiovascular disease compared to men. This may be due to gender differences in presentation and treatment of coronary heart disease and acute coronary syndrome, different abnormalities with regard to electrocardiography and scintigraphy. Women with coronary heart disease tend to have more risk factors such as diabetes, hypertension, and hypercholesterolemia. Young women (pre-menopausal) have a higher mortality rate in response to the primary event compared to men. This may be because despite oestrogen protection these women have developed severe clinical disease and therefore, worse outcome. By the end of the 1990s, postmenopausal hormone replacement therapy (HRT) was used to prevent chronic diseases such as coronary heart disease, and large prevention trials were undertaken in this context. The initial findings reported were largely negative, resulting in the dramatic decline in HRT use. These reports noted surprisingly increased risks, notably of coronary heart disease and stroke. Nowadays, HRT seems to be beneficial and safe for postmenopausal symptomatic women aged < 60 years. Treatments with a high safety profile should be the preferred option, low-dose HRT, oestrogen-only treatment in women who have had a hysterectomy, and vaginal oestrogen therapy for women with atrophic vaginitis. Non-androgenic progestin might have a reduced thrombotic and breast cancer risk, and transdermal oestrogen could have a reduced thrombotic risk. Nevertheless, HRT should not be used for the prevention of chronic diseases in the elderly (> 70 years old) owing to the increased risk of stroke and breast cancer in these patients.
EVALUATION AND TREATMENT
Many individuals with reversible myocardial ischaemia will have a normal physical examination between events. However, in those with chronic ischaemia, the examination may disclose rapid pulse or extra heart sounds, indicating impaired left ventricular function during ischaemia. The presence of xanthelasmas (small fat deposits; see Fig. 23.13) around the eyelids or arcus senilis of the eyes (a yellow
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lipid ring around the cornea) suggests dyslipidaemia and possible atherosclerosis. Electrocardiography is a critical tool for the diagnosis of myocardial ischaemia. Because many individuals have normal electrocardiograms when there is no pain, diagnosis requires that electrocardiography be performed during an episode of angina or during stress testing. The ST segment and T wave segment of the electrocardiogram correlate with ventricular contraction and relaxation. Transient ST
segment depression and T wave inversion are characteristic signs of subendocardial ischaemia. ST elevation, indicative of transmural (full thickness of the heart wall) ischaemia, is seen in individuals with Prinzmetal’s angina and transmural myocardial infarction (see Fig. 23.14). The ECG may also indicate which coronary artery is involved. Exercise stress testing is useful in differentiating angina from other types of chest pain, as well as detecting ischaemic changes that occur in the absence of angina pain. Coronary angiography helps determine the anatomical extent of coronary heart disease. The procedure involves threading a small aperture catheter into the coronary arteries, via arterial cannulation (usually using the femoral artery), and injecting dye directly into the coronary arteries. Sophisticated x-rays allow visualisation of the vessels and the extent of disease can be determined. The primary aim of therapy for myocardial ischaemia and angina is to reduce myocardial oxygen consumption by favourably altering its various determinants. The factors most amenable to pharmacological manipulation are blood pressure, heart rate, contractility and left ventricular volume. Medications that reduce vasospasm, lower cholesterol and prevent clotting are also useful. These drugs include nitrates, β-adrenergic blocking agents, calcium channel blockers, ACE inhibitors, lipid-lowering agents (statins) and antiplatelet agents. Such drugs are recommended by the National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand.34 It has also been demonstrated that long-acting calcium channel blockers reduce the risk of stroke, angina pectoris and heart failure in patients with coronary heart disease.35
FIGURE 23.13
Xanthelasmas. Xanthelasmas around the eyes (arrows) are indicative of high blood lipid levels and possible atherosclerosis. This is not always evident in those with high blood lipid levels.
A Normal ECG deflections
R
T
P QS Atrial depolarisation
Ventricular repolarisation
Ventricular depolarisation
B ST segment depression
T wave inversion
ST segment elevation
R
R
R
T
P
P
Q
T Q S
S
FIGURE 23.14
Electrocardiogram and ischaemic changes. A Normal ECG rhythm. B Associated ECG changes with ischaemia.
P Q
CHAPTER 23 Alterations of cardiovascular function across the life span
One of the main treatment options for cardiac tissue that is affected by myocardial ischaemia includes percutaneous (through the skin) coronary intervention, which involves accessing the coronary arterial system in a similar manner to performing coronary angiography as described above. Percutaneous coronary intervention includes angioplasty and stenting. Percutaneous transluminal coronary angioplasty (PTCA) is a procedure whereby stenotic (narrowed) coronary vessels are dilated with a balloon. As the balloon is inflated (temporarily) a number of times, the plaque becomes compressed, thereby increasing the blood vessel lumen. Several different types of catheters with balloons can be used to open the blocked vessel. PTCA is generally used to treat single-vessel disease, but it can be effective with multiple-vessel disease or restenosis (reocclusion) of a coronary artery bypass graft. Restenosis of the artery is the major complication of the procedure.36,37 Improved outcomes following PTCA have been achieved by the use of coronary stenting. Following balloon treatment during PTCA, a small cylinder of metal called a stent is inserted into the artery — this remains permanently within the coronary vessel. Multiple stents are often used where a few blockages are treated. Although the stent initially maintains the vessel lumen, stents have been thrombogenic (tending to produce a thrombus [clot]) in nature and have tended to promote hypertrophy of vessel endothelium as well as platelet plug formation.37 Use of antiplatelet drugs such as abciximab (pronounced ‘ab-sick-see-mab’) has improved outcomes.36 Furthermore, stents can be coated with drugs that are slowly released to reduce the restenosis. Coronary heart disease and associated ischaemic events can be surgically treated using coronary artery bypass graft. This technique uses grafts from blood vessels (for example, the internal mammary artery or saphenous vein
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from the leg) to oversew the diseased coronary artery portion, such that blood flow to the myocardium can be restored. The surgery can be performed either using cardiopulmonary bypass (the heart is stopped and blood is circulated and oxygenated external to the body using a bypass circuit and artificial pump) or without bypass. The requirement for this surgical treatment is based on the degree of symptoms arising from myocardial ischaemia (angina), the extent of coronary heart disease in multiple vessels and which coronary arteries are affected. This treatment option would be used when coronary occlusions are severe (only a small lumen remaining open) or widespread (affecting a number of vessels). FOCU S ON L EA RN IN G
1 Define atherosclerosis and briefly describe how it forms. 2 Discuss why hypertension and increased cholesterol increase the risk of developing coronary heart disease. 3 Discuss the relationships among myocardial ischaemia, angina and silent ischaemia.
The acute coronary syndromes
The acute coronary syndromes are one of the most common causes of acute medical admissions to Australian hospitals.38 The syndromes are a continuum of clinical presentations that encompasses unstable angina without myocyte death through to myocardial infarction with and without ST segment elevation. However, the terminology used to describe the acute coronary syndromes has been changing to match clinical approaches that are more appropriate to the patient’s condition, rather than forming a definitive diagnosis upon presentation (see Fig. 23.15).
Presentation (clinical presentation, initial ECG)
Working diagnosis
ST elevation myocardial infarction
Non-ST elevation acute coronary syndrome
Time Evolution of ECG and biomarkers
Final diagnosis
Myonecrosis confirmed ST elevation myocardial infarction
Myonecrosis not confirmed Non-ST elevation myocardial infarction
Unstable angina
FIGURE 23.15
The acute coronary syndromes: clinical presentation and possible changes to the initial working diagnosis. The initial ECG provides a working diagnosis, which is later confirmed (or not confirmed), depending on the ECG and presence of cardiac biomarkers in the blood. ECG = electrocardiogram.
Part 4 Alterations to body maintenance
Atherosclerotic plaque partially obstructs coronary blood flow Stable plaque
Unstable plaque with ulceration or rupture
Stable angina
Acute coronary syndromes Transient ischaemia
Unstable angina
Myocardial remodelling
Thrombus
Increased inflammation with release of multiple cytokines, platelet activation and adherence, production of thrombin and vasoconstrictors
Sustained ischaemia Myocardial infarction Myocardial inflammation and necrosis
Shear forces, inflammation, apoptosis, macophagederived degradative enzymes
Death
FIGURE 23.16
The pathophysiology of the acute coronary syndromes. Atherosclerosis may lead to stable angina or unstable angina. If the ischaemia is sustained, it can lead to myocardial infarction.
The process of atherosclerotic plaque progression can be gradual, taking several decades before angina manifests. Eventually plaque formation will ensue, which can be either stable and result in stable angina, or unstable and prone to rupture and thrombus formation. When there is sudden coronary obstruction caused by thrombus formation over a ruptured atherosclerotic plaque, the acute coronary syndromes result. Thrombus formation on a ruptured plaque that disperses in less than 20 minutes leads to transient ischaemia and unstable angina. If vessel obstruction is sustained, myocardial infarction with inflammation and necrosis of the myocardium results (see Fig. 23.16). Unstable angina is the result of reversible myocardial ischaemia and is a strong indicator of impending myocardial infarction. Acute myocardial infarction (AMI) results when there is prolonged ischaemia causing irreversible damage to the myocytes (heart muscle cells). Plaque disruption occurs because of shear forces, inflammation with release of multiple inflammatory mediators, secretion of macrophage-derived degradative enzymes, immune cell activation and apoptosis of cells at the edges of the lesions (see Fig. 23.17).21,22,39,40 The underlying layer of plaque is then exposed and this causes activation of the coagulation cascade. The resulting thrombus can form quickly. The thrombus may break up before permanent myocyte damage has occurred (unstable angina) or it may cause prolonged ischaemia by impeding blood flow past the thrombus and
Acute decrease in coronary blood flow
Atherosclerotic plaque with a lipid-rich core and a thin fibrous cap
Rupture of plaque
Thrombus formation over lesion plus vasoconstriction of vessel
Unstable angina or myocardial infarction
FIGURE 23.17
The pathogenesis of unstable plaques and thrombus formation. Atherosclerosis can be affected by inflammation and other processes that can cause plaque rupture, with further complications promoting vasoconstriction which further decreases the oxygen supply to the heart muscle.
causing lack of oxygen and nutrients to the myocardium, resulting in infarction of the heart muscle (acute myocardial infarction; see Fig. 23.18). Acute myocardial infarction can be further subdivided into non-ST elevation MI (non-STEMI) and ST elevation MI (STEMI). Sudden cardiac death can occur as a result of any of the acute coronary syndromes. There are also alternative descriptions for the acute coronary syndromes, which are STEACS (ST elevated MI), and NSTEACS (non-ST elevation acute coronary syndromes). NSTEACS includes unstable angina if there is no evidence of heart cell death (by cardiac biomarkers in the blood), and it also includes MI where there is no ST elevation. These terms are also described below in the section ‘Evaluation and treatment’.
Unstable angina
Unstable angina is a form of acute coronary syndrome that results from reversible myocardial ischaemia. It is important to recognise this syndrome, because it signals that the atherosclerotic plaque has become complicated and infarction may soon follow. Unstable angina occurs when a fairly small fissuring or superficial erosion of the plaque leads to transient episodes of thrombotic vessel occlusion and vasoconstriction at the site of plaque damage. This thrombus is unstable and may occlude the vessel for no more than 10–20 minutes, with return of perfusion before significant myocardial necrosis occurs. Unstable
CONCEPT MAP
CONCEPT MAP
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CHAPTER 23 Alterations of cardiovascular function across the life span
Adventitia Media Intima
629
Adventitia Media Intima Lipids
Atherosclerosis
Atherosclerotic plaque NORMAL
FIXED CORONARY OBSTRUCTION (Typical angina)
Platelet aggregate
Healing
PLAQUE DISRUPTION Thrombus
MURAL THROMBUS WITH VARIABLE OBSTRUCTION / ? EMBOLI (Unstable angina or acute subendocardial myocardial infarction or sudden death)
SEVERE FIXED CORONARY OBSTRUCTION (Chronic coronary heart disease) Thrombus
OCCLUSIVE THROMBUS (Acute transmural myocardial infarction or sudden death)
ACUTE CORONARY SYNDROMES FIGURE 23.18
Acute coronary syndromes and thrombus formation resulting in angina, myocardial infarction or sudden death. Schematic representation of sequential progression of coronary artery lesion morphology, beginning with stable chronic plaque responsible for typical angina and leading to the various acute coronary syndromes.
angina presents as new-onset angina, angina occurring at rest or angina that is increasing in severity or frequency. Individuals may experience increased dyspnoea (difficulty breathing), diaphoresis (excessive sweating) and anxiety as the angina worsens. Physical examination may reveal evidence of ischaemic myocardial dysfunction such as tachycardia. The ECG most commonly reveals ST segment depression and T wave inversion during pain that resolves as the pain is relieved (see Fig. 23.14). Approximately 20% of individuals with unstable angina will progress to acute myocardial infarction or death. Management of unstable angina usually requires some form of antithrombotic therapy. In most cases, individuals are given aspirin and clopidogrel when percutaneous coronary intervention (PCI) is anticipated — these drugs are used to prevent platelet aggregation and therefore avoid platelet plug formation.
Acute myocardial infarction
When coronary blood flow is interrupted for an extended period of time, myocyte necrosis occurs.21 This results in acute myocardial infarction. Pathologically, there are two major types of myocardial infarction: subendocardial infarction and transmural infarction. Plaque progression, disruption and subsequent clot formation are the same for acute myocardial infarction as they are for unstable angina (see Figs 23.16, 23.17 and 23.18). In this case, however, the thrombus is lodged in the coronary artery and occludes the vessel for a prolonged period, such that myocardial ischaemia progresses to myocyte necrosis and death. • If the thrombus breaks up before complete distal tissue necrosis has occurred, the infarction will involve only the myocardium directly beneath the endocardium (subendocardial infarction).
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• If the thrombus lodges permanently in the vessel, the infarction will extend through the myocardium all the way from the endocardium to the pericardium, resulting in severe cardiac dysfunction (transmural infarction). Clinically, it is important to identify those individuals with transmural infarction, who are at highest risk for serious complications and should receive definitive intervention without delay. These individuals usually have marked elevations in the ST segments on ECG and are categorised as having STEMI. Those without ST segment elevation are more likely to have subendocardial infarction and are said to have non-STEMI (see Fig. 23.14). PATHOPHYSIOLOGY CELLULAR INJURY
Cardiac cells can withstand a lack of oxygen and blood flow for about 20 minutes before cellular death takes place. After only 30–60 seconds of hypoxia (low oxygen levels in the tissues), electrocardiograph changes are visible. Yet even if cells are metabolically altered and non-functional, they can remain viable if blood flow is restored within 20 minutes. After 8–10 seconds of decreased blood flow, the affected myocardium becomes cyanotic and cooler. Myocardial oxygen reserves are used quickly (within about 8 seconds) after complete cessation of coronary flow. Glycogen stores decrease as anaerobic metabolism begins. Glycolysis can supply only 65–70% of the total myocardial energy requirement and produces much less ATP than aerobic (oxygen-dependent) processes. Hydrogen ions and lactic acid accumulate. Because myocardial tissues have poor buffering capabilities and myocardial cells are sensitive to low cellular pH (build-up of acid), accumulation of these products further compromises the myocardium. Acidosis may make the myocardium more vulnerable to the damaging effects of lysosomal enzymes and may suppress impulse conduction and contractile function, thereby leading to heart failure. Oxygen deprivation is also accompanied by electrolyte disturbances, specifically the loss of potassium, calcium and magnesium from inside the cell. Myocardial cells deprived of necessary oxygen and nutrients lose contractility, thereby diminishing the pumping ability of the heart. Normally, the myocardium takes up varying quantities of catecholamines (adrenaline and noradrenaline). Significant coronary artery occlusion causes the myocardial cells to release catecholamines, predisposing the individual to serious imbalances of sympathetic and parasympathetic function, irregular heartbeat (arrhythmia) and heart failure (see Fig. 23.19). Catecholamines mediate the release of glycogen, glucose and stored fat from body cells. Therefore, plasma concentrations of free fatty acids and glycerol rise within 1 hour after the onset of acute myocardial infarction. Excessive levels of free fatty acids can have a harmful effect on cell membrane structure. Noradrenaline elevates blood glucose levels through stimulation of liver and skeletal muscle cells and suppresses pancreatic beta-cell activity, which reduces insulin secretion and elevates blood glucose further. Not
surprisingly, hyperglycaemia is noted approximately 72 hours after acute myocardial infarction.41 Angiotensin II is released during myocardial ischaemia and contributes to the pathogenesis of myocardial infarction in several ways. First, it promotes catecholamine release and causes coronary artery spasm. Second, it results in peripheral vasoconstriction and fluid retention. Finally, it is a growth factor for vascular smooth muscle cells, myocytes and cardiac fibroblasts, resulting in structural changes in the myocardium called ‘remodelling’.42 CELLULAR DEATH
After about 20 minutes of myocardial ischaemia, irreversible hypoxic injury causes cellular death and tissue necrosis. This lack of blood flow deprives myocytes of oxygen and nutrients, and ultimately damage to the sarcolemma (cell membrane in myocytes) and coagulation and necrosis develop (see Chapter 4). This results in the release of intracellular enzymes such as creatine kinase and myocyte proteins such as the troponins through the damaged cell membranes into the interstitial spaces, and the lymphatic vessels pick up the enzymes and transport them into the bloodstream, where they can be detected by blood tests. STRUCTURAL AND FUNCTIONAL CHANGES
With infarction, ventricular function is abnormal and the ejection fraction (the percentage of blood ejected from the ventricles with each heartbeat, usually about 65%) falls, which results in increases in ventricular end-diastolic volume. If the coronary obstruction involves the perfusion to the left ventricle, pulmonary venous congestion ensues; if the right ventricle is ischaemic, increases in systemic venous pressures occur. Myocardial infarction results in both structural and functional changes of cardiac tissues (see Figs 23.20 and 23.21). Gross tissue changes at the area of infarction may not become apparent for several hours, despite the almost immediate onset (within 30–60 seconds) of electrical conduction changes. Cardiac tissue surrounding the area of infarction also undergoes changes that can be categorised into: 1 myocardial stunning — a temporary loss of contractile function that persists for hours to days after perfusion has been restored 2 hibernating myocardium — tissue that is persistently ischaemic and undergoes metabolic adaptation to prolong myocyte survival until perfusion can be restored 3 myocardial remodelling — a process mediated by angiotensin II, aldosterone, catecholamines, adenosine and inflammatory cytokines that causes myocyte hypertrophy and loss of contractile function in the areas of the heart distant from the site of infarction.42–45 All these changes can be limited through the rapid restoration of coronary flow and the use of ACE inhibitors or angiotensin receptor blockers and β-blockers after acute myocardial infarction, although the magnitude of tissue damage will influence the degree of repair.
CHAPTER 23 Alterations of cardiovascular function across the life span
leads to Myocardial perfusion results in
leads to
Partially ischaemic cells
Totally ischaemic cells
leads to Accumulation of lactate
leads to
Anaerobic metabolism
No ATP
causes Inhibition of glycolysis
Ion pumping and membrane integrity
producing
leads to causes
Cell rupture and death
Hypocontractile state causes
causes Cardiac output
Ion leak results in ST changes on ECG
Loss of membrane integrity
Noncontractile state
Reduced ATP leads to
results in
producing
Sympathetic nerve activity activation
Arrhythmias
CONCEPT MAP
Acute myocardial infarction
631
evidenced by
No electrical potentials
Biomarker release
Q waves
CK-MB, LDH and troponin
results in Heart rate
Vasoconstriction
Clinical signs Pathophysiological processes FIGURE 23.19
Cellular and systemic events occurring after acute myocardial infarction. This figure shows the changes caused by acute myocardial infarction. The systemic changes are shown in pink and cellular changes in blue. ATP = adenosine triphosphate; CK-MB = myocardial band of creatine kinase; LDH = lactate dehydrogenase.
The severity of functional impairment depends on the size of the lesion and the site of infarction. Functional changes can include: (1) decreased cardiac contractility with abnormal wall motion; (2) altered left ventricular compliance; (3) decreased stroke volume; (4) decreased ejection fraction; (5) increased left ventricular end-diastolic pressure; and (6) sinoatrial node malfunction. Life-threatening arrhythmias and heart failure often follow myocardial infarction. REPAIR
Acute myocardial infarction causes a severe inflammatory response that ends with wound repair. Damaged cells
undergo degradation, fibroblasts proliferate and scar tissue is produced. Many cell types, hormones and nutrient substrates must be available for optimal healing to proceed. Within 24 hours, leucocytes infiltrate the necrotic area and proteolytic enzymes from scavenger neutrophils degrade necrotic tissue. The collagen matrix that is deposited is initially weak, mushy and vulnerable to re-injury. Unfortunately, it is at this time in the recovery period (10–14 days after infarction) that individuals may feel like increasing their activities and so may stress the newly formed scar tissue. After 6 weeks, the necrotic area is completely replaced by scar tissue, which is at full strength
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Aorta Pulmonary artery
Left circumflex coronary artery
Right coronary artery
Left anterior descending coronary artery Acute coronary arterial occlusion Zone of perfusion (area at risk) Completed infarct involving nearly the entire area at risk
Cross-section of myocardium Obstructed coronary artery Endocardium Zone of necrosis
Zone of perfusion (area at risk)
0 hr
Zone of necrosis
2 hr
24 hr
FIGURE 23.20
A schematic representation of myocardial infarction after acute coronary artery occlusion. Necrosis begins in a small zone of the myocardium beneath the endocardial surface in the centre of the ischaemic zone. This entire region of myocardium (shaded) depends on the occluded vessel for perfusion and is the area at risk. Note that a very narrow zone of myocardium immediately beneath the endocardium is spared from necrosis because it can be oxygenated by diffusion from the ventricle. The end result is necrosis of the muscle that was dependent on perfusion from the obstructed coronary artery. Nearly the entire area at risk loses viability.
but cannot contract and relax like healthy myocardial tissue. CLINICAL MANIFESTATIONS
The first symptom of acute myocardial infarction is usually sudden, severe chest pain. The pain is similar to angina pectoris but more severe and persistent and is not relieved by medication or rest. It may be described as heavy and crushing. Pain radiating to the neck, jaw, back, shoulder or left arm is common. Some individuals, especially those who are elderly or have diabetes mellitus, experience no pain, thereby having a ‘silent’ infarction. Infarction often simulates a sensation of unrelenting indigestion. Nausea and vomiting may occur because of reflex stimulation of vomiting centres by pain fibres. Reflexes from the area of
the infarcted myocardium may also result in stimulation of the gastrointestinal tract via parasympathetic nervous system reflexes. Catecholamine release results in sympathetic stimulation, producing diaphoresis (excessive sweating) and peripheral vasoconstriction that cause the skin to become cool and clammy. Various cardiovascular changes are found on physical examination: 1
Blood pressure initially decreases. 2 The sympathetic nervous system is reflexively activated to compensate, resulting in a temporary increase in heart rate and blood pressure. 3 Abnormal extra heart sounds reflect left ventricular dysfunction.
CHAPTER 23 Alterations of cardiovascular function across the life span
FIGURE 23.21
Evidence of acute myocardial infarction of the left ventricle. The large arrow at the top indicates an area of necrosis, coloured yellow. The far edge (right side) of the myocardial infarction contains a myocardial haemorrhage that was associated with cardiac rupture. An old infarct is also evident (arrowhead).
4
Pericardial friction rub (roughened membranes rubbing against each other) and cardiac murmurs may result from inflammation. 5 Pulmonary findings of congestion, including dullness to percussion and inspiratory crackles at the lung bases, can occur if the individual develops pulmonary oedema. The number and severity of post-infarction complications depend on the location and extent of necrosis, the physiological condition of the individual before infarction and the availability of rapid therapeutic intervention, such as thrombolysis. Sudden cardiac death may occur in individuals with myocardial ischaemia even if infarction is absent or minimal and is a multifactorial problem. Risk factors for sudden death are related to three factors: ischaemia, left ventricular dysfunction and electrical instability. Table 23.5 lists the most common complications from acute myocardial infarctions. EVALUATION AND TREATMENT
The diagnosis of acute myocardial infarction is made on the basis of the history, physical examination, ECG and serial enzyme alterations. The cardiac enzymes, troponin I (cTnI) and troponin T (cTnT), are the most specific indicators of an acute myocardial infarction; these are measured from blood tests and are referred to as cardiac biomarkers. A transient rise in these plasma enzyme levels can confirm the occurrence of acute myocardial infarction and indicate its severity. Other enzymes released by myocardial cells include creatine kinase-myocardial band (CK-MB) and lactate dehydrogenase. Cardiac troponins will be within normal levels when tissue other than cardiac muscle is damaged, therefore, troponin I and troponin T are more specific and are elevated soon after infarction and
633
remain elevated for longer than other enzymes (see Fig. 23.22). Clinically, repeated measures of elevated troponin and isoenzymes (enzymes with slightly different structures) over time are essential to determine if an acute myocardial infarction has occurred. Elevation of troponin, CK-MB and lactate dehydrogenase may be noted at characteristic times and laboratory confirmation that an infarction has occurred may be delayed up to 12 hours. Myocardial infarction can occur in various regions of the heart wall and may be described as anterior, inferior, posterior, lateral, subendocardial or transmural, depending on the anatomical location and extent of tissue damage from infarction. Twelve-lead electrocardiograms help localise the affected area through identification of Q waves and changes in ST segments and T waves (see Fig. 23.23). The infarcted myocardium is surrounded by a zone of hypoxic injury, which may progress to necrosis or return to normal. Adjacent to this zone of hypoxic injury is a zone of reversible ischaemia. Ischaemic and injured myocardial tissue causes ST and T wave changes. If the thrombus breaks up before complete distal tissue necrosis has occurred, the infarction will involve only the myocardium directly beneath the endocardium. This type of myocardial infarction most often presents with no elevation of the ST segment on ECG and therefore is termed non-STEMI.21,40 A non-STEMI is also known as a NSTEACS. It is especially important to recognise this form of acute coronary syndrome because recurrent clot formation on the disrupted atherosclerotic plaque is likely, with resultant infarct expansion. If the thrombus lodges more permanently in the vessel, the infarction will extend through the myocardium from endocardium to pericardium, resulting in severe cardiac dysfunction. This usually presents with significant ST segment elevation on ECG (STEMI). Often a characteristic Q wave will develop on ECG some hours later. An ST elevated myocardial infarction (STEMI) requires rapid intervention to prevent serious complications and sequelae. STEMI is also referred to as STEACS, as it represents a ST elevation acute coronary syndrome. Additional laboratory data may reveal leucocytosis, elevated sedimentation rate and C-reactive protein, all of which indicate inflammation. The blood glucose level is usually elevated and the glucose tolerance level may remain abnormal for several weeks.41 Hypoxaemia may also accompany heart failure. TREATMENT
Acute myocardial infarction requires admission to hospital, often directly into an acute cardiac unit. The individual may be given aspirin immediately, with sublingual glyceryl trinitrate providing both pain relief as well as promoting coronary vasodilation to improve oxygenation to the heart muscle cells. Pain relief is of utmost importance, and frequently also involves the use of intravenous morphine. Continuous monitoring of cardiac rhythms and enzymatic changes is essential, because the first 24 hours after onset of symptoms is the time of highest risk for sudden death. Both non-STEMI and STEMI are frequently managed with the
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TABLE 23.5 Complications from acute myocardial infarctions TYPE
CHARACTERISTICS
Arrhythmias
Disturbances of cardiac rhythm, which affect 90% of cardiac infarction patients Caused by ischaemia, hypoxia, autonomic nervous system imbalances, lactic acidosis, electrolyte abnormalities, alterations of impulse conduction pathways or conduction abnormalities, drug toxicity or haemodynamic abnormalities
Left ventricular failure
Characterised by pulmonary congestion, reduced myocardial contractility and abnormal heart wall motion Cardiogenic shock can develop
Inflammation of the pericardium (pericarditis)
Includes pericardial friction rubs
Organic brain syndrome
Can occur if brain blood flow is impaired secondary to acute myocardial infarction
Transient ischaemic attacks or stroke
Occur if thromboemboli break loose from clots that form in the cardiac chambers or on cardiac valves
Rupture of heart structures
Caused by necrosis of tissue in or around papillary muscles
Often noted 2–3 days later and associated with anterior chest pain that worsens with respiratory effort
Affects papillary muscles of chordae tendineae cordis Predisposing factors include thinning of wall, poor collateral flow, shearing effect of muscular contraction against stiffened necrotic area, marked necrosis at terminal end of blood supply and ageing of myocardium with laceration of myocardial microstructure
Rupture of wall of infarcted ventricle
Can be caused by aneurysm formation when pressure becomes too great
Left ventricular aneurysm
Late (month to years) complication of acute myocardial infarction that can contribute to heart failure and thromboemboli
Infarctions around septal structures
Occur in those structures that separate the heart chambers and lead to septal rupture
Systemic thromboembolism
May disseminate from debris and clots that collect inside dilated aneurysmal sacs or from infarcted endocardium
Pulmonary thromboembolism
Usually from deep venous thrombi of legs
Sudden death
Arrhythmias frequently causative, particularly ventricular fibrillation
Associated with audible, harsh cardiac murmurs, increased left ventricular end-diastolic pressure and decreased systemic blood pressure
Reduced incidence associated with early mobilisation and prophylactic anticoagulation therapy Risk of death increased by age more than 65 years, previous angina pectoris, hypotension or cardiogenic shock, acute systolic hypertension at time of admission, diabetes mellitus, arrhythmias and previous acute myocardial infarction
urgent administration of thrombolytics or by percutaneous coronary intervention along with antithrombotics. Further management may include ACE inhibitors and β-blockers depending on haemodynamic state. Individuals who are in shock require aggressive fluid resuscitation, inotropic drugs (drugs that increase contraction of the myocardium) and possible emergency invasive procedures (see the section on shock later in this chapter).
Aneurysm
An aneurysm is a localised dilation or outpouching of a vessel wall or cardiac chamber. Aneurysms form in arteries when there is disruption of the wall of the vessel associated with changes in collagen and elastin, which make the vessel more vulnerable to intravascular pressures. The aorta is
FOCU S ON L EA RN IN G
1 Describe the coronary heart disease–myocardial ischaemia continuum. 2 Describe the pathophysiology of a myocardial infarction. 3 Detail complications associated with the period after infarction.
particularly susceptible to aneurysm formation because of constant stress on the vessel wall. Some 75% of all aneurysms occur in the abdominal aorta (see Fig. 23.24). Atherosclerosis is the most common cause of arterial aneurysms because plaque formation erodes the vessel wall and contributes to
CHAPTER 23 Alterations of cardiovascular function across the life span
A Enzyme levels Increase Normal above range normal
5× 4× 3× 2×
Troponin CK
2 Chest pain
B
635
Cardiac biomarker Troponin level (Cardiac troponin I or T)
4
6 8 10 12 14 Days after infarction
Recommendation
LDH 16
Rationale
On arrival
Troponin rise indicates myonecrosis and is a high-risk feature in NSTEACS.Troponin is the preferred marker because about a third of patients with elevated troponin, but normal CK and CK-MB levels, will develop an adverse outcome.
Not repeated if positive
Troponin remains elevated for 5–14 days, and therefore may not be useful for identifying early re-infarction.
Repeated > 8 hours after last episode of pain or other symptoms of coronary insufficiency if initially negative
Troponin elevation is often delayed by 4–6 hours. Therefore, repeat troponin testing is necessary to identify patients at high risk who may benefit from aggressive therapy and an early invasive strategy.
Serial troponin measurements in patients with NSTEACS suspected to be at high risk
The appearance of typical rise of troponin indicates high-risk NSTEACS and may be an indication for more aggressive therapy.
Total CK level
Serial measurements performed for 48 hours in patients with myocardial infarction
Can be remeasured to confirm a second event if re-infarction is suspected later.
CK-MB level
Should be measured in all patients with an ACS if troponin assay unavailable
While troponin is the preferred marker of myocardial damage, if it is unavailable CK-MB is more specific than CK for myocardial injury. CK-MB may also be used to confirm a re-infarction.
ACS = acute coronary syndrome. CK = creatine kinase.
CK-MB = creatine kinase-MB isoenzyme. NSTEACS = non-ST elevation acute coronary syndromes.
FIGURE 23.22
Serum cardiac enzymes (biomarkers) after acute myocardial infarction. A Graphical representation of changes in enzymes (cardiac specific and nonspecific) over time. B Recommended times for measuring cardiac enzymes (biomarkers) when acute myocardial infarction is suspected.
inflammation that can further weaken the vessel. Hypertension also contributes to aneurysm formation by increasing wall stress. Aortic aneurysms are often asymptomatic until they leak and possibly rupture, when they become painful. Symptoms of dysphagia (difficulty swallowing) and dyspnoea (breathlessness) are caused by the pressure of a thoracic
aneurysm on surrounding organs. An aneurysm that impairs flow to an extremity causes symptoms of ischaemia. Cerebral aneurysms are associated with signs and symptoms of increased intracranial pressure and can relate to stroke. (Cerebral aneurysms are described in Chapter 9.) The diagnosis of an aneurysm is usually confirmed by ultrasonography, CT scan, MRI or angiography. The goals
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Zone of ischaemia Zone of infarction and necrosis Zone of hypoxic injury Normal
Ischaemia
Injury
Infarction/necrosis
FIGURE 23.23
Electrographic changes associated with different zones of myocardial infarction. The pattern of changes in the ECG resemble the time course of progression from ischaemia (T wave inversion), injury (ST elevation), and finally infarction (deep Q wave).
of medical treatment of aneurysms are to maintain a low blood volume and low blood pressure to decrease the mechanical forces thought to contribute to vessel wall dilation. Medical treatment is indicated for slow-growing aortic aneurysms, particularly in the early stages, and includes smoking cessation, reducing blood pressure and blood volume. For those aneurysms that are dilating rapidly, surgical treatment is often indicated. Surgery may be considered when aortic aneurysms become large and usually includes replacement with a prosthetic graft. New endovascular surgical techniques make aneurysm repair possible for more individuals.
Thrombus formation
*
FIGURE 23.24
Aortic aneurysm. An abdominal aortic aneurysm (*) is distal to the renal arteries (white arrows). The large pouching of the artery occurs due to atherosclerosis weakening the wall, and the high pressure of the arterial system causes the bulging of the vessel. Aortic aneurysms tend to enlarge over time and if undiscovered or untreated can rupture, often leading to death.
As in venous thrombosis, arterial thrombi tend to develop when intravascular conditions promote activation of coagulation or when there is stasis of blood flow. These conditions include those in which there is intimal irritation or roughening (such as in surgical procedures), inflammation, traumatic injury, infection, low blood pressures or obstructions that cause blood stasis and pooling within the vessels. Inflammation of the endothelium leads to activation of the coagulation cascade causing platelets to adhere readily. An anatomical change in an artery can contribute to thrombus formation, particularly if the change results in a pooling of arterial blood. Thrombi also form on heart valves altered by calcification or bacterial vegetation. Valvular thrombi are most commonly associated with inflammation of the endocardium (endocarditis) and rheumatic heart disease. Shock (circulatory failure), particularly shock resulting from septicaemia, can also activate the intrinsic and extrinsic pathways of coagulation. The impaired cellular metabolism that occurs with all types of shock activates the extrinsic pathway of coagulation, whereas blood stasis
CHAPTER 23 Alterations of cardiovascular function across the life span
caused by very low blood pressures activates the intrinsic pathway. Arterial thrombi pose two potential threats to the circulation. First, the thrombus may grow large enough to occlude the artery, causing ischaemia in tissue supplied by the artery. Second, the thrombus may dislodge, becoming a thromboembolus that travels through the vascular system until it occludes flow into a distal systemic vascular bed. Diagnosis of arterial thrombi is usually accomplished through the use of Doppler ultrasonography and angiography. Pharmacological treatment involves the administration of heparin, warfarin derivatives, thrombin inhibitors or thrombolytics. A balloon-tipped catheter can also be used to remove or compress an arterial thrombus. Various combinations of drug and catheter therapies are sometimes used concurrently.
Embolism
Embolism is the obstruction of a vessel by an embolus (a bolus of matter circulating in the bloodstream). The embolus may consist of a dislodged thrombus; an air bubble; an aggregate of amniotic fluid; an aggregate of fat, bacteria or cancer cells; or a foreign substance (see Table 23.6 for more details). An embolus travels in the bloodstream until it reaches a vessel through which it cannot fit. No matter how tiny it is, an embolus will eventually lodge in a systemic or pulmonary vessel determined by its source. Pulmonary emboli originate on the venous side (mostly from the deep veins of the legs) of the systemic circulation or in the right side of the heart; systemic (or arterial) emboli most commonly originate in the left side of the heart and are associated with thrombi after myocardial infarction, valvular
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disease, left heart failure, endocarditis and arrhythmias. Embolism causes ischaemia or infarction in tissues distal to the obstruction.
Peripheral artery disease
Peripheral artery disease refers to atherosclerotic disease of the arteries that perfuse the limbs, especially the lower extremities. The risk factors for peripheral artery disease are the same as those previously described for atherosclerosis and it is especially prevalent in individuals with diabetes mellitus. Lower extremity ischaemia resulting from arterial obstruction in peripheral artery disease can be gradual or acute. In most individuals, gradually increasing obstruction to arterial blood flow to the legs caused by atherosclerosis in the iliofemoral vessels results in pain with ambulation called intermittent claudication. If a thrombus forms over the atherosclerotic lesion, perfusion can cease acutely with severe pain, loss of pulses and skin colour changes in the affected extremity. Peripheral artery disease is often asymptomatic; therefore, evaluation for peripheral artery disease requires a careful history and physical examination that focuses on looking for evidence of atherosclerotic disease and non-invasive Doppler measurement of blood flow. Treatment includes risk factor reduction (smoking cessation and treatment of diabetes mellitus, hypertension and dyslipidaemia) and antiplatelet therapy. Symptomatic peripheral artery disease is often managed with vasodilators in combination with antiplatelet or antithrombotic medications (aspirin or clopidogrel) and exercise rehabilitation.46 If acute symptoms occur, percutaneous or surgical revascularisation may be indicated.
TABLE 23.6 Types of emboli TYPE
CHARACTERISTICS
Arteries Arterial thromboembolism
Dislodged thrombus; source is usually from the heart; most common sites of obstruction are lower extremities (femoral and popliteal arteries), coronary arteries and cerebral vasculature
Veins Venous thromboembolism
Dislodged thrombus; source is usually from the lower extremities; obstructs branches of the pulmonary artery
Air embolism
Bolus of air displaces blood in the vasculature; source is usually room air entering the circulation through intravenous cannula; trauma to the chest may allow air from lungs to enter vascular space
Amniotic fluid embolism
Bolus of amniotic fluid; extensive intraabdominal pressure attending labour and delivery can force amniotic fluid into the maternal bloodstream; introduces antigens, cells and protein aggregates that trigger inflammation, coagulation and immune responses
Bacterial embolism
Aggregates of bacteria in bloodstream; source is subacute bacterial endocarditis or abscess
Fat embolism
Globules of fat floating in the bloodstream associated with trauma to long bones; the lungs in particular are affected
Foreign substances
Small particles introduced during trauma or through an intravenous cannula; the coagulation cascade is initiated and thromboemboli form around the particles
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FOCUS O N L E ARN IN G
1 Explain the mechanisms involved in thrombus formation. 2 Discuss why emboli are dangerous.
Alterations to veins Venous thromboembolus
The insidious nature of venous thromboembolus is often overlooked in hospital patients. In Western countries, venous thromboembolism is both a common cause of morbidity and one of the most preventable causes of hospital mortality. An understanding of the pathophysiology and treatment options is vital for all healthcare workers. Venous thrombi are more common than arterial thrombi because flow and pressure are lower in the veins than in the arteries. The two main presentations of venous thromboembolus are deep vein thrombosis (DVT) and pulmonary embolism (see Fig. 23.25). In this section, we discuss DVT; pulmonary embolism is discussed in detail in Chapter 25. DVT occurs primarily in the lower extremities. Three factors promote venous thrombosis: (1) venous stasis (e.g. immobility, age, heart failure); (2) venous endothelial damage (e.g. trauma, medications); and (3) hypercoagulable states (e.g. inherited disorders, malignancy, pregnancy, oral contraceptives, hormone replacement). Orthopaedic trauma (such as hip or leg fractures) or surgery, spinal cord injury and major trauma and general surgery can be associated
Inferior vena cava
Iliac vein
with the likelihood of DVT.47 Genetic abnormalities are also associated with an increased risk for venous thrombosis primarily related to states of hypercoagulability. Accumulation of clotting factors and platelets leads to thrombus formation in the vein, often near a venous valve. Inflammation around the thrombus promotes further platelet aggregation and the thrombus propagates or grows proximally. This inflammation may cause pain and redness, but because the vein is deep in the leg, it is usually not accompanied by clinical symptoms or signs. If the thrombus creates significant obstruction to venous blood flow, increased pressure in the vein behind the clot may lead to oedema of the extremity. Most thrombi eventually dissolve without treatment, but untreated DVT is associated with a high risk of an embolus forming and lodging in the lungs (pulmonary embolism). Prevention is important in at-risk individuals. DVT prophylaxis (preventative therapies) is commonly used in hospital and out-of-hospital settings. This may include pharmacological therapies and mechanical devices to prevent formation of a DVT. Heparin, warfarin or rivoroxoban are anticoagulants used to prevent or decrease the incidence of DVT.48 Mechanical devices include graduated compression stockings of which there are two types: those used to prevent DVT (e.g. thromboembolic deterrent stockings (TED)) and those used for chronic venous insufficiency. Pneumatic devices that rhythmically compress the calf muscle are also effective; however, patients have limited mobilisation with these devices as they do not facilitate walking. One effective and simple measure is early ambulation (walking around) after a period of being bedridden, such as after surgery.
Thrombosed vein
Propagation towards heart
Resolution
Embolisation to lungs
Organised and incorporated into wall
Organised and recanalised
FIGURE 23.25
Venous thromboembolism: potential outcomes. Venous thromboembolism may result in an embolus which reaches the lungs, incorporation of the thromboembolism into the vessel wall, or full recovery.
CHAPTER 23 Alterations of cardiovascular function across the life span
This facilitates blood flow and decreases venous stasis in peripheral veins. If thrombosis does occur, best practice guidelines indicate that venous duplex ultrasound scanning for DVT and pulmonary imaging for pulmonary embolism are the most accurate.
Varicose veins
A varicose vein is a vein in which blood has pooled, producing distended, tortuous and palpable vessels. Veins are thin-walled, highly distensible vessels with valves to prevent backflow and pooling of blood. If a valve is damaged, a section of the vein is subjected to the pressure of a larger volume of blood under the influence of gravity. The vein becomes engorged with blood, which increases hydrostatic pressure and increases movement of plasma through the vessel wall, resulting in interstitial oedema (see Fig. 23.26). Venous distension can develop over time in individuals who habitually stand for long periods, wear constricting garments or cross their legs at the knees, which diminishes the action of the skeletal muscle pump (which assists venous return). Risk factors also include age, being female, family history, obesity, pregnancy, phlebitis and previous leg injury.49 Eventually, the pressure in the vein damages venous valves, rendering them incompetent and unable to maintain normal venous pressure. Hydrostatic pressure increases, further distending the vein and making it tortuous; oedema then develops in the extremity. Chronic venous insufficiency is inadequate venous return over a long period. Venous hypertension, circulatory stasis
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and tissue hypoxia may lead to an inflammatory reaction in vessels and tissue, resulting in fibrosclerotic remodelling of the skin and then ulceration.50 Symptoms may include chronic pooling of blood in the veins of the lower extremities and hyperpigmentation of the skin of the feet and ankles. Oedema in these areas may extend to the knees. Circulation to the extremities can become so sluggish that the metabolic demands of the cells for oxygen, nutrients and waste removal are barely met. Any trauma or pressure can therefore lower the oxygen supply and cause cell death and necrosis (venous stasis ulcers) (see Fig. 23.27). Patients with venous ulcers typically have a poor quality of life. Infection can occur because poor circulation impairs the delivery of the cells and biochemicals for the immune and inflammatory responses. This same sluggish circulation makes infection following reparative surgery a significant risk. Varicose veins and chronic venous insufficiency may be associated with DVT in up to 15% of affected individuals because of changes in collateral flow and shared risk factors; therefore, anyone with new-onset varicose veins should be evaluated for the possibility of underlying DVT.51 Treatment of varicose veins and chronic venous insufficiency begins conservatively and excellent woundhealing results have followed non-invasive treatments such as leg elevation, compression stockings and physical exercise.
FIGURE 23.27
Venous ulcer on the medial aspect of the lower leg. The venous ulcer has an irregular margin, pale surrounding neoepithelium (new skin) and a pink base of granulation tissue. The skin is warm and oedema is often present.
FIGURE 23.26
Varicose veins, indicated by the arrow and above the knee. Varicosities are best observed when the patient is standing because standing increases the pressure and causes the tortuous veins to become more visible.
FOCU S ON L EA RN IN G
1 List the major risk factors for DVT. 2 Describe chronic venous insufficiency and the clinical presentation.
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Congenital heart disease Congenital heart disease (present at birth) accounts for approximately one-third of all congenital defects and is the major cause of death in the first year of life other than prematurity. The incidence varies according to the particular defect; however, the overall rate is about 75 per 10 000 births (inclusive of live births and still births with at least 20 weeks of gestational age).1,52 Several environmental and genetic risk factors are associated with the incidence of different types of congenital heart disease. Among the environmental factors are: • maternal conditions, such as intrauterine viral infections (especially rubella), diabetes mellitus, phenylketonuria, alcoholism, hypercalcaemia, drugs (e.g. phenytoin) and complications of increased age • antepartal bleeding • prematurity (see Table 23.7).52 Genetic factors also have been implicated in the incidence of congenital heart disease, although the mechanism of causation is often unknown. The incidence of congenital heart disease is three to four times higher in siblings of affected children and chromosomal defects account for about 6% of all cases of congenital heart disease. However, the cause of most defects is multifactorial.53
TABLE 23.7 Maternal conditions and environmental exposures and the associated congenital heart defects CAUSE
CONGENITAL HEART DEFECT
Infection Intrauterine
Patent ductus arteriosus, pulmonary stenosis, coarctation of aorta
Systemic viral
Patent ductus arteriosus, pulmonary stenosis, coarctation of aorta
Rubella
Patent ductus arteriosus, pulmonary stenosis, coarctation of aorta
Metabolic disorders Diabetes
Ventricular septal defect, cardiomegaly, transposition of the great vessels
Phenylketonuria (PKU)
Coarctation of aorta, patent ductus arteriosus
Drugs Alcohol
Defects with increased pulmonary blood flow Ventricular septal defect PATHOPHYSIOLOGY
Tetralogy of Fallot, atrial septal defect, ventricular septal defect
Peripheral conditions Prematurity
Congenital heart defects can be described with respect to three principal areas: 1 Anatomical defects include valvular abnormalities; abnormal openings in the septa, including persistence of the foramen ovale; continued patency of the ductus arteriosus; and malformation or abnormal placement of the great vessels. 2 Haemodynamic alterations caused by these anatomical defects consist of: (a) increases or decreases of blood flow through the pulmonary or systemic circulatory systems; and (b) the mixing of pulmonary and systemic blood through an abnormal communication that permits flow between the two circulatory systems. The movement of blood between the normally separate pulmonary and systemic circulations is termed a shunt. Movement from the pulmonary to the systemic circulation (i.e. from the right side of the heart to the left side of the heart) is called a right-to-left shunt. Movement from the systemic to the pulmonary circulation (from the left heart to the right heart) is a left-to-right shunt. Shunt direction depends on relative pressures and resistances of the heart and surrounding vessels. 3 The status of tissue oxygenation is gauged by the presence or absence of cyanosis. Cyanosis is a bluish discolouration of the skin indicating that the tissues are not receiving normal amounts of oxygen, a condition known as hypoxia. Hypoxia may result from any disorder that prevents oxygen from reaching the body’s cells. Ischaemia, for example, is hypoxia from lack of blood flow. Some congenital heart defects that cause hypoxia and therefore cyanosis involve a right-to-left shunt, which directs blood flow away from the lungs (see Fig. 23.28). These defects are commonly called cyanotic defects. Congenital defects that do not cause cyanosis, or acyanotic defects, may involve a left-to-right shunt, which directs blood towards the lungs, or no shunt at all. One way to categorise congenital heart defects is according to: (a) whether they cause cyanosis; (b) whether they increase or decrease blood flow into the pulmonary circulation; and (c) whether they obstruct blood flow from the ventricles. In the following sections we examine the most common defects (rates >10%).
Patent ductus arteriosus, ventricular septal defect
A ventricular septal defect (VSD) is an opening of the septal wall between the ventricles (see Fig. 23.29A). VSDs are the most common type of congenital heart defect and are classified by location, either high in the septal wall of the ventricle underneath the aortic valve or low in the septal wall. They can also be located in the inlet
PAEDIATRICS
Paediatrics and alterations of cardiac function
CHAPTER 23 Alterations of cardiovascular function across the life span
Deoxygenated blood
A
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Oxygenated blood
B
NORMAL
C TETRALOGY OF FALLOT
ASD/VSD
RA
LA
RA
LA
RA
LA
RV
LV
RV
LV
RV
LV
C Deoxygenated blood to lungs
Oxygenated blood to body
FIGURE 23.28
Shunting of blood in congenital heart diseases. A Normal. B Acyanotic defect. C Cyanotic defect. ASD = atrial septal defect; LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle; VSD = ventricular septal defect.
or outlet portion of the ventricle. VSDs shunt blood from left to right. Depending on the size and location, VSDs can spontaneously close, most often within the first 2 years of life. CLINICAL MANIFESTATIONS
Depending on the size, location and degree of pulmonary vascular resistance, children may have no symptoms or they may have clinical effects from excessive pulmonary blood flow. Clinically, children with large left-to-right shunts present with poor growth (failure to thrive) and tachypnoea (rapid breathing). If the degree of shunting is significant and not corrected, the child is at risk for developing pulmonary hypertension. Children with VSD are also at increased risk of developing endocarditis. EVALUATION AND TREATMENT
Diagnosis is confirmed by echocardiography. Cardiac catheterisation may be needed to calculate the degree of left-to-right shunting. Depending on the size of the VSD and the degree of symptoms, management may be minimal. Small VSDs may close completely or become small enough that surgical closure is not required. If the infant has severe heart failure or failure to thrive that is unmanageable with medical therapy, early surgical repair is performed.
Atrial septal defect PATHOPHYSIOLOGY
An atrial septal defect (ASD) is an opening in the septal wall between the two atria (see Fig. 23.29B). This opening allows blood to shunt from the higher pressure left atrium to the lower pressure right atrium. CLINICAL MANIFESTATIONS
Children with an ASD are usually asymptomatic. Infants with a large ASD may, in rare cases, develop pulmonary overcirculation and slow growth. Some older children and adults will experience shortness of breath with activity as the right ventricle becomes less compliant with age. Pulmonary hypertension and stroke are associated rare complications. A systolic ejection murmur and a widely split second heart sound are the expected findings on physical examination. EVALUATION AND TREATMENT
Diagnosis is confirmed by echocardiography. The ASD may be closed surgically with primary repair (sutured closed) or with a patch. Surgical repair involves openheart surgery with cardiopulmonary bypass. Interventional catheterisation closure involves placement of a closure device. Long-term follow-up finds atrial arrhythmias (10%) in both groups after closure. Continued
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Patent ductus arteriosus
A
Ventricular septal defect
B FIGURE 23.30
Atrial septal defect
FIGURE 23.29
A Ventricular septal defect. B Atrial septal defect.
Note the colour of the oxygenated (red) and deoxygenated (blue) blood, and the mixing of blood in the right ventricle and pulmonary artery. This is an example of a left-to-right shunt.
Patent ductus arteriosus. Note the colour of the oxygenated (red) and deoxygenated (blue) blood, and the flow of blood under high pressure from the aorta to the pulmonary arteries.
EVALUATION AND TREATMENT
Diagnosis is confirmed by echocardiography. Administration of indomethacin (a prostaglandin inhibitor) has proved successful in closing a patent ductus arteriosus in premature infants and some newborns. Surgical division of the patent ductus arteriosus needs to be performed when pharmacological therapies are unsuccessful. Closure with an occlusion device during cardiac catheterisation is performed for mostly older children. Both surgical and nonsurgical procedures can be considered low risk. Defects with decreased pulmonary blood flow Tetralogy of fallot
Patent ductus arteriosus PATHOPHYSIOLOGY
Patent ductus arteriosus is failure of the fetal ductus arteriosus (the artery connecting the aorta and pulmonary artery) to close within the first weeks of life (see Fig. 23.30). The continued patency of this vessel allows blood to flow from the higher pressure aorta to the lower pressure pulmonary artery, causing a left-to-right shunt. CLINICAL MANIFESTATIONS
Infants may be asymptomatic or show signs of pulmonary overcirculation, such as dyspnoea, fatigue and poor feeding. There is a characteristic machinery-like murmur. Children are at risk for bacterial endocarditis and, rarely, may develop pulmonary hypertension in later life from chronic excessive pulmonary blood flow.
PATHOPHYSIOLOGY
The classic form of tetralogy of Fallot includes four defects: (1) VSD, (2) pulmonary stenosis, (3) overriding aorta and (4) right ventricular hypertrophy (see Fig. 23.31). The pathophysiology varies widely, depending not only on the degree of pulmonary stenosis but also on the pulmonary and systemic vascular resistance to flow. If total resistance to pulmonary flow is higher than systemic resistance, the shunt is from right to left. If systemic resistance is higher than pulmonary resistance, the shunt is from left to right. Pulmonary stenosis decreases blood flow to the lungs and, consequently, the amount of oxygenated blood that returns to the left heart. Physiological compensation to chronic hypoxia includes production of more red blood cells, development of collateral bronchial vessels and enlargement of the nail beds (clubbing).
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CLINICAL MANIFESTATIONS
Pulmonary stenosis
Overriding aorta Ventricular septal defect
Right ventricular hypertrophy FIGURE 23.31
Tetralogy of Fallot. Tetralogy of Fallot includes ventricular septal defect, pulmonary stenosis, overriding aorta and right ventricular hypertrophy.
F O CUS O N L E A R N IN G
1 Describe the 3 principal classifications of congenital heart disease. 2 Describe the different characteristics that determine whether the defects are cyanotic or acyanotic. 3 Name the most common types of congenital heart defect.
Alterations of the heart wall Disorders of the pericardium
As you will recall, the pericardium is the outer layer of the heart, having approximately 10–30 mL of pericardial fluid to lubricate and protect the heart from infection and inflammation. Inflammation of the pericardium, known as pericarditis, is usually a response to other cardiac conditions, such as acute myocardial infarction or diseases of the thorax. The most common symptom arising from pericarditis is pain. Pericardial disease is often a localised manifestation of another disorder, such as infection (bacterial, viral, fungal or parasite); trauma or surgery; neoplasm; or a metabolic, immunological or vascular disorder (uraemia, rheumatoid arthritis, systemic lupus erythematosus).
Acute pericarditis
Approximately 90% of cases of acute pericarditis are caused by viruses or are idiopathic.54 Acute pericarditis can also
Some infants may be acutely cyanotic at birth. In others, progression of hypoxia and cyanosis may be more gradual over the first year of life as the pulmonary stenosis worsens. Chronic cyanosis may cause clubbing of the fingers, poor growth and squatting. Without being instructed to do so, these children squat in compensation — the squatting position traps blood in the legs and allows for greater oxygenation of blood in the central organs. Children with unrepaired tetralogy of Fallot are at risk for emboli, cerebrovascular disease, brain abscess, seizures and loss of consciousness or sudden death. EVALUATION AND TREATMENT
Diagnosis is confirmed with echocardiography. Elective surgical repair is usually performed in the first year of life. Indications for earlier repair include increasing cyanosis or the development of hypercyanotic spells. Complete repair involves closure of the VSD, resection of the stenosis and enlargement of the right ventricular outflow tract.
be caused by acute myocardial infarction, uraemia, cardiac surgery, some medications and autoimmune disorders. There are many forms of acute pericarditis, including serous, fibrinous, purulent and haemorrhagic. The pericardial membranes become inflamed and roughened and an exudate may develop. Symptoms include the sudden onset of severe retrosternal chest pain that worsens with respiratory movements and with lying down. The pain may radiate to the back as a result of irritation of the phrenic nerve (which innervates the trapezius muscles) as it traverses the pericardium.54 Individuals with acute pericarditis also report dysphagia, restlessness, irritability, anxiety, weakness and malaise. Physical examination often discloses low-grade fever and sinus tachycardia. Friction rub — a short, scratchy, grating sensation similar to the sound of sandpaper — may be heard at the cardiac apex and left sternal border and is diagnostic for pericarditis. The rub is caused by the roughened pericardial membranes rubbing against each other. Friction rubs are not present in approximately 15% of individuals with acute pericarditis or they may be intermittently heard and transient. Hypotension or the presence of pulsus paradoxus (an exaggerated decrease in systolic blood pressure with inspiration) is suggestive of cardiac tamponade (pericardial fluid impairing heart function; see below), which can be lethal. Electrocardiographic changes may reflect inflammatory processes through PR segment depression and diffuse ST segment elevation without Q waves, and they may remain abnormal for days or even weeks. Treatment for uncomplicated acute pericarditis consists of relieving symptoms and includes anti-inflammatory
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agents. Exploration of the underlying cause is important. If pericardial effusion develops, aspiration of the excessive fluid may be necessary. Acute pericarditis is usually self-limiting.
Pericardial effusion
Pericardial effusion — the accumulation of fluid in the pericardial cavity — can occur in all forms of pericarditis. The fluid may be a transudate, such as the serous effusion that develops with left heart failure, overhydration or hypoproteinaemia. More often, however, the fluid is an exudate, which reflects pericardial inflammation like that seen with acute pericarditis, heart surgery, some chemotherapeutic agents, infections and autoimmune disorders such as systemic lupus erythematosus. Pericardial effusion, even in large amounts, is not necessarily clinically significant, except that it indicates an underlying disorder. If an effusion develops gradually, the pericardium can stretch to accommodate large quantities of fluid without compressing the heart. If the fluid accumulates rapidly, however, even a small amount (50–100 mL) may create sufficient pressure to cause cardiac compression, a serious condition known as cardiac tamponade. The danger is that pressure exerted by the pericardial fluid eventually will equal diastolic pressure within the heart chambers, which will interfere with right atrial filling during diastole. This causes increased venous pressure, systemic venous congestion, and signs and symptoms of right heart failure (distension of the jugular veins, oedema, hepatomegaly). Decreased atrial filling leads to decreased ventricular filling, decreased stroke volume and reduced cardiac output. Life-threatening circulatory collapse may occur. An important clinical finding is pulsus paradoxus, in which there is a substantial decrease in systolic blood pressure during inspiration. Pulsus paradoxus in the setting of a pericardial effusion indicates tamponade and reflects impairment of diastolic filling of the left ventricle plus reduction of blood volume within all four cardiac chambers. Other clinical manifestations of pericardial effusion are distant or muffled heart sounds, poorly palpable apical pulse, dyspnoea on exertion and dull chest pain. A chest x-ray film may disclose a water-bottle configuration of the cardiac silhouette. Doppler echocardiogram can detect an effusion as small as 20 mL. Treatment of pericardial effusion or tamponade generally consists of pericardiocentesis (aspiration of excessive pericardial fluid) and treatment of the underlying condition. Persistent pain may be treated with analgesics, antiinflammatory medications or steroids.
Disorders of the myocardium: the cardiomyopathies
The cardiomyopathies are a diverse group of diseases that primarily affect the myocardium itself. Most are the result of remodelling caused by myocardial and neurohumoral
responses (both neural and hormonal) to ischaemic events and hypertension. They may, however, be secondary to infectious disease, exposure to toxins, systemic connective tissue disease, infiltrative and proliferative disorders or nutritional deficiencies.55 However, many cases are idiopathic. The cardiomyopathies are categorised as dilated (formerly, congestive), hypertrophic or restrictive, depending on their physiological effects on the heart (see Fig. 23.32 and Table 23.8). FOCU S ON L EA RN IN G
1 Explain why pericarditis develops. 2 Describe the cardiomyopathies and list the major disorders. 3 Briefly describe the pathophysiological effects of the cardiomyopathies.
Disorders of the endocardium Valvular dysfunction
Disorders of the endocardium (the innermost lining of the heart wall) damage the heart valves, which are composed
A
C
Normal
Hypertrophic cardiomyopathy
B Dilated cardiomyopathy
D Restrictive cardiomyopathy
FIGURE 23.32
Diagram showing the three types of cardiomyopathy. A Normal heart. B Dilated cardiomyopathy demonstrating enlargement of all four chambers. C Hypertrophic cardiomyopathy showing a thickened left ventricle. D Restrictive cardiomyopathy characterised by a small left ventricular volume.
CHAPTER 23 Alterations of cardiovascular function across the life span
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TABLE 23.8 Pathophysiological effects of types of cardiomyopathy PATHOPHYSIOLOGY
DILATED
HYPERTROPHIC
Major symptoms
Fatigue, weakness, palpitations
Dyspnoea, angina pectoris, fatigue, Dyspnoea, fatigue dizziness (syncope), palpitations
Cardiomegaly
Moderate to marked
Mild to moderate
Mild
Alterations of chamber volume Volume increased
Volume decreased, particularly in left ventricle
Volume normal to decreased
Alterations of chamber compliance
Compliance increased
Compliance decreased, particularly Compliance decreased, in left ventricle particularly in left ventricle
Alterations of systolic function (myocardial contractility)
Contractility decreased in left ventricle
Contractility increased or vigorous
None
Conduction defects
Intraventricular
Nonspecific
Atrioventricular
Arrhythmias
Sinus tachycardia; atrial and ventricular arrhythmias
Atrial and ventricular arrhythmias
Tachyarrhythmias
Thromboembolism
Systemic or pulmonary
Systemic or pulmonary
Systemic or pulmonary
Associated conditions
Infiltrative disease Coronary heart disease, Hypertension, aortic stenosis, alcoholism, pregnancy, possibly inherited defect of muscle infection, nutritional deficiency, growth and development exposure to toxins
Eventual cardiovascular event
Left heart failure
of endocardial tissue. Endocardial damage can be either congenital or acquired. The acquired forms cause inflammatory, ischaemic, traumatic, degenerative or infectious alterations of valvular structure and function. One of the most common causes of acquired valvular dysfunction is degeneration or inflammation of the endocardium secondary to rheumatic heart disease (see Table 23.9). Valvular stenosis occurs when the valve orifice is constricted and narrowed, so that blood cannot flow forwards and the workload of the cardiac chamber ‘behind’ the diseased valve increases (see Fig. 23.33). Pressure within the ventricular or atrial chamber rises to overcome resistance to flow through the valve, causing the myocardium to work harder and producing myocardial hypertrophy. In valvular regurgitation (also called insufficiency or incompetence), the valve leaflets, or cusps, fail to shut completely, permitting blood flow to continue even when the valve is supposed to be closed (see Fig. 23.33). Blood can leak back into the chamber ‘upstream’, which increases the volume of blood the heart must pump and increases the workload of both the atrium and the ventricle. Increased volume leads to chamber dilation with cardiomegaly (see Fig. 23.34) and increased workload leads to hypertrophy. Although all four heart valves may be affected, in adults those of the heart’s left side (the mitral and aortic valves) are far more commonly affected than those of the right (the tricuspid and pulmonary valves). Valvular dysfunction stimulates chamber dilation and myocardial hypertrophy, both of which are compensatory mechanisms intended to increase the pumping capability of the heart but which lead to cardiac dysfunction over time. Eventually, myocardial contractility diminishes, the
Left heart failure
RESTRICTIVE
Right heart failure
ejection fraction is reduced, diastolic pressure increases and the ventricles fail from overwork. Depending on the severity of the valvular dysfunction and the capacity of the heart to compensate, valvular alterations cause a range of symptoms and some degree of incapacitation (see Table 23.9).
Stenosis AORTIC STENOSIS
Aortic stenosis is one of the most common valvular abnormalities, and has three common causes: 1 congenital bicuspid valve abnormalities 2 inflammatory damage caused by rheumatic heart disease 3 degeneration with ageing (see Fig. 23.35). Aortic valve degeneration with ageing is associated with lipoprotein deposition in the tissue with chronic inflammation and leaflet calcification.56 The orifice of the aortic semilunar valve narrows, causing diminished blood flow from the left ventricle into the aorta. Outflow obstruction increases pressure within the left ventricle as it tries to eject blood through the narrowed opening. Aortic stenosis tends to develop gradually. Clinical manifestations include decreased stroke volume, reduced systolic blood pressure and narrowed pulse pressure (the difference between systolic and diastolic pressure). Heart rate is often slow and pulses are faint. Left ventricular hypertrophy develops to compensate for the increased workload. Eventually, hypertrophy increases myocardial oxygen demand, which the coronary arteries may be unable to meet. In addition, aortic stenosis is frequently accompanied by atherosclerotic coronary disease, further contributing to inadequate coronary perfusion.56
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TABLE 23.9 Clinical manifestations of valvular stenosis and regurgitation AORTIC REGURGITATION
MITRAL REGURGITATION
TRICUSPID REGURGITATION
Rheumatic heart disease
Infective endocarditis; aortic root disease; dilation of the aortic root due to hypertension and ageing
Myxomatous degeneration (mitral valve prolapse)
Congenital
Left atrial hypertrophy and dilation with fibrillation, followed by right ventricular failure
Left ventricular hypertrophy and dilation, followed by left heart failure
Left atrial hypertrophy and dilation, followed by left heart failure
Right heart failure
Pulmonary effects Pulmonary oedema: dyspnoea on exertion
Pulmonary oedema: dyspnoea on exertion, orthopnoea, paroxysmal nocturnal dyspnoea, predisposition to respiratory infections, haemoptysis, pulmonary hypertension
Pulmonary oedema with dyspnoea on exertion
Pulmonary oedema with dyspnoea on exertion
Dyspnoea
Central nervous system effects
Syncope, especially on exertion
Neural deficits only associated with emboli
Syncope
None
None
Pain
Angina pectoris
Atypical chest pain
Angina pectoris
Atypical chest pain
Palpitations
Heart sounds
Systolic murmur heard best at the right parasternal second intercostal space and radiating to the neck
Low rumbling diastolic murmur heard best at the apex and radiating to the axilla, accentuated first heart sound, opening snap
Diastolic murmur heard best at the right parasternal second intercostal space and radiating to the neck
Murmur throughout systole heard best at the apex and radiating to the axilla
Murmur throughout systole heard best at the left lower sternal border
MANIFESTATION
AORTIC STENOSIS
MITRAL STENOSIS
Aetiology
Congenital bicuspid valve, degenerative (calcific) changes with ageing, rheumatic heart disease
Cardiovascular outcome (untreated)
Left ventricular hypertrophy followed by left heart failure; decreased coronary blood flow with myocardial ischaemia
Untreated aortic stenosis can lead to arrhythmias, myocardial infarction and heart failure. Echocardiography can be used to assess the severity of valvular obstruction before the onset of symptoms, and management almost always includes valve replacement with a prosthetic valve (see Fig. 23.36), followed by long-term anticoagulation and prophylaxis for endocarditis, as needed. MITRAL STENOSIS
Mitral stenosis impairs the flow of blood from the left atrium to the left ventricle. Mitral stenosis is most commonly caused by rheumatic heart disease. In addition, mitral stenosis is two to three times more common in women than in men.57 Autoimmunity in response to group A β-haemolytic streptococcal protein antigens leads to inflammation and scarring of the valvular leaflets. Scarring causes the leaflets to become fibrous and fused and the chordae tendineae become shortened. Impedance to blood flow results in incomplete emptying of the left atrium and elevated atrial pressure as the chamber tries to force blood through the stenotic valve. Continued
increases in left atrial volume and pressure cause atrial dilation and hypertrophy. The risk of developing atrial arrhythmias (especially fibrillation) and arrhythmia-induced thrombi is high. As mitral stenosis progresses, symptoms of decreased cardiac output occur, especially during exertion. Continued elevation of left atrial pressure and volume causes pressure to rise in the pulmonary circulation. If untreated, chronic mitral stenosis develops into pulmonary hypertension, pulmonary oedema and right ventricular failure. Management includes anticoagulation and endocarditis prophylaxis along with β-blockers or calcium channel blockers to slow the heart rate. Mitral stenosis can often be repaired surgically but may require valve replacement (see Fig. 23.36) in advanced cases.
Regurgitation AORTIC REGURGITATION
Aortic regurgitation results from an inability of the aortic valve leaflets to close properly during diastole resulting
CHAPTER 23 Alterations of cardiovascular function across the life span
A
B Fused cusps
Cusp
Orifice Normal valve (open)
Cusp
Orifice Normal valve (closed)
Stenosed valve (open)
C
Stenosed valve (closed)
D Stenosed mitral valve Mitral valve does not close completely
FIGURE 23.33
Valvular stenosis and regurgitation. A Normal position of the valve leaflets, or cusps, when the valve is open and closed. B Open position of a stenosed valve (left) and open position of a closed regurgitant valve (right). C Haemodynamic effect of mitral stenosis. The stenosed valve is unable to open sufficiently during left atrial systole, inhibiting left ventricular filling. D Haemodynamic effect of mitral regurgitation. The mitral valve does not close completely during left ventricular systole, permitting blood to re-enter the left atrium.
A
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from abnormalities of the leaflets or the aortic root and annulus, or both.58 It can be congenital (bicuspid valve abnormalities) or acquired. Acquired aortic regurgitation can be caused by rheumatic heart disease, bacterial endocarditis, syphilis, hypertension, connective tissue disorders (e.g. Marfan’s syndrome), appetite-suppressing medications, trauma or atherosclerosis. In more than one-third of cases of aortic regurgitation there is no known cause. The haemodynamic abnormalities depend on the size of the ‘leak’. During systole, blood is ejected from the left ventricle into the aorta. During diastole, some of the ejected blood flows back into the left ventricle. Volume overload occurs in the ventricle because it receives blood from both the left atrium and the aorta during diastole. Over time, the end-diastolic volume of the left ventricle increases and myocardial fibres stretch to accommodate the extra fluid. Compensatory dilation permits the left ventricle to increase its stroke volume and maintain cardiac output. Ventricular hypertrophy also occurs as an adaptation to the increased volume and because of increased afterload created by the high stroke volume and resultant systolic hypertension. Ventricular dilation and hypertrophy eventually cannot compensate for aortic incompetence and heart failure develops. Clinical manifestations include widened pulse pressure resulting from increased stroke volume and diastolic backflow. Other symptoms are usually associated with heart failure, which occurs when the ventricle can no longer pump adequately. Arrhythmias and endocarditis are common
B
RA
LA
LA RV
RA RV
LV
LV
FIGURE 23.34
Cardiomegaly due to mitral and tricuspid regurgitation. Note the enlarged heart, which is wider than normal. A On the posteroanterior chest x-ray there is marked enlargement of not only the left atrium (LA) but also the left ventricle (LV; seen as straightening of the left cardiac border), as well as right-sided enlargement, particularly of the right atrium (RA; seen by marked prominence of the right cardiac border). B On the lateral view of the chest the left ventricle can be seen overlapping the spine, and the right atrium and right ventricle (RV) have filled in the retrosternal space to more than the usual lower one-third.
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AA
AB
AC
AD
FIGURE 23.35
Aortic stenosis. A Normal aortic valve. B Congenital bicuspid aortic stenosis. C Rheumatic aortic stenosis. D Calcified degenerative aortic stenosis.
complications of aortic regurgitation. The severity of regurgitation can be estimated by echocardiography, and surgical management (valve replacement; see Fig. 23.36) may be delayed for many years through careful use of vasodilators and inotropic agents. MITRAL REGURGITATION
Mitral regurgitation has many possible causes, including mitral valve prolapse, rheumatic heart disease, infective endocarditis, acute myocardial infarction, connective tissue diseases (such as Marfan’s syndrome) and congestive cardiomyopathy (myocardial disease).59 Mitral regurgitation permits backflow of blood from the left ventricle into the left atrium during ventricular systole. Eventually, the left ventricular volume increases, causing it to become dilated and hypertrophied to maintain adequate cardiac output. The volume of backflow re-entering the left atrium gradually increases, causing atrial dilation and associated atrial fibrillation. As the left atrium enlarges, the valve structures stretch and become deformed, leading to further backflow. As mitral valve regurgitation progresses, left ventricular function may become impaired to the point of failure. Eventually, increased atrial pressure also causes pulmonary hypertension and failure of the right ventricle. Mitral incompetence is usually well tolerated — often for years — until ventricular failure occurs. Most clinical manifestations are caused by heart failure. The severity of regurgitation can be estimated by echocardiography, and surgical
repair or valve replacement may become necessary (see Fig. 23.36). TRICUSPID REGURGITATION
Tricuspid regurgitation is more common than tricuspid stenosis (narrowing) and is usually associated with failure and dilation of the right ventricle secondary to pulmonary hypertension. Tricuspid valve incompetence leads to volume overload in the right ventricle, increased systemic venous blood pressure and right heart failure. Pulmonary semilunar valve dysfunction can have the same consequences as tricuspid valve dysfunction.
Rheumatic heart disease
Rheumatic fever is a diffuse, inflammatory disease caused by a delayed exaggerated immune response to infection by the group A β-haemolytic streptococcus in genetically predisposed individuals. In its acute form, rheumatic fever is a febrile illness characterised by inflammation of the joints, skin, nervous system and heart.60 If untreated, rheumatic fever can cause scarring and deformity of cardiac structures resulting in rheumatic heart disease. With increases in living standards and infection control, the incidence of rheumatic heart disease has been in decline in Western countries, although it remains highly prevalent in developing countries, where it is the most common cause of cardiac mortality in children and adults less than 40 years. In Australia, rheumatic fever is now a rare disease
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PATHOPHYSIOLOGY
A
B
C
Acute rheumatic fever can develop only as a sequel to pharyngeal infection by group A β-haemolytic streptococcus. Streptococcal skin infections do not progress to acute rheumatic fever, although both skin and pharyngeal infections can cause acute glomerulonephritis. This is because the strains of the microorganism that affect the skin do not have the same antigenic molecules in their cell membranes as those that cause pharyngitis and therefore do not elicit the same kind of immune response. Acute rheumatic fever is the result of an abnormal humoral and cell-mediated immune response to group A streptococcal cell membrane antigens called M proteins (see Fig. 23.37). Diffuse, proliferative and exudative inflammatory lesions develop in the connective tissues, especially in the heart. The inflammation may subside before treatment, leaving behind damage to the heart valves and increasing the individual’s susceptibility to recurrent acute rheumatic fever after any subsequent streptococcal infections. Repeated attacks of acute rheumatic fever cause chronic proliferative changes (scarring) in the affected regions. Approximately 10% of individuals with rheumatic fever develop rheumatic heart disease. The primary lesion usually involves the endocardium. Endocardial inflammation causes swelling of the valve leaflets, with secondary erosion along the lines of leaflet contact. Small bead-like clumps of vegetation containing platelets and fibrin are deposited on eroded valvular tissue and on the chordae tendineae (see Fig. 23.38). Myocarditis (inflammation of the myocardium) may occur. Cardiomegaly and left heart failure may occur during episodes of untreated acute or recurrent rheumatic fever. Conduction defects and atrial fibrillation are often associated with rheumatic heart disease. CLINICAL MANIFESTATIONS
FIGURE 23.36
Various valve replacements. A A porcine bioprosthesis. B A mechanical valve prosthesis of the tilting disc variety replacing the native mitral valve. C A mechanical valve prosthesis of the older ball-and-cage variety.
in the affluent population; however, it has a substantial impact on Aboriginal and Torres Strait Islander communities, with the highest rates of rheumatic fever in children aged 5–14 years and the higher rates of rheumatic heart disease found in adults aged 35–39. Aboriginal and Torres Strait Islander people are up to eight times more likely to be hospitalised for rheumatic fever and rheumatic heart disease, and 20 times more likely to die than non-Indigenous people.61
Many common clinical manifestations of acute rheumatic fever — fever, lymphadenopathy, arthralgia (painful joints), nausea, vomiting, epistaxis (nose bleeds), abdominal pain and tachycardia — are also associated with other disorders and are therefore not diagnostic of the disease. The major clinical manifestations of acute rheumatic fever are carditis, acute migratory polyarthritis (inflammation of more than one joint), chorea (a central nervous system disorder — see Chapter 9) and erythema marginatum (truncal rash), which may occur singly or in combination 1–5 weeks after streptococcal infection of the pharynx. EVALUATION AND TREATMENT
When combined with physical assessment findings, laboratory values lend significant support to the diagnosis of acute rheumatic fever. A positive throat culture for group A β-haemolytic streptococci can be an important finding when associated with certain physical signs. Elevated white blood cell count, erythrocyte sedimentation rate and C-reactive protein indicate inflammation. All three are usually increased at the time cardiac or joint symptoms
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Streptococcal pharyngitis
Group A streptococcus
Activation of T cells by streptococcal antigen Synthesis of antistreptococcal antibodies by B cells Vegetation
Inflammation
Mitral leaflet Short, thickened chordae tendineae
1 ENDOCARDITIS Fibrinoid Fibrosis material Giant cell
Aschoff bodies
3
FIBRINOUS PERICARDITIS
Lymphocyte Macrophage 2 MYOCARDITIS
FIGURE 23.37
The pathogenesis and structural changes of rheumatic heart disease. Beginning usually with a sore throat, rheumatic fever can develop only as a sequel to pharyngeal infection by group A β-haemolytic streptococcus. Suspected as a hypersensitivity reaction, it is proposed that antibodies directed against the M proteins of certain strains of streptococci cross-react with tissue glycoproteins in the heart, joints and other tissues. The exact nature of cross-reacting antigens has been difficult to define, but it appears that the streptococcal infection causes an autoimmune response against self-antigens. Inflammatory lesions are found in various sites; the most distinctive within the heart are called Aschoff bodies. The chronic sequelae result from progressive fibrosis because of healing of the inflammatory lesions and the changes induced by valvular deformities.
FIGURE 23.38
Mitral stenosis with vegetation. Mitral stenosis and clumps of vegetation (V) containing platelets and fibrin are shown in this micrograph. The mitral leaflets are thickened and fused.
begin to appear. They are more useful in identifying an acute inflammatory process and suggesting prognosis than in diagnosing acute rheumatic fever. These test results return towards normal levels as the inflammatory process resolves. Therapy for acute rheumatic fever is aimed at eradicating the streptococcal infection and involves a 10-day regimen of oral penicillin or erythromycin administration. Non-steroidal anti-inflammatory drugs (NSAIDs) are used as anti-inflammatory agents for both rheumatic carditis and arthritis. Serious carditis may require adding cardiac glycosides, corticosteroids, diuretics and bed rest to the regimen. Surgical repair of damaged valves may be needed in chronic recurrent rheumatic fever and carditis leading to rheumatic heart disease. Research suggests that a rheumatic recurrence will develop in 50–65% of children with known rheumatic fever if they have another group A streptococcal infection. To prevent a recurrence of acute rheumatic fever, continuous prophylactic antibiotic therapy may be necessary for as long as 10 years.62 Appropriate antibiotic therapy given within the first 9 days of infection usually prevents rheumatic fever.
Infective endocarditis
Infective endocarditis is a general term used to describe infection and inflammation of the endocardium, especially the cardiac valves. Bacteria are the most common cause of infective endocarditis including Streptococcus viridans, Staphylococcus aureus, Staphylococcus epidermidis and group A β-haemolytic streptococci. Infective endocarditis was once a lethal disease, but morbidity and mortality diminished significantly with the advent of antibiotics and improved diagnostic techniques (see Box 23.2 ‘Risk factors for infective endocarditis’).
CHAPTER 23 Alterations of cardiovascular function across the life span
Risk factors for infective endocarditis
• Acquired valvular heart disease (especially mitral valve prolapse) • Implantation of prosthetic heart valves • Congenital lesions associated with highly turbulent flow (e.g. VSD) • Previous episodes of infective endocarditis • Male gender • Intravenous drug use • Long-term haemodialysis • Recent cardiac surgery
PATHOPHYSIOLOGY
The pathogenesis of infective endocarditis requires at least three critical elements (see Fig. 23.39): (1) the endocardium (e.g. heart valve) must be ‘prepared’, usually by endothelial damage, for microorganism colonisation; (2) blood-borne microorganisms must adhere to the damaged endocardial surface; and (3) the microorganisms must proliferate and promote the propagation of infective endocardial vegetation. Endocardial damage exposes the collagen within the endothelial basement membrane — this collagen attracts platelets and thereby stimulates thrombus formation on the membrane. This causes an inflammatory reaction. Infective endocarditis cannot develop unless microorganisms gain access to the bloodstream. They may enter the bloodstream during intravenous drug use, trauma or minor procedures such as dental cleaning or bladder catheterisation, or they may spread from uncomplicated upper respiratory or skin infections. A significant number of cases of infective carditis are healthcare-acquired infections in origin, especially those that result from genitourinary or gastrointestinal procedures or from surgical wound infections. Once the endocardial surface is colonised, infected vegetations form (see Fig. 23.40). Bacteria may accelerate fibrin formation by activating the coagulation cascade. Although endocardial tissue is constantly bathed in antibody-containing blood and is surrounded by scavenging monocytes and leucocytes, bacterial colonies are inaccessible to host defences because they are embedded in the protective fibrin clots. The lesions can form anywhere on the endocardium but usually occur on the endocardial surfaces of heart valves and surrounding structures. CLINICAL MANIFESTATIONS
Infective endocarditis may be acute, subacute or chronic. It causes varying degrees of valvular dysfunction and may be associated with manifestations involving several organ systems (lungs, eyes, kidneys, bones, joints, central nervous system), making diagnosis exceedingly difficult. The ‘classic’ findings are fever and petechial lesions of the skin, conjunctiva and oral mucosa. Other manifestations include weight loss, back pain, night sweats and heart failure.
Endothelial damage Development of thrombi Non-bacterial thrombotic endocarditis Haemodialysis
Genitourinary instrumentation Dental procedure
Intravenous drug abuse
Skin infection
Cardiac surgery
Pathogen entry into bloodstream Failure of platelet inhibition causing platelet deposition
Failure of mechanisms of self-defence (serum complement, antibodies)
Bacteraemia Bacterial infiltration of platelet-fibrin thrombi
Colonisation on endocardial surfaces Adherence of more platelets
Formation of more fibrin Growth of vegetation Infective endocarditis
CAUSES – Turbulent blood flow – Stress – Cardiac catheterisation – Deposit of immune complex (systemic lupus erythematosus, rheumatic heart disease) – High altitude* – Cold exposure*
FIGURE 23.39
The pathogenesis of infective endocarditis. Infective endocarditis commences with endothelial damage, and aspects which promote the microorganism to enter the blood then allow them to adhere to the damaged endothelium. These microorganisms then proliferate leading to infective endocarditis. *Rare in Australia
CONCEPT MAP
BOX 23.2
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RESEARCH IN F CUS Endocarditis risk in children Children with congenital heart disease are at risk for developing endocarditis. Although the risk is low, a transient bacteraemia has been noted to follow dental and surgical procedures and instrumentation involving mucosal surfaces. A blood-borne pathogen can settle in areas of the heart where there is high turbulence, an abnormal valve or vessel, or an artificial material such as a valve or homograft. Streptococcus viridans (α-haemolytic streptococci) is the most commonly found pathogen following dental or oral procedures. Enterococcus faecalis (enterococci) is the most common bacterium found following genitourinary and gastrointestinal tract surgery or instrumentation. The Infective Endocarditis Prophylaxis Expert Group convened by the Therapeutics Guidelines has provided updated guidelines for the prevention of bacterial endocarditis. The type and dose of antibiotic prophylaxis recommended depend on the procedure and the cardiac classification of risk for endocarditis.
EVALUATION AND TREATMENT
The criteria for the diagnosis of infective endocarditis include persistent bacteraemia, new heart murmurs, vascular complications and appropriate echocardiographic findings.63 Antimicrobial therapy is generally given for 4 to 6 weeks. Other drugs may be necessary to treat left heart failure secondary to valvular dysfunction. Surgery to remove infected tissue, with or without valve replacement, improves outcomes in many patients with infective endocarditis, especially those with severe heart failure or persistent bacteraemia despite antibiotic therapy.64 FOCU S ON L EA RN IN G
1 Compare the effect of aortic stenosis with mitral stenosis on the left ventricle and atrium. 2 Describe aortic regurgitation, mitral regurgitation and tricuspid regurgitation. 3 Explain how inflammation predisposes individuals to rheumatic heart disease. 4 Discuss the 3 critical elements required for the pathogenesis of infective endocarditis.
A
5 Explain why infective endocarditis involves several organ systems.
Alterations of cardiac conduction
B
FIGURE 23.40
Infective endocarditis. A Endocarditis of the mitral valve (subacute, caused by Streptococcus viridans). The large, friable vegetations are denoted by arrows. B Acute endocarditis of congenitally bicuspid aortic valve (caused by Staphylococcus aureus) with extensive cuspal destruction and ring abscess (arrow).
So far in this chapter we have examined the effects of pathophysiological changes to the blood vessels and the heart. These changes have typically altered the function of cardiac structures and we have explored how this impacts on mechanical contraction. In this section, we look at the pathophysiological changes that alter electrical conduction of the heart. Normal cardiac conduction requires the autorhythmic cells to produce action potentials that spread sequentially throughout conduction pathways in a coordinated fashion (refer to Chapter 22). Briefly, normal heart rhythm is generated by the sinoatrial (SA) node and travels through the atrioventricular node, down the atrioventricular bundle and through the bundle branches to the Purkinje fibres. These depolarisations initiate cardiac contraction and the heart oscillates through systole and diastole to maintain cardiac output. Cardiac conduction alterations may occur because of a variety of reasons, such as electrolyte disturbances, myocardial ischaemia and acute myocardial infarction, drug therapy and intrinsic problems of the autorhythmic cells. Technically, the term dysrhythmia refers to a disturbance of heart rhythm. Although this term is entirely accurate and appropriate, in Australia and New Zealand we commonly refer to dysrhythmias as arrhythmias. The word arrhythmia actual means without cardiac rhythm (the prefix ‘a’ meaning no or without). Despite the fact that there are differences
CHAPTER 23 Alterations of cardiovascular function across the life span
between the terms, they are often used interchangeably. However, we believe that dysrhythmia has not been universally accepted and so, for the purposes of consistency and to align with clinical terminology, we refer to alterations of cardiac conduction as arrhythmias.
Arrhythmias
Arrhythmias can range in severity from occasional ‘missed’ or rapid beats to serious disturbances that impair the pumping ability of the heart and that may result in heart failure and death. Arrhythmias can be caused by either an abnormal rate of impulse generation by the SA node or other pacemakers, or the abnormal conduction of impulses through the conduction system of the heart, including the myocardial cells themselves. Furthermore, arrhythmias can be non-pathological in origin, such as a missed beat in an athlete who has bradycardia (slowed heart rate) as a result of endurance training, ranging to potentially life-threatening conditions that may cause sudden death. Tables 23.10 and 23.11 explore the most common conduction alterations.
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Atrial fibrillation is the most common arrhythmia and is most prevalent in the elderly population.65 It can occur due to a variety of reasons, although the treatment should be aggressive to prevent unwanted complications, such as blood clotting and pulmonary embolism or embolic strokes. The life-threatening arrhythmias include ventricular tachycardia, ventricular fibrillation, asystole (without systole) and pulseless electrical activity. These arrhythmias cause cardiorespiratory arrest, as the heart has either stopped contractions or is abnormal to the extent that there is no cardiac output. Breathing cessation usually accompanies cardiac arrest. The management of these arrhythmias involves immediate life support.
FOCU S ON L EA RN IN G
1 Discuss the difference between life-threatening arrhythmias and other arrhythmias.
TABLE 23.10 Disorders of impulse formation TYPE
ECG
EFFECT
PATHOPHYSIOLOGY
TREATMENT
Sinus bradycardia
P rate 60 or less PR interval normal QRS for each P
Increased preload Decreased mean arterial pressure
Hyperkalaemia: slows depolarisation Digoxin toxicity common Late hypoxia: lack of ATP
If hypotensive, treat cause Sympathomimetics, anticholinergics Pacemaker placement
Sinus tachycardia
P rate 100–150 PR interval normal QRS for each P
Decreased filling times Decreased mean arterial pressure Increased myocardial demand
Catecholamines: rise in resting potential and calcium influx Fever: unknown Early heart failure: compensatory response to decreased stroke volume Lung disease: hypoxic cell metabolism Hypercalcaemia
Oxygen, bed rest Calcium channel blockers
Continued
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TABLE 23.10 Disorders of impulse formation—cont’d TYPE
ECG
EFFECT
PATHOPHYSIOLOGY
TREATMENT
Premature atrial contractions
Early P waves that may have changed morphology PR interval normal QRS for each P
Occasional decreased filling time and mean arterial pressure
Electrolyte disturbances (especially hypercalcaemia): alter action potentials Hypoxia and elevated preload: cell membrane disturbances
Treat underlying cause Digoxin
Atrial tachycardia (includes premature atrial tachycardia if onset is abrupt)
P rate 151–250 P morphology may differ from sinus P PR interval normal P/QRS ratio variable
Decreased filling time Decreased mean arterial pressure Increased myocardial demand
Same as premature atrial contractions: leads to increased atrial automaticity, atrial reentry Digoxin toxicity: common Ageing
Control ventricular rate Digoxin, calcium channel blockers, vagus stimulation Pacemaker to override atrial conduction Cardioversion
Atrial flutter^
P rate 251–300, morphology may vary from sinus P PR interval usually not observable P/QRS ratio variable
Decreased filling time Decreased mean arterial pressure
Same as atrial tachycardia
Same as atrial tachycardia
Atrial fibrillation^
P rate > 300 and usually not observable No PR interval QRS rate variable and rhythm irregular
Same as atrial flutter
Same as atrial tachycardia
Same as atrial tachycardia
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TABLE 23.10 Disorders of impulse formation—cont’d TYPE
ECG
EFFECT
PATHOPHYSIOLOGY
TREATMENT
Pulseless electrical activity*
Any rhythm that does not produce a cardiac contraction Can appear as sinus rhythm
No cardiac output and no pulse Not compatible with life
Depolarisation and contraction not coupled: electrical activity present with little or no mechanical activity Usually caused by profound hypoxia
CPR, see advanced lifesupport guidelines High mortality rate
Asystole*
P absent or independent QRS absent
No cardiac output Not compatible with life
Profound ischaemia, hyperkalaemia, acidosis
CPR, see advanced lifesupport guidelines High mortality rate
Premature ventricular contractions or ventricular ectopic beat
Early beats with P waves QRS occasionally opposite in deflection from usual QRS
Decreased cardiac output from loss of ventricular contraction
Ageing and induction of anaesthesia Impulse originates in cell outside normal conduction system and spreads through intercalated discs
Pharmacology to change thresholds, refractory periods; reduce myocardial demand, increase supply
Ventricular tachycardia*
P absent or independent QRS > 0.11 and rate 100 or more
Can have pulse or no cardiac output
Same as premature ventricular contractions
CPR, see advanced lifesupport guidelines Pharmacology to change thresholds, refractory periods
Ventricular fibrillation*
P absent QRS > 300 and usually not observable
Same as ventricular standstill
Same as premature ventricular contractions Rapid infusion of potassium
CPR, see advanced lifesupport guidelines
^Most common in adults. *Life-threatening arrhythmias.
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TABLE 23.11 Disorders of impulse conduction TYPE
ECG
EFFECT
PATHOPHYSIOLOGY
TREATMENT
Sinus arrest
Occasionally absent P, with loss of QRS for that beat
Occasional decrease in cardiac output Increase in preload for the following beat
Conservative Local hypoxia, scarring of intraatrial conduction Usually does not progress in severity pathways, electrolyte imbalances
First-degree block^
PR interval >0.2 sec
None
Conservative Same as sinus block Discovery and Hyperkalaemia correction of cause (> 7 mmol/L) Hypokalaemia (< 3.5 mmol/L) Formation of myocardial abscess in endocarditis
Second-degree heart block Mobitz I or Wenckebach^
Progressive prolongation of PR interval until one QRS is dropped Pattern of prolongation resumes
Same as sinus arrest
Hypokalaemia Same as sinus arrest (< 3.5 mmol/L) Faulty cell metabolism in AV node Severity increases as heart rate increases Supports theory that AV node is fatiguing Digoxin toxicity, β blockade hypoxia, increased preload, valvular surgery and disease, diabetes
Second-degree heart block Mobitz II
Same as sinus arrest
Same as sinus arrest
Hypokalaemia (< 3.5 mmol/L) Faulty cell metabolism below AV node Antiarrhythmics, tricyclic antidepressants Hypoxia, increased preload, valvular surgery and disease, diabetes
More aggressively than Mobitz I Pacemaker after pharmacological treatment
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TABLE 23.11 Disorders of impulse conduction—cont’d TYPE
ECG
EFFECT
PATHOPHYSIOLOGY
TREATMENT
Third-degree heart block*
P waves present and independent of QRS No observed relationship between P and QRS Always AV dissociation
Decreased cardiac output from loss of atrial contribution to ventricular preload
Hypokalaemia (< 3.5 mmol/L) Faulty cell metabolism low in bundle of His, acute myocardial infarction, especially inferior wall, as nodal artery interrupted; results in ischaemia of AV node
Pacemaker after pharmacological treatment Temporary pacing if caused by inferior myocardial infarction, since ischaemia usually resolves
^Most common in adults. *Life-threatening.
Heart failure Heart failure is a syndrome encompassing several different types of cardiac dysfunction that result in inadequate perfusion of tissues with oxygen and blood-borne nutrients. Providing a definition of heart failure is difficult because consensus has been hard to achieve; however, it is now considered that both clinical features and an objective measure of abnormal ventricular function are required to adequately diagnose heart failure. The National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand have formulated the following definition: Heart failure is a complex clinical syndrome that is frequently, but not exclusively, characterised by an underlying structural abnormality or cardiac dysfunction that impairs the ability of the left ventricle (LV) to fill with or eject blood, particularly during physical activity. Symptoms of CHF (congestive heart failure) (e.g. dyspnoea and fatigue) can occur at rest or during physical activity.66 Heart failure occurs in up to 1.5–2% of all Australians;66 with over one-third with the condition aged 75 years or over. Most causes of heart failure result from dysfunction of the left ventricle (systolic and diastolic heart failure). The right ventricle may also be dysfunctional, especially in pulmonary disease (right ventricular failure). Coronary
heart disease and acute myocardial infarction are documented in about two-thirds of systolic heart failure patients. Essential hypertension is also strongly associated with heart failure and is present in approximately two-thirds of all newly diagnosed cases.66 In the following sections we examine heart failure and its relationship to other cardiovascular diseases.
Left heart failure
Left heart failure, commonly called congestive heart failure, can be further categorised as systolic heart failure or diastolic heart failure. These two types of heart failure can occur together or in isolation.
Systolic heart failure
Systolic heart failure is defined as an inability of the heart to generate adequate cardiac output to perfuse vital tissues. Cardiac output depends on the heart rate and stroke volume. Stroke volume is influenced by three major determinants: contractility, preload and afterload (refer to Chapter 22). Contractility is reduced by diseases that disrupt myocyte activity. Myocardial infarction is the most common primary cause of decreased contractility; other causes include myocarditis and the cardiomyopathies. Secondary causes of decreased contractility, such as recurrent myocardial ischaemia and increased myocardial workload, contribute
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to inflammatory, immune and neurohumoral changes that mediate a process called ventricular remodelling (see ‘Research in Focus: Inflammation, immunity and humoral factors in the pathogenesis of heart failure’).16,67 Ventricular remodelling results in hypertrophy and dilation of the myocardium and causes progressive myocyte contractile dysfunction over time (see Fig. 23.41). When contractility is decreased, stroke volume falls and ventricular end-diastolic volume increases. This causes dilation of the heart and an increase in preload.
RESEARCH IN F CUS Inflammation, immunity and humoral factors in the pathogenesis of heart failure The treatment of the haemodynamic abnormalities of heart failure can provide short-term improvement in symptoms but will not prevent the progression of myocardial dysfunction over time. Studies have shown that neurohumoral responses to heart failure (including changes in the renin-angiotensinaldosterone system, catecholamines, natriuretic peptides, endothelin and nitric oxide) exert direct cardiotoxicity that results in progressive damage to the heart muscle. Drugs such as ACE inhibitors, angiotensin II receptor blockers and β-blockers can slow disease progression and are now the standard of care for heart failure. In 2016, a new treatment was approved for clinical use that combines an angiotensin II receptor antagonist with a neprilysin (protease) inhibitor. Inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukins have been implicated in the pathogenesis of heart failure and its systemic complications. However, trials with anticytokine drugs have failed to show significant improvements.
Preload increases with decreased contractility or an excess of plasma volume (intravenous fluid administration, renal failure, mitral valvular disease). Increases in preload can actually improve cardiac output, but as preload continues to rise, it causes a stretching of the myocardium that eventually can lead to dysfunction of the sarcomeres and decreased contractility. This relationship is described by the Frank-Starling law of the heart, which details the length–tension relationship between end-diastolic volume and stroke volume in the ventricle. (This was reviewed in Chapter 22.) However, with sarcomere dysfunction resulting in decreased contractility, increases in end-diastolic volume do not result in increases in stroke volume. In fact, decreased contractility leads to further increases in preload (see Fig. 23.42), which causes a lowering of cardiac output for a given ventricular end-diastolic volume (see Fig. 23.43). In this scenario, across the range of end-diastolic volumes, cardiac performance is less than normal, as increases
in stroke volume do not occur to the same magnitude as the normal heart because of the damage to the myocytes. Increased afterload is most commonly a result of increased peripheral vascular resistance, such as that seen with hypertension. With increased afterload, there is resistance to ventricular emptying and more work for the ventricle, which results in myocardial hypertrophy. Hypertrophy is mediated by angiotensin II and catecholamines and results in an increase in oxygen demand by the thickened myocardium. A state of relative ischaemia develops, which further contributes to changes in the myocytes themselves and ventricular remodelling (see Fig. 23.44). In addition, hypertrophy results in the deposition of collagen between the myocytes, which can disrupt the integrity of the muscle, decrease contractility and make the ventricle more likely to dilate and fail. As cardiac output falls, renal perfusion diminishes with activation of the renin-angiotensin-aldosterone system, which acts to increase both peripheral vascular resistance and plasma volume, thus further increasing afterload and preload. In addition, baroreceptors in the central circulation detect the decrease in perfusion and stimulate the sympathetic nervous system to cause yet more vasoconstriction and the hypothalamus to produce antidiuretic hormone. The neurohumoral aspects of systolic heart failure suggest that treatment must include inhibition of angiotensin, aldosterone and catecholamines to prevent long-term damage to the myocardium.16,67 Immune and inflammatory processes also play an important role in the pathogenesis of heart failure and its systemic complications. This vicious cycle of decreasing contractility, increasing preload and increasing afterload causes progressive worsening of systolic heart failure (see Fig. 23.45). The clinical manifestations of systolic heart failure are the result of pulmonary vascular congestion and inadequate perfusion of the systemic circulation. Individuals experience dyspnoea, orthopnoea (experiencing dyspnoea when lying flat — individuals compensate by sitting upright), cough of frothy sputum, fatigue, decreased urine output and oedema. Physical examination often reveals pulmonary oedema (see Chapter 25), hypotension or hypertension and evidence of underlying coronary heart disease or hypertension. The diagnosis can be further confirmed with echocardiography revealing decreased cardiac output and cardiomegaly. Management of systolic left heart failure is aimed at interrupting the worsening cycle of decreasing contractility, increasing preload and increasing afterload.66 The acute onset of systolic left heart failure is most often the result of acute myocardial ischaemia and must be managed in conjunction with managing the underlying coronary disease. Oxygen, nitrate and morphine administration improves myocardial oxygenation and helps relieve coronary spasm while lowering preload through systemic venodilation. Intravenous inotropic drugs, such as dopamine or dobutamine, increase contractility and can help raise
CHAPTER 23 Alterations of cardiovascular function across the life span
CONCEPT MAP
Myocardial dysfunction • Myocardial infarction • Ischaemic heart disease • Hypertension • Other Cardiac output Systemic blood pressure
Baroreceptors activated • Left ventricle • Aortic arch • Carotid sinus
Perfusion to kidneys
Renin-angiotensin-aldosterone system activated
Angiotensin II Aldosterone
Vasomotor regulatory centres in medulla stimulated
Lungs Renin
Sympathetic nervous system activated
Catecholamines (adrenaline and noradrenaline)
Angiotensin I
Angiotensin II Aldosterone
Vasoconstriction Afterload Blood pressure Heart rate
Angiotensinogen
• Retain sodium and water • Arginine vasopressin • Endothelin • Cytokines (tumour necrosis factor-α)
Ventricular remodelling
Remodelled
659
• Hypertrophy and dilation of ventricle • Genetically large cells • Impaired contractility
Normal
FIGURE 23.41
The pathophysiology of ventricular remodelling. Myocardial dysfunction activates the renin-angiotensin-aldosterone and sympathetic nervous systems releasing neurohormones (angiotensin II, aldosterone, catecholamines and cytokines). These neurohormones contribute to ventricular remodelling.
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CONCEPT MAP
↑ Preload (↑ End-diastolic volume) results in
over time results in
↓ Lumen of coronary arteries ↓ blood flow to myocardium leading to
Stretching of myocardium
causes
causes
Myocardial ischaemia
Sarcomere dysfunction
results in
leads to
↓ Contractility
FIGURE 23.42
The effect of elevated preload on myocardial oxygen supply and demand. Increased preload beyond optimal levels, causes excess myocardial stretching and ischaemia, which may decrease contractility.
Increased resistance to ventricular ejection (afterload) causes Increased workload for the left ventricle
compensates by
causes
causes release of ↑ renin-angiotensin-aldosterone and sympathetic nervous system over time leads to stimulates release
Hypertrophy causes
FIGURE 23.43
The relationship between ventricular end-diastolic volume and stroke during normal contraction and heart failure. The Frank-Starling law of the heart is the relationship between length (end-diastolic volume) and tension (stroke volume) in the heart. In the normal heart, increases in end-diastolic volume cause an increase in stroke volume, thereby increasing cardiac output. In heart failure, decreased contractility leads to reduced cardiac output, as increases in end-diastolic volume do not cause similar increases in stroke volume. Therefore, the curve is shifted downwards over the range of end-diastolic volumes.
Increased myocyte demand for oxygen (relative ischaemia) eventually Ventricular remodelling chronic long-term effect Decreased contractility (↓ cardiac output and underperfusion of vital tissues)
FIGURE 23.44
The role of increased afterload in the pathogenesis of heart failure. Increased afterload causes increased resistance in the aorta and other arteries, and as a result it is more difficult for the left ventricle to eject blood. As a result, the cardiac output from the left side is insufficient, which can lead to impairment of blood flow to the kidneys. In turn, this activates the reninangiotensin-aldosterone system and sympathetic nervous system. Together, these lead to ventricular remodelling which can decrease contractility.
CONCEPT MAP
Increased peripheral vascular resistance
CONCEPT MAP
CHAPTER 23 Alterations of cardiovascular function across the life span
Chamber dilation Wall stress Ventricular dysfunction
Heart rate arrhythmia
Toxic effects
661
Individuals with diastolic dysfunction present with dyspnoea on exertion, fatigue and evidence of pulmonary oedema. There may also be evidence of underlying coronary heart disease, hypertension or valvular disease. Diagnosis is made initially by echocardiography, which demonstrates poor ventricular filling with normal ejection fractions. Management is aimed at improving ventricular relaxation and prolonging diastolic filling times to reduce diastolic pressure.
Neurohormones
Right heart failure Vasoconstriction (afterload)
Renal vasoconstriction (Na+, H2O, preload)
FIGURE 23.45
The vicious cycle of heart failure. Insufficient ventricular function leads to increased vasoconstriction, and decreased renal perfusion leading to fluid retention. Together, these increase the workload of the heart, leading to further ventricular dysfunction. Source: Reproduced with permission from Guidelines for the prevention, detection and management of chronic heart failure in Australia Updated October 2011. © 2011 National Heart Foundation of Australia.
the blood pressure in hypotensive individuals. Diuretics reduce preload and ACE inhibitors, angiotensin receptor blockers and aldosterone blockers reduce both preload and afterload by decreasing aldosterone levels and reducing peripheral resistance. Short-acting intravenous β-blockers also have been found to reduce mortality in selected people. Management of chronic left heart failure also relies on increasing contractility and reducing preload and afterload. The current evidence-based standard of care for individuals in Australia and New Zealand is outlined in Tables 23.12 and 23.13.
Diastolic heart failure
Diastolic heart failure is also known as heart failure with preserved systolic function. Diastolic heart failure can occur in isolation or along with systolic heart failure. Isolated diastolic heart failure is common and may account for up to 40% of all chronic heart failure cases.66 It is defined as pulmonary congestion (see Chapter 25) despite a normal stroke volume and cardiac output. It results from decreased compliance of the left ventricle and abnormal diastolic relaxation such that a normal left ventricular end-diastolic volume results in an increased left ventricular end-diastolic pressure. This pressure is reflected back into the pulmonary circulation and results in pulmonary oedema. The major causes of diastolic dysfunction include hypertension-induced myocardial hypertrophy and myocardial ischaemia with resultant ventricular remodelling.
Right heart failure can result from left heart failure when an increase in left ventricular filling pressure is reflected back into the pulmonary circulation. As pressure in the pulmonary circulation rises, the resistance to right ventricular emptying increases (see Fig. 23.46). The right ventricle is poorly prepared to compensate for the increased afterload and dilates and fails. When this happens, pressure rises in the systemic venous circulation, resulting in peripheral oedema and hepatosplenomegaly (enlarged liver and spleen). Treatment relies on management of the left ventricular dysfunction. When right heart failure occurs in the absence of left heart failure, it is caused most commonly by diffuse hypoxic pulmonary disease such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, cor pulmonale and adult respiratory distress syndrome (ARDS) (see Chapter 25). These disorders result in an increase in right ventricular afterload.
FOCU S ON L EA RN IN G
1 Differentiate between systolic and diastolic heart failure. 2 Outline the process of ventricular remodelling. 3 Describe the vicious cycle of systolic heart failure.
Shock In shock, the cardiovascular system fails to perfuse the tissues adequately, resulting in widespread impairment of cellular metabolism. Because tissue perfusion can be disrupted by any factor that alters heart function, blood volume or blood pressure, shock has many causes and various clinical manifestations. Ultimately, however, a vicious cycle ensues and shock progresses to organ failure and death unless compensatory mechanisms reverse the process or clinical intervention succeeds. Untreated severe shock overwhelms the body’s compensatory mechanisms through positive feedback loops that initiate and maintain a downward physiological spiral. The term multiple organ dysfunction syndrome (MODS) describes the failure of two or more organ systems
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TABLE 23.12 Non-pharmacological management of heart failure GRADE OF RECOMMENDATION*
Regular physical activity is recommended. All patients should be referred to a specifically designed physical activity program, if available
B
Patient support by a doctor and pre-discharge review and/or home visit by a nurse is recommended to prevent clinical deterioration
A
Patients frequently have coexisting sleep apnoea and, if suspected, patients should be referred to a sleep clinician as they may benefit from nasal CPAP
D
Patients who have an acute exacerbation, or are clinically unstable, should undergo a period of bed rest until their condition improves
D
Dietary sodium should be limited to below 2 g/day
C
Fluid intake should generally be limited to 1.5 L/day with mild to moderate symptoms, and 1 L/day in severe cases, especially if there is coexistent hyponatraemia
C
Alcohol intake should preferably be nil, but should not exceed 10–20 g a day (1 or 2 standard drinks)
D
Smoking should be strongly discouraged
D
D Patients should be advised to weigh themselves daily and to consult their doctor if their weight increases by more than 2 kg in a 2-day period, or if they experience dyspnoea, oedema or abdominal bloating Patients should be vaccinated against influenza and pneumococcal disease
B
High-altitude destinations should be avoided. Travel to very humid or hot climates should be undertaken with caution, and fluid status should be carefully monitored
C
Sildenafil and other phosphodiesterase V inhibitors are generally safe in patients with heart failure. However, these medications are contraindicated in patients receiving nitrate therapy, or those who have hypotension, arrhythmias or angina pectoris
C
Obese patients should be advised to lose weight
D
A diet with reduced saturated fat intake and a high fibre intake is encouraged in patients with chronic heart failure
D
No more than 2 cups of caffeinated beverages per day recommended
D
Pregnancy should be avoided in patients with chronic heart failure
D
CPAP = continuous positive airway pressure. *GRADE OF RECOMMENDATION
DESCRIPTION
A
Rich body of high-quality RCT data
B
Limited body of RCT data or high-quality non-RCT data
C
Limited evidence
D
No evidence available — panel consensus judgment
RCT = randomised control trial.
after severe illness and injury and is a frequent complication of severe shock. The disease process is initiated and perpetuated by uncontrolled inflammatory and stress responses. It is progressive and is associated with significant mortality.
Impairment of cellular metabolism
The final common pathway in shock of any type is impairment of cellular metabolism. Fig. 23.47 illustrates the pathophysiology of shock at the cellular level.
Impairment of oxygen use
In all types of shock, the cell either is not receiving an adequate amount of oxygen or is unable to use oxygen. Without oxygen, the cell shifts from aerobic to anaerobic metabolism. Anaerobic metabolism decreases ATP stores and affects the pH of the cell. Without ATP, the cell cannot operate the Na+-K+ pump such that cells of the nervous system and myocardium cannot function properly. The lack of pH control leads to metabolic acidosis. Enzymes necessary for cellular function dissociate under acid conditions.
CHAPTER 23 Alterations of cardiovascular function across the life span
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TABLE 23.13 Pharmacological management of heart failure RECOMMENDATIONS FOR PREVENTING CHF AND TREATING ASYMPTOMATIC LV DYSFUNCTION
GRADE OF RECOMMENDATION*
All patients with asymptomatic systolic LV dysfunction should be treated with an ACEl indefinitely, unless intolerant
A
Anti-hypertensive therapy should be used to present subsequent CHF in patients with elevated blood pressure
A
Preventive treatment with an ACEI may be considered in individual patients at high risk of ventricular dysfunction
B
Beta-blockers should be commenced early after an Ml, whether or not the patient has systolic ventricular dysfunction
B
Statin therapy should be used as part of a risk management strategy to prevent ischaemic events and subsequent CHF in patients who fulfil criteria for lipid-lowering
B
RECOMMENDATIONS FOR PHARMACOLOGICAL TREATMENT OF SYMPTOMATIC CHF
GRADE OF RECOMMENDATION*
First-line agents ACEIs. unless not tolerated or contraindicated, are recommended for all patients with systolic heart failure (LVEF < 40%), whether symptoms are mild, moderate or severe
A
Every effort should be made to increase doses of ACEIs to those shown to be of benefit in major trials. If this is not possible, a lower dose of ACEI is preferable to none at all
B
Diuretics should be used, if necessary, to achieve euvolaemia in fluid-overloaded patients. In patients with systolic LV dysfunction, diuretics should never be used as monotherapy, but should always be combined with an ACEl to maintain euvolaemia
D
Beta-blockers are recommended, unless not tolerated or contraindicated, for all patients with systolic CHF who remain mildly to moderately symptomatic despite appropriate doses of an ACEI
A
Beta-blockers are also indicated for patients with symptoms of advanced CHF
B
Aldosterone receptor blockade with spironolactone is recommended for patients who remain severely symptomatic, despite appropriate doses of ACEIs and diuretics
B
Aldosterone blockade with eplerenone should be considered in systolic heart failure patients who still have mild (NYHA Class II) symptoms despite receiving standard therapies (ACEl, beta- blocker)
B
Angiotensin II receptor antagonists may be used as an alternative in patients who do not tolerate ACEIs due to kinin-mediated adverse effects (e.g. cough). They should also be considered for reducing morbidity and mortality in patients with systolic CHF who remain symptomatic despite receiving ACEIs
A
Direct sinus node inhibition with ivabradine should be considered for CHF patients with impaired systolic function and a recent heart failure hospitalisation who are in sinus rhythm where their heart rate remains ≥ 70 bpm despite efforts to maximise dosage of background beta-blockade
B
Second-line agents Digoxin may be considered for symptom relief and to reduce hospitalisation in patients with advanced CHF. It remains a valuable therapy in CHF patients with AF
B
Hydralazine-isosorbide dinitrate combination should be reserved for patients who are truly intolerant of ACEIs and angiotensin II receptor antagonists, or for whom these agents are contraindicated and no other therapeutic option exists
B
Fish oil (n-3 polyunsaturated fatty acids) should be considered as a second-line agent for patients with CHF who remain symptomatic despite standard therapy which should include ACEIs or ARBs and betablockers if tolerated
B
Other agents Amlodipine and felodipine can be used to treat comorbidities such as hypertension and CHD in patients with systolic CHF. They have been shown to neither increase nor decrease mortality
B
Iron deficiency should be looked for and treated in CHF patients to improve symptoms, exercise tolerance and quality of life
B
*Refer to Table 23.12 for description of grades of recommendation. Source: Reproduced with permission from Guidelines for the prevention, detection and management of chronic heart failure in Australia Updated October 2011. © 2011 National Heart Foundation of Australia.
CONCEPT MAP
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over time causes
Lung disease
impacts on
Impairment of glucose use ↓ Oxygen supply
↑ Pulmonary vascular resistance need to overcome by ↑ Force of RV contraction causes ↑ RV oxygen demand
further aggravates
causes
Right ventricle hypoxia resulting in
↓ Force of RV contraction leads to ↑ RV end-diastolic pressure causes
cells, the lysosomal enzymes that leak from the cells extend the areas of impaired metabolism and cellular injury.
causes ↑ RV preload and ↑ RA preload results in Peripheral oedema
FIGURE 23.46
Right-sided heart failure. Lung disease is a main cause of right-sided heart failure, as it increases the work required by the right side of the heart to eject blood into the dysfunctional lungs. The lung disease alters the blood pressure in the pulmonary circuit, increasing the workload for the right side of the heart. RA = right atrial; RV = right ventricular.
Enzyme dissociation stops cell function, repair and division. As lactic acid is released systemically, blood pH drops, reducing the oxygen-carrying capacity of the blood. Therefore, less oxygen is delivered to the cells. Further acidosis triggers the release of more lysosomal enzymes because the low pH disrupts lysosomal membrane integrity — and the vicious cycle continues. Three positive feedback loops further impair oxygen use: (1) activation of the coagulation cascade; (2) decreased circulatory volume; and (3) toxin (lysosomal enzyme) release. The coagulation cascade activates the inflammatory response and causes clotting in the peripheral venous circulation leading to a decrease in venous return. Decreased blood volume causes the second positive feedback loop and magnifies decreased tissue perfusion in all types of shock. Toxin release, the third positive feedback loop, not only injures the cell that released it but also injures adjacent cells. By damaging the mechanisms of the surrounding
Impaired glucose use can be caused by either impaired glucose delivery or impaired glucose uptake by the cells. Cells shift to alternative processes (namely glycogenolysis, gluconeogenesis and lipolysis) to generate fuel for survival. The energy costs of glycogenolysis and lipolysis are considerable and contribute to cellular failure. When gluconeogenesis causes proteins to be used for fuel, these proteins are no longer available to maintain cellular structure, function, repair and replication. As proteins are broken down, ammonia and urea are produced. Ammonia is toxic to living cells. Uraemia (high urea levels) develops and uric acid further disrupts cellular metabolism. Serum albumin and other plasma proteins are consumed for fuel first. Serum protein consumption decreases capillary osmotic pressure and contributes to the development of interstitial oedema, creating another positive feedback loop that decreases circulatory volume. A final outcome of impaired cellular metabolism is the build-up of metabolic end products in the cell and interstitial spaces. Waste products are toxic to the cells and further disrupt cellular function and membrane integrity. Once a sufficiently large number of cells from vital organs have damage to their cellular membranes, leakage of lysosomal enzymes and ATP depletion, shock can be irreversible.
Types of shock
There are several different types of shock: cardiogenic, hypovolaemic, neurogenic, anaphylatic and septic shock. Cardiogenic shock is defined clinically by ‘myocardial dysfunction and tissue hypoxia in the presence of adequate intravascular volume’ and most cases follow acute myocardial infarction. Hypovolaemic shock is caused by a large loss of fluid volume, whether it be blood, plasma or interstitial fluid. Neurogenic or vasogenic shock is the result of vasodilation that results from parasympathetic overstimulation and sympathetic understimulation. Anaphylatic shock results as an allergic reaction to an allergen and leads to similar physical alterations as neurogenic shock. Septic shock is part of the systemic inflammatory response syndrome (SIRS). It begins with an infection that progresses to bacteraemia, then sepsis, severe sepsis and septic shock. All shocks may lead to multiple organ dysfunction syndrome (MODS). Table 23.14 summarises the key components of the different types of shock.
Cardiogenic shock
Cardiogenic shock is defined as ‘decreased cardiac output and evidence of tissue hypoxia in the presence of adequate intravascular volume’. Most cases of cardiogenic shock follow acute myocardial infarction, because the myocardium is damaged and therefore contractions are inadequate. Cardiogenic shock is often unresponsive to treatment, with a mortality of more than 70% reported. The pathophysiology
CHAPTER 23 Alterations of cardiovascular function across the life span
665
causes ↓ Tissue perfusion
leads to
Impaired oxygen use leads to
results in
↓ Oxygen affinity for haemoglobin
Anaerobic metabolism leads to ↓ ATP
pump
Lactate
leads to
shifts ↓ Circulatory volume
causes
further precipitates
Inflammatory response
↑ Gluconeogenesis
Serum triglycerides, free fatty acids
↓ Serum albumin ↑ Serum alanine
causes
stimulates ↑ Clotting cascade
↑ Lipolysis leads to
further aggravates
Cellular oedema
all stimulate
↑ Pyruvate
causes
leads to
leads to ↑ Intracellular Na+and water
leads to
increases
Metabolic acidosis
Adrenaline, noradrenaline, cortisol, growth hormone
↑ Serum glucose
causes
evidenced by
decreases ability of + Na , K+
Impaired glucose use
↑ Glycogenolysis
CONCEPT MAP
Impaired cellular metabolism
results in ↓ Energy stores
↑ Serum branched chain amino acids ↑ Urea, ammonia formation and synthesis
Release of lysosomal enzymes
FIGURE 23.47
Impaired cellular metabolism in shock. Significant alterations in oxygen and glucose usage lead to severely dysfunctional cell metabolism.
of cardiogenic shock is outlined as a concept map in Fig. 23.48. The clinical manifestations of cardiogenic shock are caused by widespread impairment of cellular metabolism. They include impaired mentation, elevated preload in the systemic and pulmonary vasculature, systemic and pulmonary oedema, dusky skin colour, hypotension, oliguria (low urine output) and dyspnoea. Management of cardiogenic shock includes careful fluid and catecholamine administration.
Hypovolaemic shock
Hypovolaemic shock is caused by loss of fluid volume: either whole blood (haemorrhage), plasma (burns) or interstitial fluid (diaphoresis, diabetes mellitus, emesis, diarrhoea or diuresis) in large amounts. Hypovolaemic
shock begins to develop when intravascular volume has decreased by about 15% (see Fig. 23.49). Hypovolaemia is offset initially by compensatory mechanisms (see Fig. 23.50). Heart rate and peripheral vascular resistance increase, boosting both cardiac output and tissue perfusion pressures. Interstitial fluid moves into the vascular compartment. The liver and spleen add to blood volume by releasing stored red blood cells and plasma. In the kidneys, renin stimulates aldosterone release and the retention of sodium (and hence water), and antidiuretic hormone from the posterior pituitary gland also increases water retention. However, if the initial fluid or blood loss is great or if loss continues, compensation fails, resulting in decreased tissue perfusion. As in cardiogenic shock, oxygen and nutrient delivery to the cells is impaired and cellular metabolism fails. Anaerobic metabolism and lactate
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TABLE 23.14 Types of shock TYPE
CAUSE
Hypovolaemic Loss of fluid volume shock
PHYSIOLOGICAL ADAPTATIONS
Heart rate ↑, peripheral resistance ↑, cardiac output ↑, tissue perfusion ↑ (initially), water retention ↑ (initially)
Failed compensation and ↓ tissue perfusion, poor skin turgor, thirst, oliguria, low preload, tachycardia, thready pulse, ↓ mental status
Cardiogenic shock
Myocardial dysfunction, tissue Heart rate ↑, preload ↑, stroke hypoxia volume ↑, systemic and pulmonary oedema ↑
↓ mental status, dusky skin colour, hypotension, oliguria, dyspnoea
Neurogenic shock
Trauma to spinal cord or medulla, Interrupted supply of oxygen or glucose to the medulla, depressive drugs, anaesthetic agents, severe emotional stress and pain
Interrupted sympathetic activity, relative hypovolaemia to vasodilation, peripheral vascular resistance ↓, tissue hypoperfusion
Bradycardia
Anaphylatic shock
Anaphylaxis
Vasodilation, peripheral pooling, hypovolaemia, tissue hypoperfusion
Sudden and progression to death within mins, anxiety, difficulty breathing, gastrointestinal cramps, oedema, hives, burning and itching of skin, ↓ blood pressure, ↓ mental status
Septic shock
Microorganism
Activated complement system and coagulation cascade, activated kinins, activated inflammatory response, widespread vasodilation, cardiac output ↑, myocardial contractility ↓, hypoperfusion, low peripheral vascular resistance, systemic oedema
Tachycardia, systemic inflammatory response syndrome (SIRS), low arterial pressure, temperature instability, deranged renal function, gastrointestinal mucosa changes that allow gut bacteria into the blood stream, jaundice, clotting abnormalities, deterioration of mental status, adult respiratory distress syndrome
production result in lactic acidosis and serum and cellular electrolyte abnormalities. The clinical manifestations of hypovolaemic shock include poor skin turgor, thirst, oliguria, low preload, tachycardia, thready pulse, high peripheral vascular resistance and deterioration of mental status. The differences between the signs and symptoms of hypovolaemic shock and those of cardiogenic shock are mainly caused by differences in fluid volume and cardiac muscle health. Management begins with rapid fluid replacement with crystalloids and blood products. If adequate tissue perfusion cannot be restored promptly, systemic inflammation and multiple organ dysfunction are likely.
Neurogenic shock
Neurogenic shock (sometimes called vasogenic shock) is the result of widespread and massive vasodilation that results from parasympathetic overstimulation and sympathetic understimulation (see Fig. 23.51). This type of shock can be caused by any factor that stimulates parasympathetic stimulation or inhibits sympathetic stimulation of vascular smooth muscle. Trauma to the spinal cord or medulla and conditions that interrupt the supply of oxygen or glucose to the medulla can cause neurogenic shock by interrupting sympathetic activity. Depressive drugs, anaesthetic agents and severe emotional stress and pain are other causes. The
loss of vascular tone results in ‘relative hypovolaemia’. Blood volume has not changed, but because of widespread vasodilation, the amount of space containing the blood has increased, so that peripheral vascular resistance decreases drastically, meaning that pressure in the vessels is inadequate to drive nutrients across the capillary membranes to the cells. In addition, bradycardia can occur with a decrease in cardiac output, which further contributes to hypotension and tissue hypoperfusion. As with other types of shock, this leads to impaired cellular metabolism. Management includes the careful use of fluids and vasopressors until blood pressure stabilises.
Anaphylactic shock
Anaphylactic shock results from a widespread hypersensitivity reaction known as anaphylaxis. The basic physiological alteration is the same as that of neurogenic shock: vasodilation, peripheral pooling and relative hypovolaemia, leading to decreased tissue perfusion and impaired cellular metabolism (see Fig. 23.52). Anaphylactic shock is often more severe than other types of shock because the hypersensitivity reaction that triggers vasodilation has other pathophysiological effects that rapidly involve the entire body. Anaphylactic shock begins as an allergic reaction to an allergen. Common allergens known to cause reactions are
CHAPTER 23 Alterations of cardiovascular function across the life span
Compensatory renin- shifts aldosterone, antidiuretic hormone Systemic and pulmonary oedema
↓ Cardiac output
Adequate or ↑ blood volume
increases effects
causes
Catecholamine (adrenaline and noradrenaline) compensatory release
leads to
↑ Preload, stroke volume and heart rate
leads to Dyspnoea
↑ SVR
stimulates release of
increases directly
causes Myocardial oxygen requirements
CONCEPT MAP
stimulates release of
667
results in Blood pressure
lowers
↓ Cardiac output, ↓ ejection fraction leads to
causes
↓ Tissue perfusion ends with Impaired cellular metabolism FIGURE 23.48
Cardiac output and arterial pressure (percentage of normal)
Cardiogenic shock. Shock becomes life threatening when compensatory mechanisms (in blue) cause increased myocardial oxygen requirements. Renal and hypothalamic adaptive responses (i.e. renin-angiotensin-aldosterone and antidiuretic hormone) maintain or increase blood volume. The adrenal gland releases catecholamines (e.g. mostly adrenaline, some noradrenaline), causing vasoconstriction and increases in contractility and heart rate. These adaptive mechanisms, however, increase myocardial demands for oxygen and nutrients. These demands further strain the heart, which can no longer pump an adequate volume, resulting in shock and impaired metabolism. SVR = systemic vascular resistance.
Arterial pressure
100
50
0
Cardiac output
0
10 20 30 40 50 Percentage of total blood removed
FIGURE 23.49
The effects of haemorrhage on cardiac output and arterial pressure. Controlled bleeding over 30 minutes demonstrates the changes in arterial pressure and cardiac output, which compensate until about 15% of blood is lost.
insect venoms, shellfish, peanuts, latex and medications such as penicillin. In genetically predisposed individuals, allergens initiate a vigorous humoral immune response (type I hypersensitivity), which results in the production of large quantities of immunoglobulin E (IgE) antibody (refer to Chapter 15). Mast cells degranulate and release a large number of vasoactive and inflammatory cytokines. This provokes an extensive immune and inflammatory response, including vasodilation and increased vascular permeability, resulting in peripheral pooling and tissue oedema. Respiratory difficulty occurs due to constriction of the smooth muscle layers in airway walls. The onset of anaphylactic shock is usually sudden and progression to death can occur within minutes unless emergency treatment is given. The first manifestations may be anxiety, difficulty breathing, gastrointestinal cramps, oedema, hives (urticaria) and sensations of burning or itching of the skin. A precipitous fall in blood pressure occurs, followed by impaired mentation. Treatment begins
CONCEPT MAP
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Part 4 Alterations to body maintenance
Decreased intravascular volume leads to ↓ Preload leads to ↓ Cardiac output temporarily moves
Shift of interstitial fluid
↑ Heart rate, contractility
Catecholamine (adrenaline and noradrenaline) release
which all stimulates
leads to
Aldosterone, antidiuretic hormone Splenic discharge
increasing
↑ Volume
causes
Systemic vascular resistance
which adds ↑ Cardiac output but causes an increase Volume loss causes ↓ Cardiac output
↓ Systemic and pulmonary pressures
causes
results in
↓ Tissue perfusion ends with Impaired cellular metabolism FIGURE 23.50
Hypovolaemic shock. This type of shock becomes life threatening when compensatory mechanisms (in purple) are overwhelmed by continued loss of intravascular volume.
with removal of the antigen (if possible). Adrenaline is administered intramuscularly to cause vasoconstriction and reverse airway constriction. Fluids are given intravenously to reverse the relative hypovolaemia, and antihistamines and corticosteroids are given to stop the inflammatory reaction FOCUS O N LE ARNIN G
1 Describe the impaired mechanisms in shock. 2 Explain why myocardial infarction often causes cardiogenic shock. 3 Discuss how hypovolaemic shock is manifest. 4 Outline why anaphylactic shock is a medical emergency.
Septic shock
Septic shock is one component of a continuum of progressive dysfunctions called the systemic inflammatory response syndrome (SIRS). The syndrome begins with an infection that progresses to bacteraemia, then sepsis, severe sepsis, septic shock and finally multiple organ dysfunction syndrome. Septic shock, a common cause of death of individuals in intensive care units, has a high mortality rate and can be caused by any class of microorganism. While it is mainly caused by bacteria, fungi and viruses (see Box 23.3), in almost one-third of cases the infectious organism is never identified. Most septic shock begins when bacteria enter the bloodstream to produce bacteraemia. These bacteria may directly stimulate an inflammatory response or they may
CHAPTER 23 Alterations of cardiovascular function across the life span
CONCEPT MAP
↓ Sympathetic and/or ↑ parasympathetic stimulation causes ↓ Vascular tone leads to Massive vasodilation results in ↓ Systemic vascular resistance results in Inadequate cardiac output results in ↓ Tissue perfusion ends with Impaired cellular metabolism FIGURE 23.51
Neurogenic shock. Insufficient sympathetic (or increased parasympathetic) function can lead to severe vasodilation, leading to impaired cardiac output.
release toxic substances into the bloodstream. Gram-negative microorganisms release endotoxins and gram-positive microorganisms release exotoxins (see Chapter 14). These substances trigger the septic syndrome by interacting with macrophages and activate the complement system, the coagulation cascade, kinins and inflammatory cells (see Fig. 23.53). The release of inflammatory mediators triggers intense cellular responses and the subsequent release of secondary mediators, including cytokines, prostaglandins, platelet-activating factor, oxygen-free radicals, nitric oxide and proteolytic enzymes. Chemotaxis, activation of granulocytes and reactivation of the phagocytic cells and inflammatory cascades result. This systemic inflammation, especially through the action of nitric oxide, leads to widespread vasodilation with compensatory tachycardia and increased cardiac output in the early stages of septic shock. As the disease progresses, inflammatory mediators, such as complement and interleukins, depress myocardial contractility such that cardiac output falls and tissue perfusion decreases. Tissue perfusion and cellular oxygen extraction are also affected by activation of the coagulation cascade through the action of platelet-activating factor and depletion of the endogenous anticoagulant protein C.
669
Risk factors for inflammatory and antiinflammatory mediators contributing to septic shock
BOX 23.3
Interleukins • Released by macrophages and lymphocytes in septic shock in response to bacterial toxins • Net effect: produce fever, vasodilation and hypotension, oedema and elevated white blood count Tumour necrosis factor • Produced from macrophages, natural killer cells and mast cells in response to endotoxin and interleukins • Net effect: generates same symptoms of septic shock that interleukins do Platelet-activating factor • Released from mononuclear phagocytes, platelets and some endothelial cells in response to endotoxin • Net effect: generates symptoms of shock, as do interleukins and tumour necrosis factor, but may also initiate multiple organ failure Myocardial depressant factor • Secreted from white blood cells in response to endotoxin • Net effect: produces myocardial depression and ventricular dilation
The inflammatory response can become overwhelming, leading to the systemic inflammatory response syndrome, which can progress to widespread tissue hypoxia and necrosis, leading to the multiple organ dysfunction syndrome. It has been determined that there is a parallel release of anti-inflammatory mediators and a depression in the immune response that accompanies the systemic inflammatory response syndrome, which contributes to the overall shock syndrome. Clinical manifestations of septic shock are low arterial pressure, low peripheral vascular resistance from vasodilation, systemic oedema and an alteration in oxygen extraction by all cells. Tachycardia causes cardiac output to remain normal or become elevated, although myocardial contractility is reduced. Temperature instability is present, ranging from hyperthermia to hypothermia. Effects on other organ systems may result in deranged renal function, gastrointestinal mucosa changes that lead to the release of bacteria from the gut into the bloodstream, jaundice, clotting abnormalities, deterioration of mental status and adult respiratory distress syndrome. Treatment includes multiple drug antibacterial therapy, removal of the source of infection if one is found, fluid resuscitation and inotropic drugs to improve haemodynamic parameters. Many experimental treatments are under study; however, because the septic syndrome is incompletely understood, recommended treatment continues to evolve.
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CONCEPT MAP
Antigen (allergen) Antibody (IgE)
large quantities trigger Complement, histamine, kinins, prostaglandins
results in
results in
↑ Capillary permeability
Peripheral vasodilation
causes
leads to
Extravasation of intravascular fluids evidenced by Oedema
leads to
Constriction of extravascular smooth muscle (bronchoconstriction, laryngospasm, gastrointestinal cramps)
↓ Systemic vascular resistance
causes
causes
Relative hypovolaemia leads to ↓ Preload leads to ↓ Cardiac output results in ↓ Tissue perfusion ends with Impaired cellular metabolism
FIGURE 23.52
Anaphylactic shock. Exposure to the allergen causes an inflammatory response leading to increased capillary permeability and decreased blood pressure, which can cause severe decline in cardiac output. In addition, there is also constriction of airways. IgE = immunoglobulin E.
CLINICAL MANIFESTATIONS OF SHOCK
The clinical manifestations of shock are variable depending on the type of shock, and observable and measurable signs and symptoms are often conflicting in nature. Subjective complaints in shock are usually nonspecific. The individual may report feeling sick, weak, cold, hot, nauseated, dizzy, confused, afraid, thirsty and short of breath. Hypotension, characterised by a mean arterial pressure below 60 mmHg, is common to almost all shock states; however, it is a late sign of decreased tissue perfusion. Cardiac output and urinary output are usually variable early in shock states but generally become decreased as the shock syndrome progresses. Moreover, the feedback loops of intravascular
clotting, decreased venous return and toxin release all contribute to a deterioration of cardiac output (see Fig. 23.54). TREATMENT FOR SHOCK
The first treatment for shock is to discover and correct the underlying cause. General supportive treatment includes intravenous fluid administered to expand intravascular volume, inotrope drugs and supplemental oxygen. Further treatment depends on the cause and severity of the shock syndrome. Once positive feedback loops are established, intervention in shock is difficult. Prevention and very early treatment offer the best prognosis.
CHAPTER 23 Alterations of cardiovascular function across the life span
CONCEPT MAP
Bacteraemia
identified as
identified as
Gram-negative organism
Gram-positive organism
release
release
Endotoxins
Exotoxins Act as triggering molecules activation of
Complement system
Kinin system
Coagulation cascade
Neutrophil, endothelial and monocyte-macrophage cell activity
all contribute to Release of central endogenous mediators which are Tumour necrosis factor-alpha (TNF-α); interleukin-1 (IL-1) Release of proinflammatory cytokines causes Endothelial cell damage leads to (with sufficient bacteraemia)
Hypotension
Decreased systemic vascular resistance
Depressed myocardial function
Lactic acidosis
Leucopenia
Thrombocytopenia
Vascular leakage
Pulmonary congestion
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Tissue necrosis
(eventually cause)
Organ dysfunction
FIGURE 23.53
Septic shock. Bacteraemia can lead to a substantial inflammatory response, which causes widespread endothelial cell damage. This can lead to serious consequences resulting in organ dysfunction.
Part 4 Alterations to body maintenance
Hypovolaemic shock
Cardiogenic shock
results in
results in Myocardial pump failure
↓ Intravascular volume
Neurogenic shock
Anaphylactic shock
results in ↓ Vascular tone
results in ↑ Vasodilation + vascular permeability
↓ Cardiac output
results in
Septic shock results in Systemic pathogenic infection
results in
causes ↓ Arterial pressure causes ↓Systemic blood flow leads to
leads to Intravascular clotting
Hypoperfusion of tissues leads to Hypoperfusion of brain
↓ Nutrition to vasculature causes ↑ Capillary permeability causes
↓ Venous return
↓ Vasomotor control
causes Toxin release
causes Vasodilation (widespread)
↓ Blood volume results in
Tissue ischaemia
causes causes
CONCEPT MAP
672
results in
causes ↓ Myocardial contractility
contributes to
results in Venous pooling of blood results in contributes to
FIGURE 23.54
The progression of shock when positive feedback loops lead to further reductions in cardiac output. The severe decline in cardiac output leads to massive vasodilation, decreased blood volume (due to increased capillary permeability), and organ ischaemia. These cause further decline in cardiac output. Blue-coloured boxes represent feedback responses.
CHAPTER 23 Alterations of cardiovascular function across the life span
Multiple organ dysfunction syndrome
Multiple organ dysfunction syndrome is the progressive dysfunction of two or more organ systems resulting from
an uncontrolled inflammatory response to a severe illness or injury. The organ dysfunction can progress to organ failure and death (see Fig. 23.55). Although sepsis and septic shock are the most common causes, any severe injury or disease process that activates a massive systemic inflammatory
CONCEPT MAP
Injury Sepsis Disease leads to Endothelial damage Neuroendocrine response Release of inflammatory mediators causes Activation of complement, coagulation and kallikrein/kinin systems initiating ↑ Vasodilation Capillary permeability causes Massive, systemic Selective vasoconstriction immune/inflammatory Microvascular thrombi response
Hypermetabolism
results in Maldistribution of systemic and organ blood flow leads to Tissue hypoperfusion
results in
leads to
lack of output causes ↓ Cardiac function
O2 supply/demand imbalance
leads to
leads to Supply-dependent O2 consumption causes
causes
Tissue hypoxia contributes to
Myocardial depression
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Acidosis Impaired cellular function
↑ O2 and fuel demand over time will cause Exhaustion of fuel supply eventually causes Metabolic failure
leads to Organ dysfunction ends with Multiple organ dysfunction syndrome FIGURE 23.55
The pathogenesis of multiple organ dysfunction syndrome. The initial injury leads to a severe inflammatory response. This results in severe decline in organ perfusion yet increased oxygen demand. As a result, the tissues become hypoxic, leading to widespread organ dysfunction.
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response in the host can initiate the multiple organ dysfunction syndrome (see Box 23.4). Clinical infection is not necessary for its development. Other common triggers are severe trauma, burns, acute pancreatitis, major surgery, circulatory shock, adult respiratory distress syndrome and necrotic tissue. Multiple organ dysfunction syndrome is a relatively new diagnosis, first recognised as a distinct clinical syndrome in the mid-1970s. Today, it is the most common cause of mortality in intensive care units. Mortality for individuals with this syndrome is between 50% and 90% and it approaches 100% if there is failure of three or more organs.68 Moreover, mortality has not improved since the 1980s. People at greatest risk for developing the syndrome are the elderly and those with significant tissue injury or pre-existing disease (see the box ‘Risk factors for the development of multiple organ dysfunction syndrome’). PATHOPHYSIOLOGY
As a result of the initiating insult (sepsis, injury or disease), the neuroendocrine system is activated with the release of
Risk factors for the development of multiple organ dysfunction syndrome
BOX 23.4
Age > 65 years Baseline organ dysfunction (e.g. renal insufficiency) Bowel infarction Coma on admission Immunosuppression (e.g. corticosteroids) Inadequate, delayed resuscitation Malnutrition Multiple blood transfusions (> 6 units/12 hours) Persistent infectious focus Pre-existing chronic disease (e.g. cancer, diabetes mellitus) • Significant tissue injury • • • • • • • • • •
the stress hormones cortisol, adrenaline and noradrenaline into the bloodstream. The sympathetic nervous system is stimulated to compensate for complications resulting from the injury, such as fluid loss and hypotension. Vascular endothelial damage occurs as a direct result of injury or from damage by bacterial toxins and inflammatory mediators released into the circulation. The vascular endothelium becomes permeable, allowing fluid and protein to leak into the interstitial spaces, contributing to hypotension and hypoperfusion. When the endothelium is damaged, platelets and tissue thromboplastin are activated, resulting in systemic microvascular coagulation. A massive systemic immune/inflammatory response then develops involving neutrophils, macrophages and mast cells (see Table 23.15). The pathways by which neutrophils and macrophages are activated vary and involve multiple events rather than individual triggers. The numerous inflammatory and clotting processes operating in the multiple organ dysfunction syndrome cause maldistribution of blood flow and hypermetabolism. Oxygen delivery to the tissues decreases despite the increased systemic blood flow. Hypermetabolism with accompanying alterations in carbohydrate, fat and lipid metabolism is initially a compensatory measure to meet the body’s increased demands for energy. The alterations in metabolism affect all aspects of fuel utilisation. The net result of hypermetabolism is depletion of oxygen and fuel supplies. Decreased oxygen delivery to the cells caused by the maldistribution of blood flow, coagulation, myocardial depression and the hypermetabolic state combine to create an imbalance in oxygen supply and demand. Tissue hypoxia ensues with cellular acidosis and impaired cellular function and results in the multiple organ failure. CLINICAL MANIFESTATIONS
There is often a predictable clinical pattern in the development of multiple organ dysfunction syndrome.69 After the initial event and aggressive resuscitation for approximately 24 hours, the individual develops a low-grade fever, tachycardia, dyspnoea, altered mental status and hyperdynamic and hypermetabolic states. The lung is often
TABLE 23.15 Cells of inflammation and multiple organ dysfunction CELL
ACTIVATORS
CONTRIBUTION TO MULTIPLE ORGAN DYSFUNCTION
Neutrophils
Complement, kinins, endotoxin, clotting factors
Release of phagocytic products: toxic oxygen-free radicals, superoxide ion, hydrogen peroxide, hydroxyl radicals, proteases, platelet-activating factor, arachidonic acid metabolites (prostaglandins, thromboxane, leukotrienes) Endothelial damage, vasodilation, vasopermeability, microvascular coagulation, selective vasoconstriction, hypotension, shock
Macrophages
Complement, endotoxin, chemotactic factors
Release of same phagocytic products as neutrophils Release of monokines: tumour necrosis factor, interleukin-1 Tumour necrosis factor produces fever, anorexia, hyperglycaemia, weight loss
Mast cells
Direct injury, endotoxin, complement
Release of histamine, platelet-activating factor, arachidonic acid metabolites Vasodilation, vasopermeability, hypotension, shock
CHAPTER 23 Alterations of cardiovascular function across the life span
the first organ to fail, resulting in acute respiratory distress syndrome. Between 7 and 10 days, the hypermetabolic and hyperdynamic states intensify, bacteraemia is common, and signs of liver and kidney failure appear. During days 14 to 24, renal and liver failure becomes more severe and the gastrointestinal system shows evidence of dysfunction. Haematological failure and myocardial failure are usually later manifestations. Death may occur as early as 14 days or after a period of several weeks. The clinical manifestations of individual organ failure within this syndrome are the result of inflammation and tissue hypoxia. Respiratory failure is characterised by tachypnoea, pulmonary oedema, use of accessory muscles and hypoxaemia. Liver failure, although developing early, is not clinically detectable until later stages of the syndrome, at which time jaundice, abdominal distension, liver tenderness, muscle wasting and hepatic encephalopathy appear. Progressive oliguria and oedema mark the development of renal failure. Anuria (no urine), hyperkalaemia and metabolic acidosis may occur if renal shutdown is severe. The gastrointestinal system is sensitive to ischaemic and inflammatory injury; clinical manifestations of bowel involvement are haemorrhage, ileus (impaired gut motility), malabsorption, diarrhoea or constipation, vomiting, anorexia and abdominal pain. The signs and symptoms of cardiac failure in the hypermetabolic, hyperdynamic phase of the syndrome are similar to those of septic shock: tachycardia, bounding pulse, increased cardiac output, decreased peripheral vascular resistance and hypotension. In the terminal stages, hypodynamic circulation with bradycardia, profound hypotension and ventricular arrhythmias may develop.
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Ischaemia and inflammation are responsible for the central nervous system manifestations, which include apprehension, confusion, disorientation, restlessness, agitation, headache, decreased cognitive ability and memory, and decreased level of consciousness. When ischaemia is severe, seizures and coma can occur. EVALUATION AND TREATMENT
Because presently there is no specific therapy for multiple organ dysfunction syndrome, early detection is extremely important so that supportive measures can be initiated immediately. Frequent assessment of the clinical status of individuals at known risk is essential. Once organ failure develops, monitoring of laboratory values and haemodynamic parameters can also be used to assess the degree of impairment. Therapeutic management consists of prevention and support. FOCU S ON L EA RN IN G
1 Discuss important causes of septic shock. 2 Describe how systemic inflammatory response syndrome arises. 3 Explain why correction of the underlying problem is important for all kinds of shock. 4 Describe why inflammation and clotting are triggered when the vascular endothelium is injured. 5 Describe the mechanisms that result in decreased oxygen delivery to the tissues in multiple organ dysfunction syndrome.
chapter SUMMARY Alterations of blood flow and pressure • Hypertension is the elevation of systemic arterial blood pressure resulting from increases in cardiac output or total peripheral resistance, or both. • Hypertension can be primary, without a known cause, or secondary, caused by an underlying disease. • The risk factors for hypertension include a family history; being male; advancing age; obesity; high sodium intake; diabetes mellitus; cigarette smoking; and heavy alcohol consumption. • The exact cause of primary hypertension is unknown, although several hypotheses have been proposed, including overactivity of the sympathetic nervous system; overactivity of the renin-angiotensin-aldosterone system; sodium and water retention by the kidneys;
•
• • •
hormonal inhibition of sodium–potassium transport across cell walls; and complex interactions involving insulin resistance, inflammation and endothelial function. Clinical manifestations of hypertension result from damage of organs and tissues outside the vascular system. These include heart disease, renal disease, central nervous system problems and musculoskeletal dysfunction. Hypertension is managed with both pharmacological and non-pharmacological methods. Systemic hypertension in children differs from adults in aetiology and presentation. Orthostatic hypotension is a drop in blood pressure that occurs on standing. The compensatory vasoconstriction
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•
•
•
• • •
•
•
• • • •
•
•
Part 4 Alterations to body maintenance
response to standing is replaced by a marked vasodilation and blood pooling in the muscle vasculature. Orthostatic hypotension may be acute or chronic. The acute form is caused by a delay in the normal regulatory mechanisms. The chronic forms are secondary to a specific disease or are idiopathic in nature. The clinical manifestations of orthostatic hypotension include fainting and may involve cardiovascular symptoms, as well as impotence and bowel and bladder dysfunction. Arteriosclerosis is a thickening and hardening of the arteries, involving the intimal layer and leading to hypertension. It seems to be a part of the normal ageing process, but it is a disease state when it occurs to the point of symptom development. Arteriosclerosis raises the systolic pressure by decreasing arterial distensibility and lumen diameter. Atherosclerosis is a form of arteriosclerosis and is the leading contributor to coronary heart disease and cerebrovascular disease. Atherosclerosis is an inflammatory disease that begins with endothelial injury (smoking, hypertension, diabetes mellitus (insulin resistance), dyslipidaemia) and progresses through several stages to become a fibrotic plaque. Once a plaque has formed, it can rupture, resulting in clot formation and instability and vasoconstriction, leading to obstruction of the lumen and inadequate oxygen delivery to tissues. Coronary heart disease is almost always the result of atherosclerosis that gradually narrows the coronary arteries or that ruptures and causes sudden thrombus formation and myocardial ischaemia and even infarction. Many risk factors contribute to the onset and escalation of coronary heart disease, including dyslipidaemia, smoking, hypertension, diabetes mellitus (insulin resistance), advancing age, obesity, sedentary lifestyle, psychosocial factors and heavy consumption of alcohol. The three risk factors most predictive of coronary heart disease are hypercholesterolaemia, cigarette smoking and hypertension. Coronary heart disease is most commonly the result of atherosclerosis to the coronary arteries and the resultant decrease in myocardial blood supply. Angina pectoris is chest pain caused by myocardial ischaemia. Therapeutic interventions for coronary heart disease include the use of vasodilators and medications to reduce cardiac workload (e.g. β-blockers), as well as surgical procedures. Atherosclerotic plaque progression can be gradual, but sudden coronary obstruction due to thrombus formation causes the acute coronary syndromes. These include unstable angina and myocardial infarction. Unstable angina results in reversible myocardial ischaemia.
• Myocardial infarction is caused by prolonged, unrelieved ischaemia that interrupts blood supply to the myocardium. After about 20 minutes of myocardial ischaemia, irreversible hypoxic injury causes cellular death and tissue necrosis. • Myocardial infarction is clinically classified as non-ST elevation myocardial infarction (non-STEMI) and ST elevation myocardial infarction (STEMI), based on ECG findings that suggest the extent of the myocardial damage (subendocardial versus transmural). • An increase in plasma enzyme levels is used to diagnose the occurrence of myocardial infarction and indicate its severity. Elevations of the creatine kinase-myocardial band (CK-MB), troponins and lactic dehydrogenase (LDH) are most predictive of a myocardial infarction. • Treatment of a myocardial infarction includes revascularisation (thrombolytics or percutaneous coronary intervention), antithrombotics, ACE inhibitors and β-blockers. Pain relief and fluid management are also key components of care. Arrhythmias and cardiac failure are the most common complications of acute myocardial infarction. • An aneurysm is a localised dilation of a vessel wall, to which the aorta is particularly susceptible. • A thrombus is a clot that remains attached to a vascular wall. Arteriosclerosis can generate thrombus formation through roughening of the intima that activates the coagulation cascade. Thrombus formation may be discrete or diffuse. • An embolus is a mobile aggregate of a variety of substances that occludes the vasculature. Sources of emboli include clots, air, amniotic fluid, bacteria, fat and foreign matter. These emboli cause ischaemia and necrosis when a vessel is totally blocked. • Emboli to the central organs cause tissue death in lungs, kidneys and mesentery. • Deep venous thrombosis results from stasis of blood flow, endothelial damage or hypercoagulability. The most serious complication of deep venous thrombosis is pulmonary embolism. • Varicosities are areas of veins in which blood has pooled, usually in the saphenous veins. • Varicosities may be caused by damaged valves as a result of trauma to the valve or by chronic venous distension involving gravity and venous constriction. • Chronic venous insufficiency is inadequate venous return over a long period of time that causes pathological ischaemic changes in the vasculature, skin and supporting tissues. • Venous stasis ulcers follow the development of chronic venous insufficiency and probably develop as a result of the borderline metabolic state of the cells in the affected extremities.
Paediatrics and alterations of cardiac function • Most congenital heart defects have begun to develop by the eighth week of gestation and some have associated causes, both environmental and genetic.
CHAPTER 23 Alterations of cardiovascular function across the life span
• Environmental risk factors associated with the incidence of congenital heart defects typically are maternal conditions. Maternal conditions include viral infections, diabetes, drug intake and advanced maternal age. • Classification of congenital heart defects is based on whether they cause: (a) blood flow to the lungs to increase, decrease or remain normal; (b) cyanosis; and (c) obstruction to flow. • Cyanosis, a bluish discolouration of the skin, indicates that the tissues are not receiving normal amounts of oxygenated blood. Cyanosis can be caused by defects that: (a) restrict blood flow into the pulmonary circulation; (b) overload the pulmonary circulation, causing pulmonary hypertension, pulmonary oedema and respiratory difficulty; or (c) cause large amounts of deoxygenated blood to shunt from the pulmonary circulation to the systemic circulation. • Congenital defects that maintain or create direct communication between the pulmonary and systemic circulatory systems cause blood to shunt from one system to another, mixing oxygenated and deoxygenated blood and increasing blood volume and, occasionally, pressure on the receiving side of the shunt. • The direction of shunting through an abnormal communication depends on differences in pressure and resistance between the two systems. Flow is always from an area of high pressure to an area of low pressure. • Acyanotic congenital defects that increase pulmonary blood flow consist of abnormal openings (atrial septal defect, ventricular septal defect, patent ductus arteriosus or atrioventricular septal defect) that permit blood to shunt from left (systemic circulation) to right (pulmonary circulation). Cyanosis does not occur because the left-toright shunt does not interfere with the flow of oxygenated blood through the systemic circulation. • If the abnormal communication between the left and right circuits is large, volume and pressure overload in the pulmonary circulation lead to left heart failure. • Initial treatment for congenital heart disease, depending on the defect, is aimed at controlling the level of congestive heart failure or cyanosis. Interventional procedures in the cardiac catheterisation laboratory and surgical palliation or repair are performed to restore circulation to as normal as possible.
Alterations of the heart wall • Inflammation of the pericardium, or pericarditis, may result from several sources (infection, drug therapy, tumours). Pericarditis presents with symptoms that are physically troublesome, but in and of themselves they are not life-threatening. • Fluid may collect within the pericardial sac (pericardial effusion). Cardiac function may be severely impaired if the accumulation of fluid occurs rapidly and involves a large volume. • The cardiomyopathies are a diverse group of primary myocardial disorders that are usually the result of remodelling, neurohumoral responses and hypertension.
•
•
•
•
• •
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The cardiomyopathies are categorised as dilated, hypertrophic and restrictive. The size of the cardiac muscle walls and chambers may increase or decrease depending on the type of cardiomyopathy, thereby altering contractile activity. The haemodynamic integrity of the cardiovascular system depends to a great extent on properly functioning cardiac valves. Congenital or acquired disorders that result in stenosis, incompetence or both can structurally alter the valves. Characteristic heart sounds, cardiac murmurs and systemic complaints assist in determining which valve is abnormal. If severely compromised function exists, a prosthetic heart valve may be surgically implanted to replace the faulty one. Mitral valve prolapse is a common finding, especially in young women. Although not grossly abnormal, the mitral valve leaflets do not position themselves properly during systole. Mitral valve prolapse may be a completely asymptomatic condition or can result in unpredictable symptoms. Afflicted valves are at greater risk for developing infective endocarditis. Rheumatic fever is an inflammatory disease that results from a delayed immune response to a streptococcal infection in genetically predisposed individuals. The disorder usually resolves without sequelae if treated early. Severe or untreated cases of rheumatic fever may progress to rheumatic heart disease, a potentially disabling cardiovascular disorder. Infective endocarditis is a general term for infection and inflammation of the endocardium, especially the cardiac valves. The most common cause of infective endocarditis is Staphylococcus aureus, followed by Streptococcus viridans. In the mildest cases, valvular function may be slightly impaired by vegetations that collect on the valve leaflets. If left unchecked, severe valve abnormalities, chronic bacteraemia and systemic emboli may occur as vegetations break off the valve surface and travel through the bloodstream. Antibiotic therapy can limit the extension of this disease.
Alterations of cardiac conduction • Arrhythmias are disturbances of heart rhythm. Arrhythmias range in severity from occasional missed beats or rapid beats to disturbances that impair myocardial contractility and are life threatening. • Arrhythmias can occur because of an abnormal rate of impulse generation or the abnormal conduction of impulses. • Atrial fibrillation is the most common arrhythmia and is most prevalent in the elderly.
Heart failure • Heart failure is an inability of the heart to supply the metabolism with adequate circulatory volume and pressure.
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• Left heart failure (congestive heart failure) can be divided into systolic and diastolic heart failure. • Systolic heart failure is caused by increased preload, decreased contractility or increased afterload. • The most common causes of systolic heart failure are myocardial infarction, fluid overload, hypertension or valvular disease. • In addition to the haemodynamic changes of systolic heart failure, there is a neuroendocrine response that tends to exacerbate and perpetuate the condition. • The neuroendocrine mediators include the sympathetic nervous system and the renin-angiotensin-aldosterone system; thus, diuretics, β-blockers and ACE inhibitors are important components of the pharmacological therapy. • Diastolic heart failure is a clinical syndrome characterised by the symptoms and signs of heart failure, a preserved ejection fraction and abnormal diastolic function. • Diastolic dysfunction means that the left ventricular enddiastolic pressure is increased, even if volume and cardiac output are normal. • Right heart failure is usually the result of chronic pulmonary hypertension caused by left heart failure or chronic hypoxic lung disease.
Shock • Shock is a widespread impairment of cellular metabolism involving positive feedback loops that places the individual on a downward physiological spiral leading to the multiple organ dysfunction syndrome. • Types of shock are cardiogenic, hypovolaemic, neurogenic, anaphylactic and septic. The multiple organ dysfunction syndrome can develop from all types of shock. • The final common pathway in all types of shock is impaired cellular metabolism — cells switch from aerobic to anaerobic metabolism. Energy stores drop and cellular mechanisms relative to membrane permeability, action potentials and lysosyme release fail. • Anaerobic metabolism results in activation of the inflammatory response, decreased circulatory volume and decreasing pH. • Impaired cellular metabolism results in cellular inability to use glucose because of impaired glucose delivery or impaired glucose intake, resulting in a shift to glycogenolysis, gluconeogenesis and lipolysis for fuel generation. • Glycogenolysis is effective for about 10 hours. Gluconeogenesis results in the use of proteins necessary
•
• •
•
•
•
•
•
•
for structure, function, repair and replication, which leads to more impaired cellular metabolism. Gluconeogenesis contributes to lactic acid, uric acid and ammonia build-up, interstitial oedema and impairment of the immune system, as well as general muscle weakness leading to decreased respiratory function and cardiac output. Cardiogenic shock is decreased cardiac output, tissue hypoxia and the presence of adequate intravascular volume. Hypovolaemic shock is caused by loss of blood or fluid in large amounts. The use of compensatory mechanisms may be vigorous, but tissue perfusion ultimately decreases and results in impaired cellular metabolism. Neurogenic shock results from massive vasodilation, causing a relative hypovolaemia, even though cardiac output may be high, and results in impaired cellular metabolism. Anaphylactic shock is caused by physiological recognition of a foreign substance. The inflammatory response is triggered and a massive vasodilation with fluid shift into the interstitium follows. The relative hypovolaemia leads to impaired cellular metabolism. Septic shock begins with impaired cellular metabolism caused by uncontrolled septicaemia. The infecting agent triggers the inflammatory and immune responses. This inflammatory response is accompanied by widespread changes in tissue and cellular function. Multiple organ dysfunction syndrome is the progressive failure of two or more organ systems after a severe illness or injury. It can be triggered by chronic inflammation, necrotic tissue, severe trauma, burns, adult respiratory distress syndrome, acute pancreatitis and other severe injuries. Multiple organ dysfunction syndrome involves the stress response; changes in the vascular endothelium resulting in microvascular coagulation; release of complement, coagulation and kinin proteins; and numerous inflammatory processes. The consequences of all these mediators are an altered blood flow distribution, hypermetabolism, hypoxic injury and myocardial depression. Clinical manifestations of the multiple organ dysfunction syndrome include inflammation, tissue hypoxia and hypermetabolism. All organs can be affected, including the kidneys, lungs, liver, gastrointestinal tract and central nervous system.
CHAPTER 23 Alterations of cardiovascular function across the life span
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CASE STUDY
ADU LT A 52-year-old man, Shane, who is fit and lean because he trains for an Ironman triathlon, begins to complain of intermittent headaches, dizziness and for the most part, several epistaxis episodes. He visits his doctor for advice thinking perhaps he is overtraining. The following vital signs are recorded: temperature 36.1°C, pulse 106 beats per minute, ventilation rate 20 breaths per minute, blood pressure 168/98 mmHg. Shane is 184 cm tall and weighs 81 kg. He relates that he has a highly stressful job, is trying to train for an Ironman triathlon, is married and is a father of two young children (ages 12 and 8 years). He says that it is difficult to eat right all of the time; however, he tries to follow a healthy, balanced diet to allow him the right energy intake for his exercise regime. Shane considers himself to be an overachiever, placing high demands on his outcomes. He further
adds that his father died of a stroke at age 60 years and that his mother died at age 75 years from a heart attack. He has two brothers, both older, and they both have coronary heart disease. He also reveals that he used to smoke cigarettes ( 12 pack a day) and was overweight (> 100 kg) until the age of 40 years when he started his ‘get-fit’ campaign. He has completed six Ironman distance races since the age of 44 years. 1 What are the major complaints of this patient? 2 What is your provisional diagnosis? 3 What key points on his physical examination led to this diagnosis? 4 What modifiable risk factors correlate with this cardiovascular disease? 5 What non-modifiable risk factors correlate with this cardiovascular disease?
CASE STUDY
AGEING A 70-year-old Caucasian woman, Sandra, presented at the Emergency Department with sudden onset chest pain. She described the pain as a severe burning sensation that radiated across the chest to the shoulders, neck and jaw region. Sandra also complained of nausea and epigastric discomfort. She was treated immediately with glyceryl trinitrate and was placed on oxygen via nasal cannula. This treatment provided partial relief, however the pain persisted. Observations were taken and it was revealed that Sandra was a pack-a-week cigarette smoker, suffered from hypertension and mild-to-moderate obesity. Cardiac catheterisation was scheduled and it was found that there was an 85% blockage of the right coronary artery. Sandra then underwent a PTCA
to open up the coronary artery blockage. She was then discharged and progressed well on an exercise program and tolerated physical activity. 1 What coronary risk factors are present for Sandra? 2 Is the patient’s chest pain syndrome typical or atypical for women? Why or why not? 3 What is the common picture of a woman’s cardiac status when referred for coronary artery bypass graft (CABG) surgery? 4 Why can chest pain radiate to other body areas (e.g. neck, jaw, arm)? 5 What impact does cigarette smoking have on coronary heart disease?
REVIEW QUESTIONS 1 Describe the factors involved in the development of primary hypertension. 2 Outline the pathogenesis of atherosclerosis. 3 Discuss the risk factors associated with coronary heart disease. 4 Describe the pathophysiological events leading to myocardial ischaemia and infarction. 5 Differentiate between thrombus and embolism. 6 List the different types of congenital heart malformations and contrast defects that increase and decrease pulmonary blood flow.
7 Discuss the differences in disorders of the pericardium, myocardium and endocardium. 8 Differentiate between life-threatening and other arrhythmias. 9 Outline the differences between systolic and diastolic heart failure. 10 Provide brief descriptions of anaphylactic, cardiogenic, hypovolaemic, neurogenic and septic shock to highlight the pathophysiological differences.
Key terms
CHAPTER
24
The structure and function of the pulmonary system Darrin Penola and Vanessa Marie McDonald
Chapter outline Introduction, 681 The structure of the pulmonary system, 681 The conducting zone, 681 The respiratory zone, 687 The pulmonary and bronchial circulation, 688 The chest wall and pleura, 688
680
The function of the pulmonary system, 689 The mechanics of breathing, 689 Ventilation, 694 Gas transport, 698 Ageing and the pulmonary system, 705
alveolar–capillary membrane, 688 alveolar ducts, 687 alveolar ventilation, 692 alveoli, 687 bronchi, 683 bronchioles, 683 carina, 683 central chemoreceptors, 697 compliance, 692 conducting zone, 681 dead space, 694 elastic recoil, 692 Haldane effect, 705 hila, 683 larynx, 682 lobar bronchi, 683 minute volume, 694 mucociliary escalator, 684 oesophagus, 682 parietal pleura, 689 partial pressure, 698 peripheral chemoreceptors, 698 pharynx, 681 pleura, 689 pleural space, 689 respiratory bronchioles, 687 respiratory centre, 696 respiratory zone, 681 segmental bronchi, 683 surfactant, 687 terminal bronchioles, 683 tidal volume, 694 trachea, 682 ventilation, 694 ventilation/perfusion ratio (V/Q), 701 visceral pleura, 689
CHAPTER 24 The structure and function of the pulmonary system
Introduction The importance of the pulmonary system in sustaining life has been known for millennia. The ancient Greeks had a rudimentary understanding of air and the relationship to breathing, and there are passages in the Bible that make reference to breathing and continuing life. However, it was not until the mid-eighteenth century that scientific experimentation was sophisticated enough to differentiate gases in the atmosphere. The pioneering work was done by two chemists: Joseph Priestley, who demonstrated that oxygen was essential for life and metabolic processes; and Antoine Lavoisier, who isolated oxygen from the atmosphere and found that carbon dioxide was the byproduct of metabolism. Their work allowed others to further our understanding of the pulmonary system and associated diseases. The pulmonary system consists of the lungs, airways, chest wall and pulmonary circulation. The primary function is the exchange of gases between the external environment (air) and the blood and then the cells. The movement of air from the environment to the body cells involves several stages. There are three critical steps in this process and it is vital that you are able to differentiate each one because alterations to homeostasis can affect all three or each one independently. The three critical steps are: 1 ventilation, the movement of air into and out of the lungs 2 diffusion, the movement of gases between air spaces in the lungs and bloodstream 3 perfusion, the movement of blood into and out of the capillary beds of the lungs to body organs and tissues. The first two functions are carried out by the pulmonary system and the third by the cardiovascular system (which is discussed in Chapter 22). Normally, the pulmonary system functions efficiently under a variety of conditions and with little energy expenditure. However, alterations to the pulmonary system, cardiovascular system or circulating blood can impact greatly on the ability of the lungs to exchange oxygen and carbon dioxide with the atmosphere and the body cells, sometimes with deleterious systemic effects. In this chapter we explore the anatomy and physiology of the pulmonary system, while Chapter 25 is devoted to alterations in the pulmonary system.
The structure of the pulmonary system The pulmonary system is made up of two lungs (including the alveoli where gases are exchanged with the blood), the associated airways (nose, nasal cavity, mouth, pharynx, larynx, trachea, bronchi and bronchioles), blood vessels that serve them (pulmonary arteries, pulmonary capillaries, pulmonary veins and bronchial arteries) and the chest wall, also referred to as the thoracic cage. The lungs are divided
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into lobes: three in the right lung (upper, middle, lower) and two in the left lung (upper, lower). The apex of the heart, which extends into the left side of the thorax, means that the left lung is smaller than the right. Each lobe is further divided into segments and lobules. The space between the lungs, which contains the heart, great vessels and oesophagus, is called the mediastinum. A set of passageways deliver air to each section of the lung. The lung tissue that surrounds the airways supports them, preventing their distortion or collapse as gas moves in and out during ventilation. Functional differences exist between these structures and they can be divided into two zones: the conducting zone, which includes all the passageways that lead from the mouth and nose into the chest cavity; and the respiratory zone, the sites of gas exchange — or what are commonly referred to as the lungs (see Figs 24.1 and 24.2). In clinical practice the terms upper respiratory tract and lower respiratory tract are frequently used to distinguish anatomical components when pulmonary disorders are present. For instance, lower respiratory tract infections are often more serious than upper respiratory tract infections. However, to adequately understand the physiological differences, the terms conducting zone and respiratory zone are more pertinent.
The conducting zone
The conducting zone consists of the nose, mouth, nasal passage (cavity), pharynx, larynx, trachea, bronchi and bronchioles. The primary role of the conducting zone is to facilitate the movement of air into and out of the respiratory zone, the site where gas exchange occurs. These conducting airways are not simply hollow tubes that allow air to move into the lungs; in fact, they have other crucial roles to filter, warm and humidify the air. These are important properties, such that air reaching the respiratory zone is cleaned of foreign particles (for instance, dust and microorganisms), warmed to match body temperature and has moisture added, which all combine to facilitate gas exchange in the respiratory zone. At rest, during normal breathing, air enters the nose through the nostrils and then the nasal cavity (see Fig. 24.3). Superiorly the bones of the skull and inferiorly the hard palate line this cavity. It is continuous with the upper aspect of the pharynx. The mouth provides an alternative route for air, and also can be utilised for ventilation during periods of increased ventilatory drive. The pharynx has three regions: (1) nasopharynx, (2) oropharynx and (3) laryngopharynx. The nasopharynx lies above where food is passed from the mouth, while the oropharynx and laryngopharynx both provide passageways for ingested food and air. These structures are lined with ciliated mucosa which is a mucus-secreting membrane that contains hair-like projections (cilia) to move the mucus across the surface and enables the inspired air to be warmed and humidified and importantly foreign particles are removed. The mouth and oropharynx are used for
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Nasal cavity Nasopharynx Oropharynx
Upper respiratory tract
Pharynx
Laryngopharynx
Conducting zone includes bronchioles
Larynx Trachea Left and right primary bronchi
Lower respiratory tract
Alveoli
Bronchioles
Alveolar duct Capillary
Respiratory zone All gas exchanging regions
Alveolar sac
FIGURE 24.1
The structures of the pulmonary system. The conducting airways from the mouth and nose to the lungs are visible. The enlargement in the circle depicts gas exchange units with corresponding blood vessels.
ventilation when the nose is obstructed or when increased flow is required during periods of increased ventilatory drive such as during exercise. It must be noted that filtering and humidifying are not as efficient during mouth breathing. The larynx connects the laryngopharynx with the trachea and is the junction between the upper and lower airways. The upper respiratory tract contains all structures from the mouth to the start of the trachea, which is different from the conducting zone, which extends beyond this region. The main purposes of the larynx are for vocalisation (speech) and directing swallowed food and inspired air into the oesophagus and trachea, respectively. The larynx is formed from a scaffold of different cartilage pieces that are supported in place by surrounding ligaments and membranes. The larynx moves during voice production and swallowing, and the cartilage aids with this movement and importantly prevents collapse of the larynx during inspiration. The most prominent of these cartilage structures is the thyroid
cartilage, which projects anteriorly and is commonly referred to as the Adam’s apple. Immediately superior to the larynx, the epiglottis moves down during swallowing to cover the larynx and prevent food and liquid from entering the lungs (there is a complete discussion of swallowing in Chapter 26). The hollow space inside the larynx encompasses two pairs of folds: the false vocal cords (supraglottis, meaning above the glottis) and the true vocal cords (the slit-shaped space between the cords, forming the glottis; see Fig. 24.3). The internal laryngeal muscles control vocal cord length and tension and the external laryngeal muscles move the larynx as a whole. Both sets of muscles are important to swallowing, ventilation and vocalisation. The internal muscles contract during swallowing to prevent aspiration into the trachea. These muscles also contribute to voice pitch. The trachea, which is supported by a C-shaped cartilage, connects the larynx to the bronchi. The common term for the trachea is ‘windpipe’. The trachea is composed of
CHAPTER 24 The structure and function of the pulmonary system
RIGHT
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LEFT Trachea
Right lung Blood vessels
Right and left bronchus
Left lung Left atrium
Diaphragm
FIGURE 24.2
Gross anatomy of the chest cavity. The frontal section of chest has been preserved and the lungs’ position in the thorax is shown along with the other structures, diaphragm, heart and ribs.
cartilage, connective tissue and smooth muscle, which provides an important combination of strength and flexibility. Rigidity is necessary, so that pressure changes in the lungs and airways do not cause the trachea to collapse during breathing. On the other hand, the posterior part of the trachea (which contains only smooth muscle and not cartilage) provides flexibility to allow the oesophagus to bulge anteriorly so that food can be swallowed. It is because the cartilage is incomplete around the diameter of the trachea that it is described as being C-shaped. Extending inferiorly, the trachea branches into two main airways, or bronchi (singular, bronchus), at the carina (see Fig. 24.1). The carina contains nerve fibres that are very sensitive and, when stimulated by foreign particles such as pollution or microorganisms, cause powerful coughing and bronchospasm. The right and left main bronchi enter the lungs at the hila (which literally means roots of the lungs and there are two, which individually are called hilum). The hila are an important region because this is where the main pulmonary vessels, major bronchi and lymphatic vessels are situated. Compared with the left, the right main bronchus is more vertical, wider and shorter, which typically results in aspiration of foreign objects, such as food and liquids, entering the right lung. The bronchial walls have three layers: an epithelial lining, a smooth muscle layer and a connective tissue layer. The epithelial lining of the bronchi contains single-celled exocrine glands (the mucus-secreting goblet cells) and ciliated cells.
Upon entering the lungs, the main bronchi divide into lobar bronchi (secondary), three on the right and two on the left (see Fig. 24.4). These provide connections for the lobes of the lungs. The bronchi continue branching to form smaller bronchi (segmental bronchi — tertiary) that have less cartilage and ciliated cells, but more smooth muscle in the walls. These branch even more to form bronchioles, which are literally ‘little bronchi’. The bronchioles are important because they not only conduct air to and from the lungs and the environment, but are also responsible for control of airflow by either dilating or constricting. This is explained in more detail later in the chapter. Successive bronchiole branching occurs until they form terminal bronchioles, which are the smallest. A useful analogy for the conducting passageways is that of a large tree. From the ground, the trunk is synonymous with the trachea and the branches arising from the trunk resemble bronchi and bronchioles spreading out through the lungs. The small branches and leaves are similar to the respiratory zone providing an increased surface area to facilitate the exchange of gas with the blood. In fact, there are 23 levels of branching and these can be seen in Fig. 24.5. The successive branching of the airways occurs with changes in the bronchial wall (see Fig. 24.6), as the layers of epithelium become thinner to the extent that only a thin membrane remains where gas exchange occurs. An important aspect is the way that the pulmonary system filters and cleans the air to ensure that the gas-exchange units are sterile. Within the air that we
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NASAL CAVITY
PHARYNX Nasopharynx Oropharynx Laryngopharynx
Nasal conchae
Vestibule Cilia
Thyroid cartilage
Hard palate
Epiglottis
Soft palate
Epiglottis
Base of tongue
Elastic fibres
Tracheal cartilage
Epiglottis
Corniculate cartilage
Vocal folds (true vocal cords)
Arytenoid cartilage Cricoid cartilage Trachea
Trachea LARYNX
Tracheal cartilage Intercartilaginous ligaments
Trachealis muscle
TRACHEA
FIGURE 24.3
The structures of the upper airway. A cross-section of the upper airways highlighting the anatomical features of the nasal cavity, pharynx, larynx and trachea.
inhale are a range of potential foreign particles that may cause infections or irritation to the lungs. The pulmonary system is very efficient at removing these foreign particles from entering the alveoli. This starts at the nasal cavity, which contains turbinates and hairs that trap foreign particles. Along the upper respiratory tract, the mucosa also traps foreign particles and the mucus that lines the tract is propelled upwards out of the upper airways using cilia — this is referred to as the mucociliary escalator.
This mucus is either swallowed or coughed out, thereby cleaning the pulmonary system. Furthermore, as the conducting zone changes to the respiratory zone, the defence mechanisms of the pulmonary system change from a series of mechanical barriers to cells of the inflammatory and immune systems, macrophages, which ingest foreign substances to prevent contamination of the lungs. For more details of the pulmonary defence mechanisms see Table 24.1.
CHAPTER 24 The structure and function of the pulmonary system
Trachea Sternum (manubrium)
First rib
Left superior lobe Left primary bronchus
Right superior lobe Right primary bronchus Horizontal fissure
Body of sternum
Right middle lobe
Oblique fissure
Oblique fissure Seventh rib
Left inferior lobe
Right inferior lobe Sternum (xiphoid process)
FIGURE 24.4
Conducting airways of the lungs. The lobes of the lungs inside the chest wall. The trachea is an airway that branches to form a tree-like formation of bronchi and bronchioles. Note that the right lung has three lobes and the left lung has two lobes and the dotted line refers to inspiration depth.
Trachea
Bronchi (cartilage)
Mainstem bronchi
Generation 0 1 2 10
Conducting airways (anatomic dead space)
11 12 13 Bronchioles (no cartilage)
Terminal bronchiole
Alveolar ducts Alveolar sacs
15 16
Respiratory bronchioles Alveolar air spaces
14
Alveolus 17 18 19 20 21 22 23
FIGURE 24.5
Airway generations from the trachea to the alveolus. While cartilage is a main component of the upper conducting airways, there is no cartilage from the bronchioles onwards. With each generation of the airways (where one divides into two), the airways become progressively smaller.
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Cellular structures
Trachea and bronchus
Mucus layer Serous cell Goblet cell Ciliated cell Basal cell Basement membrane Lamina propria Mucus layer Ciliated cell
Bronchiole
Basal cell Basement membrane Lamina propria Mucus layer
Respiratory bronchiole
Ciliated cell Nerve Basement membrane Lamina propria Capillary lumen Type II alveolar cell Basement membrane Surfactant Alveolar macrophage Type I alveolar cell
Alveoli FIGURE 24.6
Changes in the bronchial wall with progressive branching. In the progression from the bronchi to the alveoli, there is a progressive decline in mucus-producing cells, and a loss of cilia by the alveoli.
TABLE 24.1 Pulmonary defence mechanisms STRUCTURE OR SUBSTANCE
MECHANISM OF DEFENCE
Nasal hairs and turbinates
Trap and remove foreign particles, some bacteria and noxious gases from inspired air
Irritant receptors in nostrils
Stimulation by chemical or mechanical irritants triggers sneeze reflex, which results in rapid removal of irritants from nasal passages
Upper respiratory tract mucosa
Maintains constant temperature and humidification of gas entering the lungs; traps and removes foreign particles, some bacteria and noxious gases from inspired air
Mucus blanket
Protects trachea and bronchi from injury; traps most foreign particles and bacteria that reach the lower airways
Cilia
Propel mucus blanket and entrapped particles towards the oropharynx, where they can be swallowed or expectorated
Irritant receptors in trachea and large airways
Stimulation by chemical or mechanical irritants triggers cough reflex, which results in removal of irritants from the lower airways
Alveolar macrophages
Ingest and remove bacteria and other foreign particles from the alveoli by phagocytosis
CHAPTER 24 The structure and function of the pulmonary system
The respiratory zone
The respiratory zone consists of structures that are involved in gas exchange. These include the respiratory bronchioles, alveolar ducts and alveoli (singular, alveolus) (see Figs 24.1 and 24.7). The respiratory bronchioles, branching from the terminal bronchioles, have fewer ciliated and mucus-producing cells than the conducting zone and more epithelial cells than the conducting zone, and mainly consist of one layer of epithelial cells, thereby allowing gas exchange. The alveolar ducts are distal to the respiratory bronchioles and although some gas exchange occurs here, the majority of gas exchange takes place in the alveoli. The alveoli are the primary gas-exchange units of the lung, where oxygen enters the blood and carbon dioxide is removed (see Fig. 24.7). Alveoli are approximately 0.2 mm in diameter; however, there are about 300 million in the adult lungs and therefore the surface area is very large. In fact, if the lungs were spread out flat they would be approximately the size of a singles tennis court! This surface area is further enhanced by tiny passages called pores of Kohn, which permit some air to pass through the septa (plural for septum, a thin membrane between two cavities) from alveolus to alveolus, promoting collateral ventilation and even distribution of air among the alveoli. The alveoli are composed of two major types of epithelial cells: • type I alveolar cells (or type I pneumocytes), which are flat-shaped squamous cells that provide structure of the alveolar wall and are specialised for gas exchange
A
Terminal bronchiole Pulmonary venule
Alveolar duct
Pulmonary arteriole
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• type II alveolar cells (or type II pneumocytes), which secrete surfactant. Therefore, while there are somewhat similar numbers of type I and type II cells, it is type I alveolar cells that constitute the majority of the surface area involved in gas exchange. Surfactant is a lipoprotein (a combination of lipid and protein) that coats the inner surface of the alveolus and lowers alveolar surface tension at the end of expiration, which helps prevent lung collapse. Type I alveolar cells comprise about 40% of all alveolar cells; however, they provide 90% of the surface area of the alveoli. In contrast, type II cells account for 60% of alveolar cells and are widely spread through the alveolar surface, but cover less than 10% of the surface area (see Fig. 24.8). Both these cell types are formed late in pregnancy and are the primary reason why premature infants are unable to survive before 24 weeks of gestational age (see ‘Paediatrics and the pulmonary system’ below for more details). Like the bronchi, the alveoli contain cellular components of inflammation and immunity, particularly the alveolar macrophages (see Fig. 24.8). The alveolar macrophages move about the alveoli scavenging foreign particles that may enter the alveoli if not filtered and removed from the conducting zone. It should be noted that a huge amount of potential contaminants are in the inspired air and while the conducting zone is very effective in removing the majority of these from the inspired air, some may still reach the alveoli. Therefore, the immune system can rapidly
B
Alveolar sac
Alveoli FIGURE 24.7
Alveoli. A Bronchioles subdivide to form tiny tubes called alveolar ducts, which end in clusters of alveoli called alveolar sacs. B Alveolar shape.
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A
B Capillary endothelium
Erythrocyte
Leucocyte Type II alveolar cells
Alveolar macrophages
Type II epithelial cell
FIGURE 24.8
Alveolar wall components. A Microscopic view of alveoli with type II cells and alveolar macrophages visible. B Microscopic view of alveoli with adjacent capillary.
counteract any foreign invasion and in this way the lungs are sterile. Alveolar macrophages remove foreign particles by phagocytosis (see Chapter 13), and the ingested foreign material is removed through the lymphatics (see Table 24.1 for a comparison with other pulmonary system defences). F OCU S O N L E ARN IN G
1 List the major components of the pulmonary system. 2 Describe the functional differences between the conducting and respiratory zones. 3 List differences in airway cellular structure and explain how this impacts on gas flow or gas exchange. 4 Describe the anatomy of the alveoli and the functional differences between the types of alveolar cells.
The pulmonary and bronchial circulation
The pulmonary circulation facilitates gas exchange, delivers nutrients to lung tissues, acts as a reservoir for the left ventricle and serves as a filtering system that removes clots, air and other debris from the circulation. Although the entire cardiac output from the right ventricle goes into the lungs, the pulmonary circulation has a lower pressure and resistance than the systemic circulation. Pulmonary arteries are exposed to about one-fifth the pressure of the systemic circulation (mean pulmonary artery pressure is approximately 15 mmHg compared to a mean arterial pressure in the aorta of 95 mmHg; see Fig. 22.38). Usually about one-third of the pulmonary vessels are filled with blood (referred to as being ‘perfused’) at any given time. More vessels become perfused when right ventricular cardiac output increases. Therefore,
increased delivery of blood to the lungs does not normally increase mean pulmonary artery pressure. The arterioles divide at the terminal bronchioles to form a network of pulmonary capillaries around the alveoli. Capillary walls consist of an endothelial layer and a thin basement membrane, which often fuses with the basement membrane of the alveoli. Therefore, very little physical separation exists between blood in the capillary and gas in the alveolus. The shared alveolar and capillary walls compose the alveolar–capillary membrane (air–blood interface) (see Fig. 24.9). Gas exchange occurs across this membrane. With normal perfusion, approximately 100 mL of blood in the pulmonary capillary bed is spread very thinly over 70–100 m2 of alveolar surface area. Any alteration to the membrane, such as that which occurs with the disease emphysema (see Chapter 25), will impact on normal gas exchange. The bronchial circulation is part of the systemic circulation and it supplies nutrients and oxygen to the cells of the conducting zone, large pulmonary vessels and membranes (pleurae) that surround the lungs. Not all of the capillaries drain into the bronchial venous system. Some empty into the pulmonary vein and contribute to the normal venous mixture of oxygenated and deoxygenated blood.
The chest wall and pleura
The chest wall consists of the skin, ribs and intercostal muscles (between the ribs). The chest wall has two important functions: (1) to coordinate with the diaphragm (the primary muscle involved in breathing) in performing the muscular work of breathing; and (2) to provide protection for the heart and lungs from injury. The thoracic cavity is contained by the chest wall and encases the lungs (see Fig. 24.10). When individuals have alterations to their pulmonary system, investigation of the condition is often conducted using chest x-rays. These can be taken in different positions
CHAPTER 24 The structure and function of the pulmonary system
Type II alveolar cell
Surfactant layer
Interstitial cell
Connective tissue
Alveolar epithelium Surfactant layer
Capillary endothelium
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Capillary endothelium
Alveolus Red blood cell O2 Alveolar epithelium
Alveolus
Basement membrane
CO2
Type I alveolar cell Alveolar macrophage
Basement membrane
Interstitial space
FIGURE 24.9
Cross-section of an alveoli (alveolar–capillary membrane). Inset shows a magnified view of the respiratory membrane composed of the alveolar wall (fluid coating, epithelial cells, basement membrane), interstitial fluid and wall of a pulmonary capillary (basement membrane, endothelial cells). The gases carbon dioxide and oxygen diffuse across the respiratory membrane.
(upright or supine) and there are many distinguishing features that can be observed. Fig. 24.11 outlines some of the pulmonary and cardiovascular anatomical features of a normal chest x-ray. A serous membrane called the pleura adheres firmly to the lungs and then folds over itself and attaches firmly to the chest wall. The membrane covering the lungs is the visceral pleura; that lining the thoracic cavity is the parietal pleura. The area between the two pleurae is called the pleural space (or pleural cavity). Normally, only a thin layer of fluid secreted by the pleura (pleural fluid) fills the pleural space, lubricating the pleural surfaces and allowing the two layers to slide over each other without separating. The pressure in the pleural space is usually negative or subatmospheric (below that of the atmosphere, or about –4 to –10 mmHg). This negative pressure is important because it assists with keeping the lungs from collapsing and moving away from the chest wall. F O CUS O N L E A R N IN G
1 List the major components of the pulmonary circulation. 2 Describe the pulmonary and cardiovascular anatomy in the thoracic cavity. 3 Differentiate between the visceral and parietal pleura.
The function of the pulmonary system The pulmonary system has three primary functions: (1) to ventilate the alveoli; (2) to allow gases to diffuse into and out of the blood; and (3) to perfuse the lungs so that the organs and tissues of the body receive blood that is rich in oxygen and low in carbon dioxide. These functions are influenced by chemical and neural input to the nervous system, which controls the movement of the chest wall muscles. Each of these components of the pulmonary system contributes to one or more of these functions, and we explore them in more detail below.
The mechanics of breathing
The physical aspects of inspiration and expiration are known collectively as the mechanics of breathing and involve: (1) major and accessory muscles of inspiration and expiration; (2) elastic properties of the lungs and chest wall; and (3) resistance to airflow through the conducting zone. Alterations in any of these properties increase the work of breathing or the metabolic energy needed to achieve adequate ventilation of alveoli and gas exchange.
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B
4th rib Horizontal fissure
A
5th rib midaxillary line
Trachea Right primary bronchus Aorta
Left primary bronchus Mediastinum
Right lung Parietal pleura Visceral pleura
Right oblique fissure
RUL
LUL
RML RLL
LLL
Left oblique fissure 6th rib midclavicular line
Left lung Pleural space Diaphragm Oesophagus
Oblique fissure
LUL LLL
RUL
T3
RLL
T10 T12
FIGURE 24.10
Thoracic (chest) cavity and related structures. A The thoracic (chest) cavity is divided into three subdivisions (left and right pleural divisions and mediastinum) by a partition formed by a serous membrane called the pleura. B Anatomical position of the lungs in the chest.
Major and accessory muscles
The major muscles of inspiration are the diaphragm and the external intercostal muscles (muscles between the ribs) (see Fig. 24.12). The diaphragm is a dome-shaped muscle that separates the abdominal and thoracic cavities. When it contracts and flattens downwards, it increases the volume of the thoracic cavity. This creates a slight negative pressure, which draws air into the lungs through the upper airways and trachea. Contraction of the external intercostal muscles elevates the anterior portion of the ribs and increases the volume of the thoracic cavity by increasing its front-to-back (anterior-posterior) diameter. Although the external intercostals may contract during quiet breathing, inspiration at rest is usually achieved by the diaphragm only. The accessory muscles of inspiration are the sternocleidomastoid and scalene muscles. Like the external intercostals, these muscles enlarge the thorax by increasing its anterior-posterior diameter. The accessory muscles assist inspiration when minute volume (the volume of air inspired and expired per minute; see ‘Ventilation’ later in the chapter) is high; for example, during strenuous exercise or when
the work of breathing is increased because of disease. However, the accessory muscles do not increase the volume of the thorax as efficiently as the diaphragm, which is the main muscle of ventilation. The movement of these accessory muscles may be observed in a patient who is experiencing breathing difficulties. There are no major muscles of expiration because normal, quiet expiration is passive and requires no muscular effort. The relaxation of the diaphragm causes it to move back towards the thoracic cavity, which decreases the volume and air moves out. Also, the properties of the smooth muscle and elastic fibres within the respiratory zone structures enable them to recoil passively during expiration. The accessory muscles of expiration, the abdominal and internal intercostal muscles, assist expiration when minute volume is high, during coughing, when airway obstruction is present or during forced expiration (such as blowing into a balloon). When the abdominal muscles contract, intraabdominal pressure increases, pushing up the diaphragm and decreasing the volume of the thorax. The internal intercostal muscles pull down the anterior ribs, decreasing the anterior-posterior diameter of the thorax.
CHAPTER 24 The structure and function of the pulmonary system
A
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Trachea Carina Aortic arch Azygous vein
Left atrium Right atrium Breast shadow Liver
Main pulmonary artery Descending thoracic aorta Left ventricle Right ventricle Stomach bubble Left costophrenic angle
B Raised humerus Trachea Ascending aorta
Scapular blades Right pulmonary artery Left atrium
Right ventricle Inferior vena cava Posterior costophrenic angle
FIGURE 24.11
Normal anatomy on the female chest x-ray. A Upright posterior-anterior position. B Lateral position.
Alveolar surface tension
Surface tension occurs at any gas–liquid interface and refers to the tendency for liquid molecules that are exposed to air to adhere to one another. This phenomenon can be seen in the way water drops ‘bead’ when splashed on a waterproof surface. Within a sphere, such as an alveolus, surface tension tends to make expansion difficult. Laplace’s law shows the relationship among pressure
to inflate the alveolus, the alveolus surface tension and radius: Pressure required 2 × surface tension to inflate the sphere = size of the radius (alveolus)
or, using terms, P = 2T/r, where P = pressure required to inflate a sphere, T = surface tension and r = radius.
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Scalenus muscles Intercostal muscles
Sternocleidomastoid
Pectoralis minor Serratus anterior
Rectus abdominis
B Intercostal muscles
Diaphragm Transversus thoracis
Serratus posterior superior
Serratus posterior interior
FIGURE 24.12
Muscles of ventilation. A Anterior view. B Posterior view.
Simply put, as the radius of the sphere (alveolus) becomes smaller, more and more pressure is required to inflate it. If the alveoli were lined with only a water-like fluid, breathing would be extremely difficult. Alveolar ventilation, or distension, is made possible by surfactant, which lowers surface tension by coating the air–liquid interface in the alveoli. Surfactant has a detergent-like effect that separates the liquid molecules, thereby decreasing alveolar surface tension. Surfactant lines the alveolar side of the alveolar–capillary membrane and reverses Laplace’s law, thereby allowing alveoli to inflate easily. If surfactant is not produced in adequate quantities, alveolar surface tension increases, which results in alveolar collapse, decreased lung expansion, increased work of breathing and severe gas exchange abnormalities. The decrease in surface tension caused by surfactant is also responsible for keeping the alveoli free of fluid. In the
absence of surfactant, water tends to move into the alveoli, which can lead to the life-threatening condition of pulmonary oedema (see Chapter 25). Also, insufficient surfactant production can contribute to the breathing difficulties experienced by premature babies.1
Elastic properties of the lung and chest wall
The lung and chest wall have elastic properties that permit expansion during inspiration and the return to resting volume during expiration. The effect is produced by elastin fibres in the alveolar walls and surrounding the small airways and pulmonary capillaries, as well as the surface tension at the alveolar air–liquid interface. The elasticity of the chest wall is the result of the configuration of the bones and muscles. Elastic recoil is the tendency of the lungs to return to the resting state after inspiration, in a similar way that an elastic band springs back into place after being stretched. Normal elastic recoil permits passive expiration, eliminating the need for major muscles of expiration. Passive elastic recoil may be insufficient during laboured breathing — that is, when minute volume is high and the accessory muscles of expiration may be needed. The accessory muscles are used also if disease compromises elastic recoil (e.g. in chronic obstructive pulmonary disease) or blocks the conducting airways. However, elastic recoil is not confined to the lungs: the chest wall also has elastic recoil. But this recoil is in the opposite direction — that is, it tends to pull the chest wall outwards, away from the lungs. In fact, the tendency of the outward elastic recoil of the chest wall is balanced by the tendency of the lungs to recoil or inwardly collapse around the hila. The negative pressure of the pleural space (between the parietal and visceral pleurae) is indicative of the different elastic recoils in the chest wall and lungs (that is, in opposite directions). Muscular effort is needed to overcome the resistance of the lungs to expand. The balance between the outward recoil of the chest wall and inward recoil of the lungs occurs at the end of expiration, where the functional residual capacity (the amount of air remaining in the lungs after normal tidal expiration) is reached (see Fig. 24.13). Compliance is the measure of lung and chest wall distensibility (stretchiness) and is defined as volume change per unit of pressure change. It represents the relative ease with which these structures can be stretched and is therefore the opposite of elasticity. Compliance is determined by alveolar surface tension and the elastic recoil of the lung and chest wall. Increased compliance indicates that the lung or chest wall is abnormally easy to inflate and has lost some elastic recoil. A decrease indicates that the lung or chest wall is abnormally stiff or difficult to inflate. Compliance is increased in the normal ageing process and in diseases such as emphysema, and is decreased in the acute respiratory distress syndrome, pneumonia, pulmonary oedema and fibrosis (these disorders are described in Chapter 25).
CHAPTER 24 The structure and function of the pulmonary system
A
Pleural space Lungs Diaphragm
Air flow
B Chest wall recoil
Chest wall
Lung recoil
Diaphragm relaxed
Diaphragm contracting
End of expiration
Inspiration Air flow
D Chest wall fully recoiled
Lung recoil
Chest wall recoil Muscular contraction dominates
Lung recoil
C
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Chest wall recoil
Muscular contraction maintains inflation
Lung recoil dominates
Diaphragm contracted
Diaphragm relaxing
End of inspiration
Expiration
FIGURE 24.13
The interaction of forces during inspiration and expiration. A Outward recoil of the chest wall equals inward recoil of the lungs at the end of expiration. B During inspiration, contraction of respiratory muscles, assisted by chest wall recoil, overcomes the tendency of the lungs to recoil. C At the end of inspiration, respiratory muscle contraction maintains lung expansion. D During expiration, respiratory muscles relax, allowing elastic recoil of the chest wall to deflate the lungs.
Airway resistance
Airway resistance, which is similar to resistance to blood flow (described in Chapter 22), is determined by the length, radius and cross-sectional area of the airways and density, viscosity and velocity of the gas (Poiseuille’s law). Airway resistance is normally very low. Most of the resistance occurs in the upper airways: half to two-thirds of total airway resistance occurs in the nose. The next highest resistance is in the oropharynx and larynx. Airway resistance increases when the diameter of the airways decreases. However, there is very little resistance in the bronchioles and alveoli of the lungs when considered in total because of their large cross-sectional area — that is, there are millions of tubes compared to the upper airways that have larger diameters but are essentially single passageways. Bronchoconstriction (narrowing of the airways), which increases airway resistance, may occur following release of
neurotransmitters from some parasympathetic nerve terminals. However, direct sympathetic nerve innervation of the airways is sparse and bronchodilation (dilation of the airways), which decreases resistance to airflow, is caused by β2 (beta)-adrenergic receptor stimulation, primarily through circulating adrenaline (see Chapter 6). Airway resistance can also be increased by oedema of the bronchial mucosa, such as that which occurs during an asthmatic episode, and by airway obstructions such as mucus, tumours or foreign substances.
The work of breathing
The work of breathing is determined by the muscular effort required for ventilation — that is, the energy expenditure. Normally very low, the work of breathing may increase considerably in diseases that disrupt the equilibrium between forces exerted by the lung and chest wall. More muscular effort is required when lung compliance decreases (e.g.
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pulmonary oedema), chest wall compliance decreases (such as in obesity or spinal deformity) or airways are obstructed by bronchospasm or mucus plugging (e.g. asthma or bronchitis). An increase in the work of breathing can result in a marked increase in oxygen consumption and can eventually lead to an inability to maintain adequate ventilation.
F OC US O N L E ARN IN G
1 Describe the work of the diaphragm in ventilation. 2 Describe the function of surfactant and how ventilation would be affected without surfactant. 3 Differentiate between elastic recoil and compliance. 4 Discuss the differences in airway resistance throughout the pulmonary system.
Ventilation
Ventilation is the mechanical movement of gas or air into and out of the lungs. It is often misnamed respiration, which is actually the exchange of oxygen and carbon dioxide during cellular metabolism. ‘Respiratory rate’ is actually the ventilatory rate, or the number of times gas is inspired and expired per minute. However, the term respiratory rate is often used in clinical practice, and you should understand that this term refers only to what we externally observe in the chest wall movement. At rest, the ventilatory rate is approximately 12 breaths per minute, but can range from 8 to 16 breaths per minute, depending on the resting state. For example, during sleep, ventilatory rate declines but is enough to sustain respiration. The size or amount of gas inspired or exhaled each breath is the tidal volume. The inspired and exhaled volumes are approximately the same and for our purposes we consider them equal. The tidal volume usually refers to the resting volume and in adults it is approximately 500 mL of air.
However, the amount of effective ventilation is calculated by multiplying the ventilatory rate (breaths per minute) by the volume or amount of air per breath (litres per breath: tidal volume). This is called the minute volume, because it is the amount of air breathed each minute and is expressed in litres per minute (L/min). The minute volume provides an approximation of the overall ventilation, but it does not account for dead space — the volume of air that does not reach the alveoli and therefore is not involved in gas exchange. The dead space in an adult is approximately 150 mL of air and is the air that resides in the conducting airways and so does not reach the gas-exchange zone. Alveolar ventilation takes into account the ‘wasted’ dead space air and is the ventilation that occurs at the alveoli: it provides a more accurate picture of the actual gas exchange. For instance, it is possible that, despite adequate minute volume, the alveolar ventilation is not sufficient for satisfactory gas exchange and therefore oxygenation. Table 24.2 provides an overview of five different tidal volume and ventilatory rate combinations with the same minute volume but vastly different alveolar ventilation rates. This issue is addressed again in Chapter 25. There are many different lung volumes and often information about these volumes aids in the diagnosis of disease and the evaluation of therapy. Pulmonary function tests are used to determine the lung volumes and, importantly, the flow rates that individuals can generate.2 Spirometry (literally meaning ‘to measure breathing’) is the most commonly used measure of determining pulmonary function. Any individual who has experienced breathing difficulties, such as asthma, will have undertaken spirometry evaluation of lung function. The different lung volumes and capacities (combinations of lung volumes) are graphically represented in Fig. 24.14; Table 24.3 explains how each is derived. Two primary variables used to determine lung volume and flow changes are (1) the forced expiratory volume in the first second of exhalation, abbreviated to FEV1 and (2) the forced vital capacity (FVC), or the maximal amount of
TABLE 24.2 Alveolar ventilation differences
DESCRIPTION
Large slow breaths
TIDAL VOLUME (mL)
VENTILATORY RATE (BREATHS/MIN)
MINUTE VOLUME (mL)
DEAD SPACE (mL)
ALVEOLAR VENTILATION (mL/MIN)
1000
6
6000
150
5100
Normal resting breaths
500
12
6000
150
4200
Fast small breaths
300
20
6000
150
3000
Faster little breaths
200
30
6000
150
1500
Rapid very shallow breaths
150
40
6000
150
0
Minute volume = ventilatory rate × tidal volume Alveolar ventilation = ventilatory rate × (tidal volume – dead space), e.g. alveolar ventilation = 12 × (500 – 150) = 4200 mL per minute Note: the shaded figures represent inadequate alveolar ventilation to maintain adequate supply of oxygen and removal of carbon dioxide from the body cells.
CHAPTER 24 The structure and function of the pulmonary system
695
5.0
Volume (L)
Inspiratory reserve volume (3000 mL)
Inspiratory capacity (3500 mL)
3.0 2.5
Tidal volume (approx. 500 mL)
Functional 1.25 residual capacity (1800–2400 mL)
Vital capacity (4000–5000 mL) Total lung capacity Expiratory (5500–6000 mL) reserve volume (1200 mL)
Residual volume (1200 mL)
0 FIGURE 24.14
Respiratory volumes and capacities as determined using spirometry. The dynamic lung volumes that can be measured by simple spirometry are the tidal volume, inspiratory reserve volume, expiratory reserve volume, inspiratory capacity and vital capacity. The static lung volumes are the residual volume, functional residual capacity and total lung capacity. Static lung volumes cannot be measured by simple spirometry and require separate methods of measurement (e.g. inert gas dilution, nitrogen washout or whole-body plethysmography).
TABLE 24.3 Respiratory volumes and capacities DESCRIPTION AND MEASUREMENT
Respiratory volumes Tidal volume (V T )
The amount of air inspired or exhaled in a normal resting breath
Inspiratory reserve volume (IRV)
The maximal amount of air that can be inhaled after tidal volume
Expiratory reserve volume (ERV)
The maximal amount of air that can be exhaled after tidal volume
Residual volume (RV)
The amount of air that remains in the lungs after a maximal exhalation
Respiratory capacities Inspiratory capacity (IC)
The amount of air inspired by maximum inspiratory effort after tidal volume, expiration IC = V T + IRV
Vital capacity (VC)
The amount of air that can be forcibly expired after a maximal inspiration, VC = V T + IRV + ERV
Functional residual capacity (FRC)
The amount of air left in the lungs after normal tidal expiration, FRC = ERV + RV
Total lung capacity (TLC)
The volume of air occupying the lungs after maximum inhalation, TLC = V T + IRV + ERV + RV
air that can be forcibly expelled from the lungs in one breath. These two variables, and the ratio of them, provide important information about the type of pulmonary alteration, the effects of medication (specifically bronchodilators — medication that causes an increased opening of the bronchioles) and the extent of disease (see Fig. 24.15). The
relationship between FEV1 and FVC can be calculated using this equation: FEV1 × 100 FVC = 70% (or greater)
FEV1 FVC ratio =
An FEV1/FVC ratio of 70% is considered to be at the lower end of the normal range. This indicates that for a healthy individual, 70% of their forced vital capacity can be exhaled within the first second, but the exact limit is age dependent. An older adult may have normal function at 70% and a younger adult may have normal function at 80% exhibiting a considerable standard deviation to the normal value. Pulmonary function test values change over the life span and are influenced by height, sex, age and race. Usually, the individual’s results are compared against predicted values. FEV1 and FVC are addressed again in Chapter 25, when characterising alterations in pulmonary function.
Control of ventilation
The air that we breathe contains many gases; however, only two gases are actively involved in respiration — oxygen and carbon dioxide. Of these, carbon dioxide has a greater influence over the chemical control of ventilation and is under tight control. This can be easily demonstrated by trying to hold your breath for an extended period of time: the impetus to breathe rises more strongly from the increase in carbon dioxide level in the blood rather than the decrease in oxygen levels. Below we explore the neural and chemical control of ventilation in more detail. Breathing is usually involuntary, because homeostatic changes in the ventilatory rate and tidal volume are adjusted automatically by the nervous system to maintain normal
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A
FEV1
Volume (L)
3 2 1 0
0
10
B
automatic ventilatory rhythm is set by the dorsal respiratory group (located in the medulla), which receives afferent input (sensory nerve) from peripheral chemoreceptors in the carotid and aortic bodies and from several different types of receptors in the lungs (see below). The ventral respiratory group (also located in the medulla) contains both inspiratory and expiratory neurons and is almost inactive during normal, quiet ventilation, becoming active when increased ventilatory effort is required. The pneumotaxic centre and apneustic centre, situated in the pons (above the medulla), do not generate primary rhythm but, rather, act as modifiers of the rhythm established by the medullary centres. It should be noted that the pattern of breathing can be influenced by many factors, such as emotions, pain and disease.
FVC
4
2
4 Time (s)
6
8
PEF
8 Expiratory curve
Flow (L/s)
6
FEV1
4 2 0
–2 –4 –6 –8
FVC 1
2
3
4
Volume (L)
Inspiratory VC Inspiratory curve
FIGURE 24.15
Normal spirogram and flow volume loop. A A normal spirogram that plots volume against time during a rapid forceful exhalation. It shows the measurement of force expired volume in one second (FEV1) and forced vital capacity. This displays only the expiratory portion. B A flow volume loop which is the measurement of normal maximal expiratory and inspiratory effort.
gas exchange. Voluntary breathing is necessary for many activities, such as talking, singing, laughing and deliberately holding one’s breath. The control of ventilation is complex and requires input from many sources — neural (autonomic and voluntary or higher centre control), mechanical (stretch and irritant receptors in the lungs and muscles involved in ventilation) and chemical (predominately carbon dioxide and oxygen levels in the blood and cerebrospinal fluid). The coordination of ventilation occurs in the medulla and pons of the brainstem, and a constant supply of information is required to make the fine adjustments needed to maintain adequate ventilation. These factors are summarised in Fig. 24.16. NEURAL CONTROL
The respiratory centre in the brainstem controls ventilation by transmitting impulses to the respiratory muscles, causing them to contract and relax. The respiratory centre is composed of several groups of neurons: the dorsal respiratory group, the ventral respiratory group, the apneustic centre and the pneumotaxic centre.4 The exact nature of each group is not entirely understood; however, it is thought that the
MECHANICAL CONTROL
Three types of lung receptors send impulses from the lungs to the dorsal respiratory group: 1 Irritant receptors are found in the epithelium of all conducting airways. They are sensitive to noxious aerosols (vapours), gases and particulate matter (e.g. inhaled dusts), which cause them to transmit impulses to the medullary centre to initiate a cough reflex. When stimulated, irritant receptors also lead to bronchoconstriction and an increase in ventilatory rate. 2 Stretch receptors are located in the smooth muscles of airways and are sensitive to increases in the size or volume of the lungs. When stimulated, ventilatory rate and volume will decrease, an occurrence sometimes referred to as the Hering-Breuer reflex. This reflex is active in newborns and assists with ventilation. In adults, this reflex is active only at high tidal volumes (such as with exercise) and may protect against excess lung inflation. 3 J-receptors are located near the capillaries in the alveolar septa (lining or membranes). They are sensitive to increased pulmonary capillary pressure, which results in rapid shallow breathing, hypotension and bradycardia. The lung is innervated by the autonomic nervous system; however, the primary neural control of the bronchioles comes from the parasympathetic fibres which travel in the vagus nerve to the lung (the structure and function of the autonomic nervous system is covered in detail in Chapter 6). The parasympathetic division controls airway diameter (interior diameter of the airway lumen) by causing bronchoconstriction of the smooth muscles. In contrast, the sympathetic nerve fibres are sparse, and bronchodilation is mediated by stimulation of β2-receptors responding to circulating adrenaline. Constriction occurs if the irritant receptors in the airway epithelium are stimulated by irritants in inspired air (such as dust and pollen), by endogenous substances (such as histamine, serotonin, prostaglandins) and by many drugs (such as β-blockers). CHEMICAL CONTROL
Chemoreceptors monitor the pH, carbon dioxide level in the arterial blood (PaCO2, with the lower case ‘a’ referring
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Blood–brain barrier Voluntary and higher centres
Capillary
HCO–3 H+
H2O + CO2 H2CO3
CO2 H+
H+ + HCO –3
Control centres Pneumotaxic centre (inspiration) Chemosensitive centre (sensitive to H+, O2 and CO2) Apneustic centre (inspiration and expiration) Dorsal respiratory group (inspiration) Ventral respiratory group (inspiration and expiration)
Stretch Vagus nerve
Irritant J-receptors
Vagus nerve Carotid body
Aortic bodies
Intercostal nerve
↓ PO2 Phrenic nerve (to diaphragm) FIGURE 24.16
Respiratory centres in the brain and the multiple inputs for the control of ventilation. The respiratory control centres in the brain are shown in the middle of the diagram. Important inputs to the respiratory control centres include the carbon dioxide and acid levels (in upper right corner), the chemoreceptors located in major blood vessels near the heart (in lower left corner), and stretch and irritant receptors in the lungs. This information is coordinated by the respiratory control centres which send outputs to control respiratory function.
to arterial) and oxygen level in the arterial blood (PaO2). There are two groups of chemoreceptors: (1) central chemoreceptors located in the brainstem near the respiratory centres; and (2) peripheral chemoreceptors located in the aortic and carotid bodies (see Fig. 24.16). Central chemoreceptors monitor arterial blood indirectly by sensing changes in the pH (hydrogen ion content) of cerebrospinal fluid. They are sensitive to hydrogen ion concentration, or the amount of acid, in the cerebrospinal
fluid. The pH of the cerebrospinal fluid reflects arterial pH because carbon dioxide in arterial blood can diffuse across the blood–brain barrier (the capillary wall separating blood from cells of the central nervous system) into the cerebrospinal fluid until the carbon dioxide level is equal on both sides. Carbon dioxide that has entered the cerebrospinal fluid combines with water to form carbonic acid (a weak acid), which subsequently dissociates into hydrogen ions that are capable of stimulating the central
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chemoreceptors. In this way, carbon dioxide regulates ventilation through its impact on the pH (hydrogen ion content) of the cerebrospinal fluid.2,3 If alveolar ventilation is inadequate or there is a substantial increase in the metabolic rate, the carbon dioxide level in the blood increases. Carbon dioxide diffuses across the blood–brain barrier until the level of carbon dioxide in the blood and cerebrospinal fluid reaches equilibrium. As the central chemoreceptors sense the resulting decrease in pH (which is actually an increase in acid), they stimulate the respiratory centre to increase the depth and rate of ventilation. Increased ventilation causes the carbon dioxide level of arterial blood to decrease below that of the cerebrospinal fluid, and carbon dioxide diffuses back out of the cerebrospinal fluid and pH returns to normal levels. The homeostatic control of this mechanism is outlined in Fig. 24.17. Central chemoreceptors are sensitive to very small changes in the pH of cerebrospinal fluid (equivalent to a 1–2 mmHg change in carbon dioxide levels) and can maintain a normal carbon dioxide level under many different conditions, including strenuous exercise. If inadequate ventilation, or hypoventilation, is long term (such as in chronic obstructive pulmonary disease), these receptors may become insensitive to small changes in carbon dioxide levels in the blood and ‘reset’ to a higher level. The carbon dioxide in the blood then needs to rise to a level above that which it normally regulates before an increase in ventilatory drive will be instigated. Peripheral chemoreceptors are somewhat sensitive to changes in carbon dioxide levels and pH but are sensitive primarily to oxygen levels in arterial blood. As oxygen levels in the blood and pH decrease, peripheral chemoreceptors, particularly the carotid bodies, send afferent signals to the respiratory centre to increase ventilation. However, the oxygen level of the blood must drop well below normal (from 100 mmHg to approximately 60 mmHg) before the peripheral chemoreceptors have much influence on ventilation. If this situation occurs with an increase in carbon dioxide levels as well, ventilation increases much more than it would in response to either abnormality alone. Also, the peripheral chemoreceptors become the major stimulus to ventilation when the central chemoreceptors are reset by chronic hypoventilation.2 F OCU S O N L E ARN IN G
1 Describe the different lung volumes and capacities and how they are related. 2 Discuss pulmonary function tests and the implications for clinical practice. 3 Describe 3 functions of the respiratory centres in the medulla and pons. 4 List the different lung receptors and their functions. 5 Differentiate between the functions of the central and peripheral chemoreceptors.
Gas transport
Gas transport, the delivery of oxygen to the cells of the body and the removal of carbon dioxide, has four steps: 1 ventilation of the lungs 2 diffusion of oxygen from the alveoli into the capillary blood 3 perfusion of systemic capillaries with oxygenated blood 4 diffusion of oxygen from systemic capillaries into the cells. Steps in the transport of carbon dioxide occur in reverse order: 1 diffusion of carbon dioxide from the cells into the systemic capillaries 2 perfusion of the pulmonary capillary bed by venous blood 3 diffusion of carbon dioxide into the alveoli 4 removal of carbon dioxide from the lung by ventilation. It is important to understand that disruption at any step can lead to inadequate gas exchange at the cellular level. The diffusion of oxygen across the alveoli into the blood and carbon dioxide from the blood into the alveoli occurs due to the change in concentration gradient, with gases moving from an area of higher to lower concentration. This occurs even when the gases are dissolved in liquid (blood and cerebrospinal fluid) or in body tissues. To gain a more complete understanding of diffusion, we now explore the physical properties of gases.
Gas pressure
The atmosphere is composed of many gases. The most prevalent gases are nitrogen and oxygen, which together account for 99% of all gases in the atmosphere (see Table 24.4). Other gases in smaller concentrations include carbon dioxide. These gases are made up of millions of molecules moving randomly and colliding with each other. When a gas is within a closed space (such as the lungs), the molecules collide with the walls of the space in which they are contained. All of these collisions exert pressure. If the same number of gas molecules are contained in a small container and a large container, the pressure will be greater in the small container because more collisions occur in the smaller space (see Fig. 24.18). If there are many gases in a confined space, the pressure exerted by each individual gas, the partial pressure, is directly proportional to the percentage of that gas in the mixture of gases. For instance, there is more nitrogen in the atmosphere than oxygen, so the partial pressure of nitrogen is greater. Heat increases the speed of the molecules, which also increases the number of collisions and therefore the pressure. Barometric pressure (which is actually atmospheric pressure) is the pressure exerted by gas molecules in the air at specific altitudes. At sea level, barometric pressure is 760 mmHg and is the sum (total) of the pressure exerted
CHAPTER 24 The structure and function of the pulmonary system
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FIGURE 24.17
Homeostatic control responding to an increase in carbon dioxide levels in the blood. Increased carbon dioxide levels are detected by chemoreceptors in major blood vessels (the carotid and aortic arch), and by chemoreceptors in the brain that monitor the CSF. These chemoreceptors communicate this to the respiratory control centres to increase the rate and depth of breathing, to remove excess carbon dioxide from the blood.
by all the gases in the air at sea level. The partial pressure of a gas is calculated as: Partial pressure = percentage of gas × total pressure Example: Partial pressure = 20.9% × 760 mmHg of oxygen (PO2 ) = 159 mmHg
Therefore, the partial pressure of the respiratory gases will change throughout the lungs and in the blood. As oxygen and carbon dioxide diffuses across membranes this will affect the partial pressure. The compositions of atmospheric air and alveolar air are shown in Table 24.4. Another important factor for gas exchange is water vapour. The amount of water vapour contained in a gas mixture is determined by the temperature of the gas, but is unrelated to barometric pressure. Gas that enters the
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TABLE 24.4 The composition of gas partial pressures in the atmosphere and how they change in the lungs ATMOSPHERIC AIR (SEA LEVEL) GAS
PERCENTAGE (%)
PARTIAL PRESSURE (mmHg)
HUMIDIFIED AIR (UPPER AIRWAY) PERCENTAGE(%)
PARTIAL PRESSURE (mmHg)
ALVEOLAR AIR (GAS-EXCHANGE UNITS) PERCENTAGE (%)
PARTIAL PRESSURE (mmHg)
Nitrogen (N2)
78.6
597
74.1
564
74.9
569
Oxygen (O2)
20.9
159
19.7
149
13.7
104
5.2
40
6.2
47
Carbon dioxide (CO2)
0.04
0.3
0.04
Water (H2O)
0.5
3.7
6.2
Total
100
760
100
0.3 47 760
100
760
Note: percentages are approximate.
lungs becomes saturated with water vapour (humidified) as it passes through the upper airway. At body temperature (approximately 37°C), water vapour exerts a pressure of 47 mmHg. The partial pressure of water vapour must be subtracted from the barometric pressure before the partial pressure of other gases in the mixture can be determined. In saturated air at sea level, the partial pressure of oxygen is therefore (760 mmHg – 47 mmHg) × 0.209 = 149 mmHg. See Table 24.4 for how this changes the partial pressures of other gases.
Distribution of ventilation and perfusion
Effective gas exchange depends on an approximately even distribution of gas (ventilation) and blood (perfusion) in all portions of the lungs. The lungs are actually suspended from the hila in the thoracic cavity. When an individual is in an upright position (sitting or standing), gravity pulls the lungs down towards the diaphragm and compresses their lower portions, commonly referred to as the bases. The alveoli in the upper portions, specifically the apices, of the lungs contain a greater residual volume of gas and are larger and less numerous than those in the lower portions. Because surface tension increases as the alveoli become larger, the larger alveoli in the upper portions of the lung are more difficult to inflate (that is, they are less compliant) than the smaller alveoli in the lower portions of the lung. Therefore, during ventilation most of the tidal volume is distributed to the bases of the lungs, where compliance is greater. Remember that an increased compliance indicates that the lungs are easier to inflate. The heart pumping blood to the lungs is also affected by gravity. As blood is pumped into the lung apices of an upright individual, some blood pressure is dissipated in overcoming gravity. As a result, blood pressure at the apices is lower than that at the bases. Because greater pressure results in greater perfusion, the bases of the lungs are better perfused than the apices. Thus, ventilation and perfusion are greatest in the same lung portions, the lower lobes.
However, if a standing or sitting individual assumes a supine position, the apex and base of the lungs are at a similar level and ventilation is relatively more uniformly distributed. In addition, the posterior region of the lungs receives more blood than the anterior, due to the effects of gravity. Distribution of perfusion in the pulmonary circulation is also affected by alveolar pressure (gas pressure in the alveoli). The pulmonary capillary bed differs from the systemic capillary bed in that it is surrounded by gas-containing alveoli. If the gas pressure in the alveoli exceeds the blood pressure in the capillary, the capillary collapses and flow ceases. This is most likely to occur in portions of the lung where blood pressure is lowest and alveolar gas pressure is greatest; that is, at the apex of the lung. The lungs are divided into three zones on the basis of relationships among all the factors affecting pulmonary blood flow: • In zone I, alveolar pressure exceeds pulmonary arterial and venous pressures. The capillary bed collapses and normal blood flow ceases. Normally zone I is a very small part of the lung at the apex. • In zone II, alveolar pressure is greater than venous pressure but not arterial pressure. Blood flows through zone II, but it is impeded to a certain extent by alveolar pressure. Zone II is normally above the level of the left atrium. • In zone III, both arterial and venous pressures are greater than alveolar pressure and blood flow is not affected by alveolar pressure. Zone III is in the base of the lung. Blood flow through the pulmonary capillary bed increases in regular increments from the apex to the base. Alveolar pressure plus the forces of gravity, arterial blood pressure and venous blood pressure affect the distribution of perfusion, as shown in Fig. 24.19. Although both blood flow and ventilation are greater at the base of the lungs than at the apices, they are not
CHAPTER 24 The structure and function of the pulmonary system
A
B
10 particles of air at a total pressure of 10
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C
20 particles of air at a higher pressure
O2 blue
N2 black
FIGURE 24.18
The relationship between the number of gas molecules and the pressure exerted by the gas in an enclosed space. A Theoretically, 10 molecules of the same gas exert a total pressure of 10 within the space. B If the number of molecules is increased to 20, total pressure is 20. C If there are different gases in the space, each gas exerts a partial pressure that is directly proportional to the percentage of that gas in the total. For instance, the partial pressure of nitrogen will be greater than oxygen as there is more nitrogen than oxygen.
Alveolus
Apex
Arteriole
Capillary Venule
Zone I PA > Pa > PV
Alveolus
Zone II Pa > PA > PV
Pulmonary artery
Pulmonary vein
Alveolus
Zone III Pa > PV > PA
FIGURE 24.19
Gravity and alveolar pressure. Effects of gravity and alveolar pressure on pulmonary blood flow in the three lung zones. In zone I, alveolar pressure (PA) is greater than arterial and venous pressure, and no blood flow occurs. In zone II, arterial pressure (Pa) exceeds alveolar pressure, but alveolar pressure exceeds venous pressure (PV). Blood flow occurs in this zone, but alveolar pressure compresses the venules (venous ends of the capillaries). In zone III, both arterial and venous pressures are greater than alveolar pressure and blood flow fluctuates depending on the difference between arterial and venous pressure.
perfectly matched in any zone. Perfusion exceeds ventilation in the bases and ventilation exceeds perfusion in the apices of the lung. The relationship between ventilation and perfusion is expressed as a ratio called the ventilation/ perfusion ratio (V/Q). The normal ventilation/perfusion ratio is approximately 0.8, which means that perfusion usually exceeds ventilation under normal conditions.
Alterations to the ventilation/perfusion ratio are discussed in Chapter 25.
Oxygen transport
Approximately 1000 mL (1 litre) of oxygen is transported to the cells of the body each minute. Oxygen is transported in the blood in two forms: a small amount dissolves in
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plasma (1.5%), as oxygen does not readily dissolve in water; and the remainder binds to haemoglobin (Hb) molecules (98.5%). Without haemoglobin, oxygen would not reach the cells in amounts sufficient to maintain normal metabolic function. DIFFUSION ACROSS THE ALVEOLAR–CAPILLARY MEMBRANE
The alveolar–capillary membrane is ideal for oxygen diffusion because it has a large total surface area (70–100 m2) and is very thin (0.5 micrometre (µm) — this is about 50 times thinner than an average human hair). In addition, the partial pressure of oxygen molecules in alveolar gas (PAO2, the capital ‘A’ referring to alveolar) is much greater than in capillary blood, a condition that promotes rapid diffusion down the concentration gradient from the alveolus into the capillary. The partial pressure of oxygen in mixed venous (deoxygenated) or pulmonary artery blood (PVO2, the ‘V’
standing for venous) is approximately 40 mmHg as it enters the capillary — this is the venous blood which has returned to the heart from the systemic circulation. The alveolar oxygen partial pressure is approximately 100 mmHg at sea level. Therefore, a pressure gradient of 60 mmHg facilitates the diffusion of oxygen from the alveolus into the capillary (Fig. 24.20). Blood remains in the pulmonary capillary at the alveoli for about 0.75 seconds, but only 0.25 seconds is required for the oxygen concentration to equilibrate across the alveolar–capillary membrane. Therefore, oxygen has ample time to diffuse into the blood, even during increased cardiac output, which speeds blood flow and shortens the time the blood remains in the capillary. DETERMINANTS OF ARTERIAL OXYGENATION
As oxygen diffuses across the alveolar–capillary membrane, it dissolves in the plasma, where it exerts pressure (the partial pressure of oxygen in arterial blood, or PaO2, the
FIGURE 24.20
The changes in the partial pressures of respiratory gases. The partial pressures for oxygen and carbon dioxide are approximations only. There will be subtle differences in each breath and dependent on the activity of the individual. The numbers shown are average values near sea level. The values of PaO2 and PaCO2 fluctuate from breath to breath.
CHAPTER 24 The structure and function of the pulmonary system
small ‘a’ standing for arterial, as opposed to a capital ‘A’). As the PaO2 increases, oxygen moves from the plasma into the red blood cells (erythrocytes) and binds with haemoglobin molecules. Oxygen continues to bind with haemoglobin until the haemoglobin binding sites are filled or fully saturated (meaning that no more oxygen can bind to the haemoglobin). Each molecule of haemoglobin can bind four molecules of oxygen, with millions of haemoglobin molecules found in each red blood cell. Oxygen then continues to diffuse across the alveolar–capillary membrane until the PaO2 (arterial oxygen) and PAO2 (alveolar oxygen) equilibrate, eliminating the pressure gradient across the alveolar–capillary membrane. At this point, diffusion ceases (see Fig. 24.20). In this way, oxygen is transported to the body cells and the reverse process occurs to unload oxygen from haemoglobin so that it can diffuse from the blood into the interstitium and ultimately the cells (see Fig. 24.21). In clinical practice, the amount of oxygen in the arterial blood (PaO2) can be measured in the blood by obtaining an arterial blood gas (ABG) measurement. This provides vital information about the individual’s oxygenation status. In addition, the percentage of the available haemoglobin that is bound to oxygen, or the oxygen saturation (SaO2), can be measured. However, more routine is the use of pulse oximetry, which provides an indirect non-invasive measure of oxygen saturation. The pulse oximeter uses light of two different wavelengths to detect the presence of haemoglobin in blood that is saturated or desaturated with oxygen. However, it should be noted that oxygen saturation measured with a pulse oximeter (SpO2) is an approximation of the
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directly measured oxygen saturation (SaO2) and there may be differences between the values. Because haemoglobin transports all but a small fraction of the oxygen carried in arterial blood, changes in haemoglobin concentration affect the oxygen content of the blood. Decreases in haemoglobin concentration below the lower limit of the reference range (males: 130 g/L; females: 115 g/L) reduce the oxygen content and increases in haemoglobin concentration may increase the oxygen content, minimising the impact of impaired gas exchange. In fact, increased haemoglobin concentration is a major compensatory mechanism in pulmonary diseases that impair gas exchange. For this reason, measurement of haemoglobin concentration is important in assessing individuals with pulmonary disease. If cardiovascular function is normal, the body’s initial response to low oxygen content is to elevate the heart rate and stroke volume, which will increase cardiac output. In individuals who also have cardiovascular disease, this compensatory mechanism will not be optimal, making increased haemoglobin concentration an even more important compensatory mechanism. (Haemoglobin structure and function are described in Chapter 16.) THE OXYGEN–HAEMOGLOBIN DISSOCIATION CURVE
The importance of haemoglobin in gas exchange is paramount. Haemoglobin has the ability to both bind and unbind oxygen, making the process of oxygen transportation very efficient. Oxygen binds to haemoglobin and becomes oxyhaemoglobin, abbreviated as HbO2 (see Fig. 24.21).
Blood vessel
FIGURE 24.21
Oxygen transport. Steps in the process are as follows. 1 Oxygen in the alveolus diffuses down the concentration gradient into the capillary. 2 Oxygen binds to haemoglobin to form oxyhaemoglobin (HbO2) and is dissolved in the blood (PaO2). 3 Oxygen is transported to all body tissues. 4 Oxygen dissociates from haemoglobin. 5 Oxygen diffuses down the concentration gradient into the body tissues.
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Oxygen binding occurs more readily following subsequent bindings — that is, the affinity of haemoglobin for oxygen increases. Once haemoglobin cannot accept more oxygen it is termed fully saturated. At the body tissues, the haemoglobin then releases its oxygen (and is thus called deoxyhaemoglobin). Oxygen is then available to diffuse into the cells. In this way, the oxygen binds to haemoglobin in the lungs and is released at the body tissues where it is needed.4 The oxygen–haemoglobin dissociation curve (see Fig. 24.22) describes the relationship between the partial pressure of oxygen (PaO2) and the oxygen bound to haemoglobin (the degree of haemoglobin saturation). The distinctive S-shaped curve has a flattened portion at the top, which represents the binding of oxygen with haemoglobin in the lungs (the association portion). Above 70 mmHg only small amounts of oxygen binding occur with increasing PaO2. This is advantageous, because at low PaO2 levels, binding and releasing of oxygen from haemoglobin will still occur normally. However, at rest, when the PaO2 is 100 mmHg the haemoglobin is 98% saturated and further increases in PaO2 do not result in increased SaO2. The steep portion of the curve represents the unloading of oxygen from haemoglobin at the tissue level. This is also advantageous
to efficient respiration because small decrements in PaO2 result in substantial unloading of oxyhaemoglobin and diffusion of oxygen into the tissues. Several factors can alter the binding and release of oxygen from haemoglobin, causing the curve to shift to the right or left (Fig. 24.23). A shift to the right results in a decreased affinity in haemoglobin for oxygen, or an increase in the ease with which oxyhaemoglobin dissociates and oxygen moves into the cells. A shift to the left results in an increased affinity in haemoglobin for oxygen, which promotes oxygen binding to haemoglobin in the lungs and inhibits release at the tissues. The factors that affect the affinity include the amount of oxygen dissolved in the blood (PaO2), the amount of carbon dioxide dissolved in the blood (PaCO2), temperature, pH and a chemical in erythrocytes called 2,3-diphosphoglycerate, abbreviated to 2,3-DPG (see Fig. 24.23).
Carbon dioxide transport
Carbon dioxide is carried in the blood in three ways: 1 Dissolved in plasma (PaCO2: about 10%): as an end product of metabolism, carbon dioxide diffuses out of the cells into the blood and dissolves in the plasma. The concentration of dissolved carbon dioxide is greater than oxygen because carbon dioxide is 20 times more soluble in plasma than oxygen. 2 Bound to haemoglobin (about 20%): carbon dioxide also binds to haemoglobin (as carbaminohaemoglobin) and this binding occurs more readily when deoxygenated haemoglobin is available (and carbon dioxide binds to a different component of haemoglobin than oxygen).
FIGURE 24.22
The oxygen–haemoglobin dissociation curve. The horizontal or flat segment of the curve at the top of the graph is the arterial or association portion, or that part of the curve where oxygen is bound to haemoglobin, and occurs in the lungs (‘oxygenated blood in lungs’ circle). This portion of the curve is flat because partial pressure changes of oxygen between 60 and 100 mmHg do not significantly alter the percentage saturation of haemoglobin with oxygen. If the relationship between SaO2 and PaO2 were linear (in a downward-sloping straight line) instead of being flat between 60 and 100 mmHg, there would be inadequate saturation of haemoglobin with oxygen. The steep part of the oxygen–haemoglobin dissociation curve represents the rapid dissociation of oxygen from haemoglobin that occurs in the tissues. During this phase there is rapid diffusion of oxygen from the blood into tissue cells (‘oxygen release into tissues’ circle).
FIGURE 24.23
Factors affecting the oxygen–haemoglobin dissociation curve. Factors that influence haemoglobin affinity for oxygen are represented as shifts to the left and right. The conditions that cause this are listed. 2,3-DPG = 2,3-diphosphoglycerate.
CHAPTER 24 The structure and function of the pulmonary system
The carbon dioxide is transported to the lungs and will release from the haemoglobin down the diffusion gradient (carbon dioxide in the lung, PACO2). − 3 As bicarbonate ion (HCO3 : about 70%): the majority of carbon dioxide transport occurs when carbon dioxide diffuses into the red blood cells. The enzyme carbonic anhydrase greatly increases the reaction of carbon dioxide and water to form carbonic acid. However, carbonic acid is unstable and quickly dissociates (separates) into hydrogen ions (H+) and bicarbonate ions (HCO3−). The bicarbonate ions move out of the red blood cell into the plasma and are transported to the lungs where the process reverses to release carbon dioxide. This relationship can be seen in the following equation: CO2
+
H2O
→
H2CO3
carbon dioxide
+
water
→
carbonic acid
+
HCO3
+
bicarbonate ion
→
H
→
hydrogen ion
+
The diffusion gradient for carbon dioxide in the lung is only approximately 6 mmHg (venous carbon dioxide is 46 mmHg and alveolar carbon dioxide is 40 mmHg) (see Fig. 24.20). Yet carbon dioxide is so soluble in the alveolar– capillary membrane that the carbon dioxide in the blood quickly diffuses into the alveoli, where it is removed from the lung during expiration. Diffusion of carbon dioxide in
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the lung is so efficient that diffusion defects that cause hypoxaemia (low oxygen concentrations in the blood) do not as readily cause hypercapnia (excessive carbon dioxide levels in the blood). The diffusion of carbon dioxide out of the blood is enhanced by oxygen binding with haemoglobin in the lung. As haemoglobin binds with oxygen, the amount of carbon dioxide carried by the blood decreases. Thus, in the tissue capillaries, oxygen release from haemoglobin facilitates the binding of carbon dioxide, and conversely the binding of oxygen to haemoglobin in the lungs facilitates the release of carbon dioxide from the blood. This effect of oxygen on carbon dioxide transport is known as the Haldane effect.5 FOCU S ON L EA RN IN G
1 List the 8 steps in gas transport. 2 Discuss the differences in the partial pressure of respiratory gases from outside to inside the lungs. 3 Describe the alveolar–capillary membrane and how it functions in ventilation and perfusion. 4 Differentiate between different forms of oxygen and carbon dioxide transport in the blood. 5 Describe the oxygen–haemoglobin dissociation curve and how different factors affect it.
Over the life span there are numerous changes to the pulmonary system. These changes are both anatomical and functional. The fetal lungs are immature and do not have definite alveoli like those of the adult. In fact, the alveolar stage, which signifies the commencement of alveoli development, begins at about 36 weeks of gestation. Moreover, these alveoli are not the same as the adult form. The ability of premature infants to survive before 24 weeks of gestation is severely limited because of the lack of lung development. The epithelial lining has sufficiently thinned at around 24 weeks, which permits gas exchange, and type II cells that produce surfactant, facilitating ventilation, also appear at this time. The final stage of lung development continues until approximately 2 years of age; however, the number of alveoli and, therefore the surface area of the lungs, increases throughout development until adulthood.
The newborn’s lungs are considerably different from the adult’s. At birth, an infant has approximately 25 million alveoli compared to the 300 million in adulthood. The reduced alveoli number means that surface area is also considerably reduced (3–4 m2 compared to 75–100 m2 in the adult). In addition, there are fewer pores of Kohn (passageways between successive alveoli) and a thicker alveolar–capillary membrane compared to adulthood. Therefore, airway resistance is higher than in adulthood (about 16-fold difference) and there is less available lung volume (150–200 mL compared to 5000 mL in the adult). The infant compensates for this smaller volume by increasing the ventilatory rate.6 Overall, the infant’s lungs are functional yet still immature. They have to undergo considerable development to increase the surface area and available alveoli.
PAEDIATRICS
Paediatrics and the pulmonary system
Ageing and the pulmonary system Extrapulmonary structural changes occur in the thoracic cage and may involve age-related calcification, articulations, and kyphosis secondary to osteoporosis.7 The result of these changes makes the chest wall still which is reflected as a decrease in chest wall compliance. Continued
AGEING
With increasing age, the pulmonary system changes in many ways from younger adulthood. Age-related changes in the respiratory system occur anatomically and physiologically and are also linked with immunological changes both within the lungs and systemically.
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Potential immune response alteration
CONCEPT MAP
This can have a direct and discernible effect on lung volumes. Manifestation of this is seen in an increased residual volume and resulting decreased vital capacity, causing the older adult to increase their work of breathing. Complementary to this is the decrease in strength of the respiratory muscles due to ageing. Changes in nutritional status and generalised muscle degeneration contribute to the impact of changes in chest wall configuration and the force generation capacity of the diaphragm. The changes increase diaphragmatic fatigue and the risk of ventilatory failure in older people. Age-related intrapulmonary changes can cause an increase in lung hyperinflation, decreased gas exchange and further decrease in lung compliance.8 This can be attributed to the degeneration of the elastic fibres around the alveolar duct occurs, associated with an increase in collagen, which results in enlargement of airspaces. Structurally these affect the elastic properties of the lung tissue leading to decreased lung compliance. Gas exchange capacity is affected by the reduced alveolar surface area which is a result of less alveoli and an increase in the size of alveolar ducts. Hyperinflation is a result of early end-of-expiration airway closure and air trapping can occur.7,8 Immunological changes related to ageing also contribute to alterations within and outside of the lungs. Studies
↓ Mucus clearance
↓ Cilia number
have identified inflammatory infiltrates in lung fluid samples obtained from older people. The presence of these cells and markers are possibly related to the lifelong exposure to antigens, prolonged exposure to environmental stimuli such as pollution and environmental tobacco smoke, or to age-related changes to inherent immunity. While newborns have relatively immature lungs at birth and development continues in the first years of life, elderly individuals gradually lose lung function through a variety of mechanisms as mentioned above. Additionally there is a decrease in the number of cilia, which reduces mucus clearance and can expose the elderly individual to pathogenic infections. The pulmonary capillary network decreases and there is a reduction in pulmonary arterial blood flow, which lowers the diffusion capacity and decreases gas exchange. This often results in ventilation– perfusion mismatches, reducing the partial pressure of oxygen (PaO2). Therefore, the ventilatory capacity of the elderly is markedly reduced compared to their younger counterparts.8 It is important to remember that the respiratory system will also reflect changes that happen in other systems of the body like the cardiovascular, musculoskeletal and nervous systems. The changes in the pulmonary system associated with ageing are summarised in Fig. 24.24.
↓ Respiratory muscle strength
Ossified ribs
↓ Elastin content
cause
↓ Cough
cause
↓ Chest wall compliance
↑ Risk of infection
↓ PaO2
results in
reduces ↓ Pulmonary blood flow
↑ WORK OF BREATHING
results in
V/Q mismatch results in
combined ↑ Surface area
results in
causes ↑ Alveolus size
↑ Residual volume
↓ Vital capacity
FIGURE 24.24
A concept map of the changes in the pulmonary system that can occur with ageing. Note that these changes do not always lead to dysfunction, but rather highlight that the capacity of the pulmonary system is altered as individuals become older.
CHAPTER 24 The structure and function of the pulmonary system
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chapter SUMMARY The structure of the pulmonary system • The pulmonary system consists of the lungs, airways, chest wall and pulmonary and bronchial circulation. • Air is inspired and expired through the conducting zone, which include the nasopharynx, oropharynx, trachea, bronchi and bronchioles to the sixteenth division. • The respiratory zone consists of structures that are involved in gas exchange. These include the respiratory bronchioles, alveolar ducts and alveoli. • The chief gas-exchange units of the lungs are the alveoli. The membrane that surrounds each alveolus and contains the pulmonary capillaries is called the alveolar– capillary membrane. • The gas-exchange airways are served by the pulmonary circulation, a separate division of the circulatory system. The bronchi and other lung structures are served by a branch of the systemic circulation called the bronchial circulation. • The chest wall, which contains and protects the contents of the thoracic cavity, consists of the skin, ribs and intercostal muscles, which lie between the ribs. • The chest wall is lined by a serous membrane called the parietal pleura; the lungs are encased in a separate membrane called the visceral pleura. The area where these two pleurae come into contact and slide over one another is called the pleural space.
•
•
•
• •
• • •
The function of the pulmonary system • The pulmonary system enables oxygen to diffuse into the blood and carbon dioxide to diffuse out of the blood. • Ventilation is the process by which air flows into and out of the gas-exchange airways. • The majority of ventilation is involuntary. It is controlled by the sympathetic and parasympathetic divisions of the autonomic nervous system, which adjust airway calibre (by causing bronchial smooth muscle to contract or relax) and control the rate and depth of ventilation. • Lung receptors monitor the mechanical aspects of ventilation. Irritant receptors sense the need to expel unwanted substances, stretch receptors sense lung
•
•
•
volume (lung expansion) and J-receptors sense pulmonary capillary pressure. Chemoreceptors in the circulatory system and brainstem sense the effectiveness of ventilation by monitoring the pH status of cerebrospinal fluid and the oxygen content of arterial blood. Successful ventilation involves the mechanics of breathing: the muscles of inspiration and expiration, alveolar surface tension, elastic properties of the lungs and chest wall, and resistance to airflow. The major muscle of inspiration is the diaphragm. When the diaphragm contracts, it moves downwards, creating a vacuum in the thoracic cavity that causes air to flow into the lungs. Type II alveolar cells produce surfactant, a lipoprotein that lines the alveoli. Surfactant reduces alveolar surface tension and permits the alveoli to expand as air flows in. Compliance is the ease with which the lungs and chest wall expand during inspiration. Lung compliance is ensured by an adequate production of surfactant, whereas chest wall expansion depends on elasticity. Elastic recoil is the tendency of the lungs and chest wall to return to their resting state after inspiration. The elastic recoil forces of the lungs and chest wall are in opposition, creating negative pressure in the pleural space. Gas transport depends on ventilation of the alveoli, diffusion across the alveolar–capillary membrane, perfusion of the pulmonary and systemic capillaries, and diffusion between systemic capillaries and tissue cells. Efficient gas exchange depends on an even distribution of ventilation and perfusion within the lungs. In the upright individual, both ventilation and perfusion are greatest in the bases of the lungs because the alveoli in the bases are more compliant (the resting volume is low) and perfusion is greater in the bases due to gravity. Almost all the oxygen that diffuses into pulmonary capillary blood is transported by haemoglobin, located within red blood cells. The remainder of the oxygen is dissolved in plasma. Oxygen enters the body by diffusing down the concentration gradient, from high concentrations in the Continued
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alveoli to lower concentrations in the pulmonary capillaries. Diffusion ceases when alveolar and capillary oxygen pressures equilibrate. • Oxygen is loaded onto haemoglobin by the driving pressure exerted by the oxygen concentration in the blood. As pressure decreases at the tissue level, oxygen dissociates from haemoglobin and enters tissue cells by diffusion, again down the concentration gradient. • Carbon dioxide is more soluble in plasma than oxygen. Therefore, carbon dioxide diffuses readily from tissue cells into plasma. Carbon dioxide returns to the lungs dissolved in plasma, as bicarbonate, or carbaminohaemoglobin — that is, bound to haemoglobin.
Paediatrics and the pulmonary system • In utero, surfactant is not produced until about 24 weeks of gestation and the epithelial lining has sufficiently thinned to permit gas exchange. • The lungs and chest wall at birth are immature; rapid development occurs in the first 6 months of life.
Ageing and the pulmonary system • Ageing affects the mechanical aspects of ventilation by decreasing chest wall compliance and elastic recoil of the lungs. Changes in these elastic properties reduce ventilatory reserve. • Ageing causes the oxygen level in the blood (PaO2) to decrease.
CASE STUDY
AD ULT Jack is 33 years old and has recently undertaken his yearly physical check-up for the fire brigade. He is fit, exercising 5 times a week for 60 minutes on each occasion. The following measures were recorded at his check-up: weight 76 kg, height 182 cm, respiratory rate 18 breaths/minute, resting heart rate 56 beats/minute, blood pressure 116/78 mmHg. Jack reported that he has no physical ailments. As part of the check-up, a pulmonary examination was undertaken. This comprised observation of chest movement and ventilation, palpation of the chest wall with hands over the ribcage at the front and back, and auscultation (listening with a stethoscope) to breath sounds over the lung fields. The following observations were noted: • Chest wall movement was symmetrical. • There was anterior, posterior and lateral outward excursion of the chest wall during inspiration. • Hands on the chest wall were easily moved outwards during inspiration. • Breath sounds were normal; no extra sounds were heard on inspiration or expiration.
Jack passed his physical check-up and can continue with his fire-fighting role for another year. 1 Jack’s chest wall was observed and palpated during normal quiet breathing. Describe 2 important functions of the chest wall. 2 Explain how the muscles of ventilation cause the lungs to inflate. 3 The breath sounds change across different lung regions. Using your knowledge of the conducting and respiratory zones and airway resistance, describe why these differences in breath sounds occur. 4 Jack was lying flat on his back during the physical checkup. Explain whether there would be differences in his ventilation and perfusion if he sat upright. Give reasoning to support your answer. 5 While it was not measured at the time of examination, Jack’s oxygen saturations were between 95% and 100%. Describe how this occurs with reference to the partial pressure of oxygen and how oxygen is unloaded at the tissue level.
CHAPTER 24 The structure and function of the pulmonary system
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CASE STUDY
AGEI NG Yvonne recently had a viral chest infection which her doctor treated with bed rest, oral hydration and small regular meals. Now she is fully recovered and has returned to her doctor for a check-up. Yvonne is 67 years old, has never smoked and has lived in the city most of her life. She has an active social life, a good social and family network and lives by herself. Yvonne tries to walk every day around the bay, which takes about 30 minutes, but she confesses that it is more like every couple of days. The doctor obtained the following information on review: height 169 cm, weight 65 kg, respiration rate 22 breaths/ minute, oxygen saturations on room air 96%, heart rate 84 beats/minute at rest, and blood pressure 124/75 mmHg. Yvonne does not have any history of respiratory disease. Yvonne reports feeling short of breath when carrying her shopping and walking up more than two flights of stairs. However, she can walk on the flat ground for several hundred metres without experiencing any breathlessness, but can feel her legs getting ‘tired’ sometimes. On physical assessment the following findings were observed. • On auscultation there were diminished breath sounds bilaterally, but no abnormal lungs sounds heard. • Chest wall movement was symmetrical but movement was limited.
• Outward excursion of the chest wall on inspiration was equal but limited. • It was noted that her spine curved forward in the region of the upper back. Yvonne’s doctor concluded that she was in good health and all findings were within the acceptable range for someone of her age. 1 Explain why Yvonne has diminished breath sounds at the bases of her lungs in the absence of an acute or chronic lung disease. 2 Describe possible reasons for a decrease in chest excursion in the elderly person. 3 Yvonne’s upper spine forward curvature can be contributed to what process/disease? How can this affect ventilation? 4 Why can Yvonne walk on the flat without much respiratory distress, but can be affected by walking up stairs or when carrying shopping? 5 Although this was not previously mentioned Yvonne says that she now gets a chest infection every year. What is a possible reason for this and what would you suggest to help decrease the risk of these chest infections?
REVIEW QUESTIONS 1 Explain the difference between the conducting zone and the respiratory zone. 2 Describe the difference between type I and II alveolar cells. 3 Outline the function of surfactant and explain why it is important in premature infants. 4 Describe the mechanisms of breathing. 5 Outline the neural control of breathing. 6 Outline the chemical control of breathing.
7 Describe the steps involved in gas transport for the delivery of oxygen to the cells and the removal of carbon dioxide. 8 Discuss the importance of the oxygen–haemoglobin dissociation curve in maintaining adequate oxygenation. 9 Describe how carbon dioxide is transported in the blood. 10 Discuss anatomical and functional differences in the pulmonary system across the life span.
Key terms
CHAPTER
25
Alterations of pulmonary function across the life span Vanessa Marie McDonald, Steven Maltby and Darrin Penola
Chapter outline Introduction, 711 Disorders of the pulmonary system, 711 Obstructive airway diseases, 711 Restrictive airway diseases, 729 Infections of the pulmonary system, 732 Pneumonia, 733 Tuberculosis, 734 Acute bronchitis, 736 Influenza, 736 Lung cancer, 738 Types of lung cancer, 738
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Obstructive sleep apnoea, 742 Alterations of pulmonary blood flow and pressure, 746 Pulmonary embolism, 747 Cor pulmonale, 748 Clinical manifestations of pulmonary alterations, 749 Conditions caused by pulmonary alterations, 749 Signs and symptoms of pulmonary alterations, 755
acute bronchitis, 736 acute respiratory distress syndrome, 730 adenocarcinoma, 739 aspiration, 754 atelectasis, 752 bronchiolitis, 737 chronic bronchitis, 721 chronic obstructive pulmonary disease (COPD), 711 cor pulmonale, 748 croup, 743 cyanosis, 756 cystic fibrosis, 723 dyspnoea, 755 emphysema, 723 empyema, 753 eupnoea, 756 haemoptysis, 756 hypercapnia, 752 hyperventilation, 756 hypoventilation, 755 hypoxaemia, 750 influenza, 736 large cell carcinoma, 739 obstructive sleep apnoea, 742 pertussis, 738 pleural effusion, 753 pneumoconiosis, 732 pneumonia, 733 pneumothorax, 752 pulmonary embolism, 747 pulmonary oedema, 749 small cell carcinoma, 740 squamous cell carcinoma, 739 status asthmaticus, 717 sudden infant death syndrome (SIDS), 746 TNM classification, 741 tubercles, 734 tuberculosis, 734
CHAPTER 25 Alterations of pulmonary function across the life span
Introduction At some stage everyone experiences an alteration to the pulmonary system. This may range from a minor respiratory illness through to chronic lung diseases and cancers. The common cold, a mild upper respiratory tract infection arising from several different viruses, is one of the most familiar pulmonary infections and most people experience one or two infections each year. Often more serious is the impact of influenza, commonly referred to as the ‘flu’, with an estimated 5–20% of the Australian and New Zealand populations infected each year and up to half a million deaths worldwide.1 Pulmonary diseases and disorders can severely limit an individual’s ability to perform activities of daily living and result in frequent hospitalisations. Moreover, alterations to the pulmonary system contribute significantly to mortality rates in Australia and New Zealand. The lungs, with their large surface area, are constantly exposed to the external environment. Therefore, lung disease is greatly influenced by conditions of the environment, occupation and personal and social habits. For instance, individuals who smoke are known to be at a greater risk of lung conditions compared to non-smokers. Symptoms of lung disease are common and associated not only with primary lung disorders but also with diseases of other organ systems. Alterations of respiratory function in children are influenced by physiological maturation as a function of age, genetics and environmental conditions. A variety of upper and lower airway infections can cause respiratory problems or play a role in the pathogenesis of more chronic pulmonary diseases. Infants, especially premature infants, may present special problems because of the immaturity of their lung, airway and chest wall structures, as well as the immaturity of pulmonary homeostasis (e.g. a lack of surfactant production) and immunological immaturity. Immunisation and attentive healthcare can greatly reduce the incidence and severity of pulmonary disorders in children. The lungs continue to mature up until about 20 years of age for females and 25 years for males. Thereafter ageing is associated with a progressive decline in lung function resulting in both airflow limitation and reduced exercise capacity. The morphological and immunological changes that occur during ageing can lead to increased air trapping and a reduction in chest wall compliance causing an increased work of breathing for older individuals.2 Pulmonary disease is often classified using different categories and may be described as acute or chronic, obstructive or restrictive, or infectious or non-infectious. Because skillful and knowledgeable clinical practice plays a major role in the management of pulmonary conditions, healthcare professionals who have a clear understanding of the pathophysiology of common pulmonary disorders can provide more optimal management of affected individuals with the goal of improving outcomes. This chapter examines the more common alterations to the pulmonary system and then provides detailed information about the signs and symptoms that arise from these
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conditions. In this way, you can learn about the pathophysiology of the pulmonary conditions and so understand how these alterations manifest in individuals.
Disorders of the pulmonary system Obstructive airway diseases
Obstructive airway diseases are characterised by airflow obstruction or limitation that causes more difficulty during expiration. More force — that is, the use of the accessory muscles of expiration — is required to expire a given volume of air or emptying of the lungs is slowed, or both. In adults and children, the major obstructive airway disease is asthma, with chronic obstructive pulmonary disease (COPD) also highly prevalent in the adult population. Airflow obstruction is usually variable in asthma, whereas in COPD it is less reversible. The unifying symptom of obstructive airway diseases is dyspnoea (difficulty breathing or breathlessness). Manifestations of obstructive airway diseases include an increased work of breathing, ventilation/perfusion mismatching, a decreased forced expiratory volume in one second (FEV1) and decreased FEV1/forced vital capacity (FVC) ratio. Obstructive airway diseases are prevalent in the Australian and New Zealand populations leading to a high disease burden. In the following section we examine the pathophysiology of asthma in both children and adults, to provide a more thorough understanding of the disease.
Asthma
There are large variations in the incidence and prevalence of asthma according to geographical regions. Worldwide it is estimated that over 300 million people have asthma and there is likely to be a marked increase in this number over the next two decades as modern lifestyles and urbanisation occur in developing countries.3 Rates of asthma are higher in Westernised societies than developing countries and indeed the prevalence of asthma in Australia and New Zealand is high by international standards.3–5 In Australia, more than two million people have asthma (10.2% of the population), with slightly higher rates in children compared to adults.6 In childhood more males than females have asthma; however, this trend reverses in adulthood, with more females than males having asthma.5 Unfortunately, as with so many chronic diseases, the Indigenous populations in both Australia and New Zealand have higher rates of asthma compared to the non-Indigenous populations: in New Zealand the prevalence of asthma in Māori and Pacific Islander adults is greater than in the non-Indigenous population4,5 and in Australia asthma is the second most common illness, affecting greater than 60% of the Indigenous population compared to non-Indigenous.5 While mortality rates from asthma decreased through to the end of the 20th century, rates remained stable between 2004–2013 in Australia, at around 1.5 deaths per 100 000
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population.7 Furthermore, Australian asthma mortality rates remain high by international standards,8 and while asthma deaths continue to occur in all age groups, the risk of dying from asthma increases with age.9 In 2015 there were 421 deaths in Australia due to asthma, representing 0.3% of all deaths that year.9 Rates of hospitalisation are fairly low, with approximately 38 000 hospitalisations in 2011–12 or 0.4% of all hospitalisations in Australia,10 with less than 5% of adults and children with asthma being hospitalised for episodes of acute asthma. Nonetheless, the economic costs are high, as the direct costs associated with asthma are estimated at $1.2 billion, total economic costs (including disability and premature mortality) at $3.3 billion and total burden of disease costs of $23.7 billion.11 Asthma is likely to result from a complex interaction of genetic and environmental components. It can be defined as: … a heterogeneous disease [meaning that it varies considerably for different people], usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation.12 Asthma is a familial disorder, and many genes have been identified that may play a role in the susceptibility and pathogenesis of asthma, including those that influence the production of interleukins IL-4, IL-5 and IL-13, immunoglobin E (IgE), eosinophils, mast cells, β(beta)adrenergic receptors (for the stress response using adrenaline) and airway hyperresponsiveness (the ability of the airways to constrict more easily and to a greater degree in response to a bronchoconstrictor or stimulus). Risk factors for asthma, in addition to family history, include allergen exposure, living in urban areas, exposure to air pollution and cigarette smoke, recurrent respiratory viral infections and other allergic diseases, such as allergic rhinitis.13 There is considerable evidence that exposure to high levels of certain allergens during childhood increases the risk for asthma. Furthermore, decreased exposure to certain infectious organisms appears to create an immunological imbalance that favours the development of allergy and asthma. This complex relationship has been called the hygiene hypothesis, in which it is thought that living with low levels of infectious organisms can make the immune system particularly prone to the development of allergy.14 People living in urban environments have been shown to have a higher disposition to asthma compared to those who reside in rural areas. The likely exposure to air pollution combined with decreased exercise also play a role in the increasing prevalence of asthma.13 PATHOPHYSIOLOGY
The principal characteristics of asthma are airway inflammation, airway hyperresponsiveness and mucus hypersecretion resulting in airflow obstruction, leading to symptoms of dyspnoea, cough, chest tightness and wheeze.12
The airflow limitation resulting from these physiological changes is episodic and usually reversible. The clinical pattern of asthma is variable, and the immunological processes underlying asthma pathophysiology also vary between individuals. Classically, asthma is associated with a predominance of CD4+ T lymphocyte cells and the release of type 2 helper T cell (TH2)-associated mediators such as IL-4, IL-5 and IL-13 and airway eosinophilia. Alternatively, non-TH2 asthma includes a predominance of TH1 (and associated IFNγ), and TH17 (with associated IL-17 cytokine production) and neutrophilic airway inflammation.15 Assessment of the inflammatory cells from sputum can identify individuals with differing patterns of airway inflammation, which is becoming increasingly important for the integration of targeted therapies (such as anti-IgE), which are only effective in subsets of patients.16 Remodelling of the airway structures also occurs in the long term. In asthma, the airways respond in an abnormal, exaggerated way to inflammatory mediators, such as an allergen or irritants or triggers like pollution, exercise, cold air or respiratory infection (bacterial or viral). Allergic responses can be initiated by a type I hypersensitivity reaction (see Chapter 15). Exposure to allergens or irritants results in a cascade of events, beginning with mast cell degranulation and the release of multiple inflammatory mediators (see Fig. 25.1). Some of the most important mediators that are released during an acute allergic asthmatic episode are histamine, interleukins, prostaglandins, leukotrienes and nitric oxide. The vasoactive effects of these cytokines include vasodilation and increased capillary permeability. This causes an increase in blood flow to the area, and inflammatory cells and chemicals move through the cells into the interstitial tissue. Alternatively, triggers such as bacterial or viral infection or exposure to pollutants can activate lung macrophages and resident innate immune cells. Activation results in local release of pro-inflammatory cytokines and tissue inflammation. In both cases, chemotactic factors (chemicals that attract inflammatory cells to the site of inflammation) are produced, which result in bronchial infiltration by eosinophils, neutrophils, and lymphocytes (different types of white blood cells). These activated immune cells, particularly eosinophils, release a variety of chemicals that contribute to inflammation and tissue damage. The resulting inflammatory process produces bronchial smooth muscle spasm, vascular congestion, oedema formation, production of thick mucus, impaired mucociliary function, thickening of airway walls and increased bronchial hyperresponsiveness (see Fig. 25.2). In addition, there is alteration to the normal autonomic control of bronchial smooth muscle because the production of neuropeptides (small protein-like substances that are released by neurons to communicate with other neurons) leads to acetylcholine-mediated bronchospasm. These changes, combined with epithelial cell damage caused by immune cell infiltration, produce airway hyperresponsiveness and obstruction and, if untreated, can lead to long-term airway damage that is irreversible.
CHAPTER 25 Alterations of pulmonary function across the life span
713
Immune activation (IL-4, IgE production)
promotes
Mast cell degranulation releases
release Vasoactive mediators
Chemotactic mediators
Chemical mediator act to
cause
increases Vasodilation Increased capillary permeability
release
results in
Cellular infiltration (neutrophils, lymphocytes, eosinophils)
Stimulate nerve terminal endings
causes Bronchospasm Vascular congestion Mucus secretion Impaired mucociliary function Thickening of airway walls Increased contractile response of bronchial smooth muscle
which results in
Autonomic dysregulation produces
over time causes
Release of neurotransmitters
Release of neuropeptides leads to
leads to Bronchial hyperresponsiveness Airway obstruction
CONCEPT MAP
Allergen or irritant exposure
leads to
Epithelial desquamation (removal of epithelial lining) and fibrosis (excessive connective tissue)
cause Colour code initiator mediators dysfunctional process FIGURE 25.1
The pathophysiology of asthma. A concept map outlining the effects of exposure to an allergen or irritant, which causes an inflammatory cascade leading to acute and chronic airway dysfunction.
Examination of postmortem lung specimens of individuals who have died from asthma reveals abnormalities consistent with both acute and chronic changes in the airways. These include extensive mucus plugging, mucosal oedema and denudation of bronchial and bronchiolar epithelium (loss of epithelium). Eosinophilia (an increased amount of eosinophils) is present in the submucosa in some cases, and a multicellular inflammatory infiltrate accumulates in the airways. Thickening of the basement membrane, airway smooth muscle hypertrophy and mucous gland hypertrophy are often noted, sometimes even in pathology specimens from people with mild asthma, providing evidence that there may be long-term airway structural changes associated with asthma.
For acute allergen-induced asthma, the paradigm of the early asthmatic response remains useful (see Fig. 25.3A). This begins immediately after exposure and lasts up to 2 hours. The allergen binds to preformed immunoglobin E (IgE) on the surface of mucosal mast cells, and cross-linking of these IgE molecules triggers degranulation of the mast cells, releasing mediators such as histamine, leukotrienes, prostaglandin D2, platelet-activating factor and certain cytokines. These mediators cause airway smooth muscle constriction (bronchospasm), increased vascular permeability (mucosal oedema) and mucus secretion. The late asthmatic response starts 4–8 hours after the initial exposure and may persist for up to 24 hours (see Fig. 25.3B). The response is characterised by inflammatory
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A
B Pulmonary artery Cartilage Submucosal gland
Mast cell Parasympathetic nerve Smooth muscle
Basement membrane
Degranulation of mast cell Smooth muscle constriction
Bronchioles Epithelium Respiratory bronchioles
Goblet cell Alveoli
Mucus plug Hyperinflation of alveoli
Mucus accumulation
FIGURE 25.2
Changes in airways due to asthma. A Normal lung with clear airways. B Thick mucus, mucosal oedema and smooth muscle spasm causing obstruction of small airways occurs in asthma, breathing becomes laboured and expiration is difficult due to the airway restrictions.
cell recruitment (neutrophils, eosinophils, basophils, lymphocytes) that was triggered earlier by chemotactic factors and endothelial adhesion molecules (molecules that attach to the endothelial). Another wave of mediator release occurs, again causing bronchospasm, oedema and mucus secretion. Epithelial damage and impaired mucociliary function (the sweeping ability of the cilia lining the airways) may be seen following immune cell activation within the lungs, including production of toxic mediators by eosinophils, neutrophils and activated macrophages. This local injury stimulates local nerve endings, which may aggravate bronchoconstriction and mucus secretion through autonomic pathways. In chronic asthma, some of these mechanisms may be operational on an ongoing basis. There are increased numbers of inflammatory cells, which may lead to long-term changes such as goblet cell hyperplasia (abnormally increased number of mucus-secreting cells) and airway wall remodelling (subepithelial fibrosis, smooth muscle hypertrophy). Airway obstruction increases resistance to airflow and decreases flow rates, primarily expiratory flow. For instance, a 10% reduction in airway calibre leads to a 2% increase in resistance. Impaired exhalation causes air trapping and hyperinflation distal to obstructions and increases the work of breathing. Intrapleural and alveolar gas pressures rise and cause decreased perfusion of the alveoli. These changes lead to uneven ventilation–perfusion relationships causing hypoxaemia (a reduction in oxygen levels in the blood). Hyperventilation is triggered by lung receptors responding to the hyperinflation and causes a decrease in carbon dioxide levels in the blood (PaCO2) and increased pH (which results in respiratory alkalosis). As the obstruction becomes more
severe, the number of alveoli being adequately ventilated and perfused decreases. Air trapping continues to worsen and the work of breathing increases further, leading to hypoventilation (decreased tidal volume), carbon dioxide retention and respiratory acidosis (from the reduction in carbon dioxide removal). Respiratory acidosis signals respiratory failure (Fig. 25.4 summarises these steps). CLINICAL MANIFESTATIONS
When asthma is well controlled individuals should experience few if any symptoms and pulmonary function tests will usually be within normal limits. However, individuals with asthma are at risk of acute exacerbations, usually as a result of exposure to triggers that cause an airway inflammatory response and acute bronchoconstriction. These may include exposure to allergens, infections, occupational exposures, tobacco smoke or from treatment non-adherence. Further, 5–10% of individuals with asthma have severe disease which requires high-dose therapy to control, or remains uncontrolled despite treatment.17 Exacerbations are defined as ‘events that require urgent action on the part of the patient and physician to prevent a serious outcome, such as hospitalization or death from asthma’.18 During an exacerbation, the individual may experience bronchoconstriction, expiratory wheezing, dyspnoea, cough, prolonged expiration, tachycardia and tachypnoea (increased ventilatory rate). Severe episodes involve the accessory muscles of ventilation and wheezing is heard during both inspiration and expiration. Pulsus paradoxus (an exaggerated decrease in systolic blood pressure during inspiration) may be noted. Lung function measured by spirometry is reduced. Because the severity of blood gas alterations is difficult to evaluate by clinical
CHAPTER 25 Alterations of pulmonary function across the life span
A
715
1 Antigen entry to airway 2 Mast cell degranulation and release of mediators
Mast cell Antigen
Mucus secretion Goblet cell Dendritic cell
Mast cell
Smooth muscle
3 Mediator effects Airway smooth muscle constriction
Vascular leak of fluid
B B
TH2 cell
Vascular cell adhesion molecule Eosinophil
Neutrophil
FIGURE 25.3
Asthmatic responses at a cellular level. A Early asthmatic response. 1 Inhaled antigen enters the airway and binds to IgE on mast cells. 2 Mast cells degranulate and release mediators such as histamine, prostaglandin D2 and platelet-activating factor, which promotes inflammation. 3 These chemicals open junctions between cells, allowing the allergen to penetrate below the epithelial surface, which induces active bronchospasm, oedema and mucus secretion. At the same time, as shown on the left, antigen may be received by dendritic cells and later present to T helper (TH) lymphocytes in the airway mucosa (see B). B Late asthmatic response. There are areas of epithelial damage caused at least in part by toxicity of eosinophil. Local T lymphocytes produce IL-4 and IL-13, which promote switching of B cells to favour IgE production, and IL-3, IL-5 and granulocyte-macrophage colony-stimulating factor, which encourage eosinophil differentiation and survival.
signs alone, arterial blood gas levels should be measured if oxygen saturation falls below 90%. The usual findings are hypoxaemia with an associated respiratory alkalosis. The severity of acute asthmatic episodes is outlined in Table 25.1. The typical arterial blood gas abnormalities seen in acute asthma are hypoxaemia, hypocapnia (low blood carbon dioxide levels) and respiratory alkalosis (a pH level above 7.45). As bronchial obstruction is non-uniform, ventilation becomes uneven, causing ventilation–perfusion mismatch and further hypoxaemia. The degree of hypoxaemia is usually mild; however, arterial saturations of less than 90% indicate severe airway obstruction. Pulmonary circulation may be
altered by regional hypoxic vasoconstriction, as well as the effect of increased intraalveolar pressure (caused by hyperinflation) to decrease perfusion of the alveolar capillaries. Typically, the ventilatory rate (commonly referred to as the respiratory rate in clinical environments) is elevated to compensate for hypoxaemia, with reduced minute ventilation because of increased airway resistance and lung hyperinflation. Thus, the carbon dioxide level is low (30–35 mmHg compared to the normal level of 35–45 mmHg) or can be normal. Retention of carbon dioxide is a late finding and reflects inadequate alveolar ventilation and increased functional dead space as little air
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CONCEPT MAP
Oedema, mucus, muscle spasm causes Resistance to airflow causes Impaired expiration causes Air trapping causes Alveolar hyperinflation leads to Uneven ventilation/perfusion
causes Decreased pulmonary blood flow
causes
Decreased alveolar ventilation
results in
leads to Impaired gas exchange causes
Respiratory failure
results in
Hypoxaemia
causes Hypercapnia
results in
FIGURE 25.4
Asthma airway obstruction cascade. The oedema, mucus and mucus spasm cause resistance to airflow, such that air remains trapped in the lungs. As a result, there are impairments in gas exchange that can lead to respiratory failure.
TABLE 25.1 Assessment of acute asthma episodes in adults FINDINGS
MILD
MODERATE
SEVERE AND LIFE THREATENING
Physical exhaustion
No
No
Yes Paradoxical chest wall movement may be present
Talks in
Sentences
Phrases
Words
Pulse rate
< 100/min
100–120/min
More than 120/min
Pulsus paradoxus
Not palpable
May be palpable
Palpable
Central cyanosis
Absent
May be present
Likely to be present
Wheeze intensity
Variable
Moderate to loud
Often quiet
PEF
More than 75% predicted (or best if known)
50–75% predicted (or best if known)
Less than 50% predicted (or best if known) or less than 100 L/min
FEV1
More than 75% predicted
50–75% predicted
Less than 50% predicted or less than 1 L
Oximetry on presentation
Less than 90% Cyanosis may be present
Arterial blood gases
Not necessary
Necessary if initial response poor
Necessary
Other investigations
Not required
May be required
Check for hypokalaemia Chest x-ray to exclude other pathology (i.e. infection, pneumothorax)
FEV1 = forced expiratory volume in first second; PEF = peak expiratory flow
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CHAPTER 25 Alterations of pulmonary function across the life span
is being moved. Alterations of pH homeostasis usually start with respiratory alkalosis (pH greater than 7.45) caused by hyperventilation, which literally ‘blows off ’ carbon dioxide. With severe airway obstruction, the end result of the pathophysiological processes may be respiratory failure, with acute carbon dioxide retention and respiratory acidosis (pH less than 7.35). When bronchospasm worsens during a severe asthmatic episode the individual may progress to a condition known as status asthmaticus. This is defined as a severe asthmatic episode that does not respond to pharmacological control. Acute airway inflammation causes bronchospasm to worsen. Mucus plugging, oedema and cellular infiltration lead to further airway narrowing. Partial obstruction leads to segmental hyperinflation, which may become extreme and compromise effective tidal volume. Expiratory flow rates such as FEV1 and peak flow are also markedly reduced. If status asthmaticus continues, hypoxaemia worsens, expiratory flows and volumes decrease further, and effective ventilation decreases. Metabolic acidosis may accompany status asthmaticus as the carbon dioxide level in the blood begins to rise. Asthma becomes a life-threatening condition at this point, often with impending respiratory or cardiac arrest if treatment does not reverse this process quickly. A silent chest (no audible air movement) and a carbon dioxide level over 70 mmHg are ominous signs of impending death. EVALUATION AND TREATMENT
The diagnosis and monitoring of asthma is undertaken using spirometry. Spirometry measures lung function and Normal
10
10
SPIROMETRIC INDICES
FEV1 — Forced expiratory volume in one second: the volume of air expired in the first second of the blow volume exhaled FVC — Forced vital capacity: the total volume of air that can be forcibly exhaled in one breath FEV1/FVC ratio — The fraction of air exhaled in the first second relative to the total VC — Vital capacity: a volume of a full breath exhaled in the patient’s own time and not forced. Often slightly greater than the FVC, particularly in COPD PEF — The maximum rate of air flow out of the lungs during forced expiration
Obstructive–reversible
10
4
6 4 2
2
1
2 3 Volume (L)
4
5
0
B
Obstructive–non-reversible
8 Flow (L/s)
Flow (L/s)
Flow (L/s)
6
A
TABLE 25.2 Common spirometric indices
8
8
0
determines how much and how quickly air can be expired from the lungs. The key variables measured during spirometry are forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio and peak expiratory flow (PEF) (see Table 25.2). Spirometry may be used to diagnose airway obstruction, assess its severity and prognosis and to demonstrate any reversible effect. An example of airway obstruction compared to normal spirometry is provided in Fig. 25.5, including the response to treatment using bronchodilators. In children less than 5 years of age spirometry is not recommended. In such cases, a history from the parents is crucial. Between episodes, the diagnosis of asthma is
6 4 2
1
2 3 Volume (L)
4
5
0
1
2 3 Volume (L)
4
5
C
FIGURE 25.5
Flow volume curves. A Normal. B Obstructive, responsive to bronchodilator treatment. C Obstructive, non-responsive to bronchodilator treatment. The defining characteristic in obstructive lung disease is a reduction in FEV1 with a normal forced vital capacity (FVC). In B & C, the FVC in both cases was identical yet FEV1was reduced. The FEV1/ FVC ratio was therefore below the normal 0.7 in healthy individuals. Note the improvement in B after bronchodilator treatment. These expiratory flow volume curves show pre- and post-bronchodilator spirometry. The pre-bronchodilator effort is represented by the blue curve and the post-bronchodilator effort by the red curve.
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supported by other clinical signs and symptoms, which may include but are not limited to a history of allergies and recurrent episodes of breathlessness or exercise intolerance. For ongoing asthma management, written asthma action plans, self-monitoring through peak expiratory flow monitoring or symptom diaries, self-management education including disease knowledge and skills (inhaler technique, adherence) and regular review are essential and lead to improved health outcomes. A written asthma action plan (Fig. 25.6) is a set of written instructions that helps people with asthma detect early signs and symptoms of an exacerbation and provides instructions about how to manage these exacerbations. The plan should include instructions for maintenance therapy, early exacerbation management and crisis management.5 The goals of long-term asthma management are to achieve and maintain asthma control, to maintain lung function and activity, and to prevent morbidity and mortality from asthma. A stepwise approach is recommended, involving education, avoidance of triggers and pharmacotherapy stepped up and down according to asthma control. The cornerstone of effective asthma management involves pharmacotherapies including, but not limited to, inhaled corticosteroids and bronchodilator therapy.5 Medications are often referred to according to their mechanistic role: • Reliever medications: these provide acute relief of symptoms by allowing rapid bronchodilation. They relax bronchial smooth muscle and are administered on an as-needed basis. Examples include salbutamol or terbutaline (short-acting β2[beta]-agonist) and ipratropium bromide (anti-muscarinic antagonist). • Symptom controllers: these provide long-acting bronchodilation (up to 12 hours) and are administered twice daily to decrease the symptoms of asthma. These medications should not be taken to provide rapid relief of symptomatic asthma. Examples include salmeterol and eformoterol, both long-acting β2-agonist drugs. • Preventer medications: these preventative medications treat inflammation and help achieve overall asthma control. When the appropriate level has been achieved, they provide substantial benefits to individuals with asthma. Examples include inhaled corticosteroids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate), leukotrienereceptor antagonists (montelukast) and cromones (cromoglycate and nedocromil).5 There are also combination medications that contain a symptom controller and preventer medication, enabling the individual to administer medication in a single inhaler. Examples include fluticasone and salmeterol (Seretide), budesonide and eformoterol (Symbicort), fluticasone furoate and vilanterol (Breo) and fluticasone propionate and formoterol (Flutiform). More recently, the use of monoclonal antibody therapies have been introduced for people with severe asthma. Anti-immunoglobulin therapy has shown promise in some
people with asthma. Omalizumab is an anti-immunoglobulin E (IgE) antibody that binds to free IgE and is effective in combination with other medications in severe persistent allergic asthma.16 Those who are symptomatic, despite being managed on high doses of inhaled and oral corticosteroids or long-acting β2-agonists, and who have failed to respond to other asthma therapies are most suitable.16 Mepolizumab is another newer medication, which is an antibody (IgG1, kappa), that targets human IL-5. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation and survival of eosinophils. In some people with severe asthma it has been shown to significantly reduce acute exacerbations. Those most likely to respond to mepolizumab are adults and adolescents with severe asthma, who experience persistent asthma exacerbations despite optimal inhaled therapy, and with evidence of high eosinophil levels from blood counts or sputum.19 There are a growing number of options for management of chronic asthma depending on the duration of the condition and the severity of the symptoms, as well as individual adherence issues. Guidelines have been outlined and widely distributed by the National Asthma Council Australia (www.nationalasthma.org.au) and the New Zealand Guidelines Group (www.nzgg.org.nz). The most important element of regular asthma management is the reduction of inflammation. Acute asthma episodes can be life threatening and therapy should be directed at maintaining a patent (open) airway and providing rapid bronchodilation and effective ventilation to maintain adequate gas exchange (see Table 25.1 for details of the severity of asthmatic episodes). Administration of oxygen and rapid-acting bronchodilators such as salbutamol (β2-agonist — that is, one that will interact with a group of adrenergic receptors in the lungs; see Chapter 6) are typically used for management of acute asthma, as well as systemic steroids for moderate to severe attacks to decrease inflammatory responses in the lungs.
RESEARCH IN F Asthma genes
CUS
Genomic screening of populations suggests that there is no single ‘asthma gene’ but rather numerous genes that may be associated with asthma. It may ultimately be possible to associate certain gene variants with specific clinical patterns of asthma and with responsiveness to specific asthma treatments. For example, one variant (or polymorphism) is the gene for the β2-adrenergic receptor, which has been shown to be associated with a poor or even adverse response to salbutamol in one study. If findings such as these can be corroborated and expanded in larger studies, ultimately it may be possible to develop individual profiles to optimise asthma therapy.
CHAPTER 25 Alterations of pulmonary function across the life span
FIGURE 25.6
Example of an asthma action plan template. This template plans out the preventer and reliever medications for the patient to use between varying symptoms (from well to worse).
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Part 4 Alterations to body maintenance
F OCU S O N L E ARN IN G
1 Discuss the mechanisms that cause obstruction in asthma. 2 Describe the differences in airflow with respect to FEV1 and FVC during asthma. 3 Discuss the clinical manifestations of asthma in childhood. 4 Explain the full progression of blood gas abnormalities in a severe asthma episode. 5 Discuss therapy options for individuals with asthma.
Asthma affects approximately 10% of children aged 0–14 years in Australia and New Zealand and although the childhood prevalence of asthma in this region is decreasing it is still among the highest in the world.5 Unlike asthma prevalence in adults where the rates of asthma are higher among Indigenous populations compared with non-Indigenous populations, asthma rates among these two populations of children are similar.4,5 However, the incidence of severe asthma episodes and the rate of hospitalisations are greater in Indigenous populations compared with non-Indigenous populations.4,5 While the pathophysiology of asthma in children is similar to that of adults, several pertinent points need to be highlighted. Asthma is clinically different in children due to the pattern of asthma, natural history and anatomical features.20 For instance, wheezing in childhood can be both associated and not associated with asthma. The classification of asthma is based on the clinical patterns, rather than objective evaluation using spirometry. There are currently many theories regarding the mechanisms of the disease in childhood. There is not one single gene responsible for the manifestation of asthma. The wide spectrum of clinical disease probably reflects a complex interaction between genetic susceptibility and environmental factors, including early exposure to allergens and infections, particularly viral respiratory infections (see ‘Research in Focus: Asthma genes’). Although the genetic expression of asthma is difficult to identify, many discrete clinical presentations have been demonstrated.21 There are at least three different manifestations for childhood asthma. These are: 1 Transient wheezing limited to the first 3–5 years of life. This is associated with decreased lung function, maternal smoking during pregnancy and exposure to other siblings or children at day-care centres. There is no association with a family history of asthma. 2 Non-atopic wheezing associated with lower respiratory tract illness before 3 years of age. 3 IgE-mediated wheezing associated with classic asthma; an early risk factor for persistent asthma. Atopy (an allergic reaction when IgE increases due to environmental allergens — associated with a strong family
history of allergies) is strongly associated with classical asthma that persists into adulthood. However, wheezing illnesses in childhood usually resolved by about 6 years of age, especially when the wheezing is intermittent.5,12,20 The classification of childhood asthma is divided into three levels: infrequent intermittent, frequent intermittent and persistent (see Fig. 25.7). Broadly speaking, these classifications include the following: 1 Infrequent intermittent asthma: isolated episodes usually triggered by an upper respiratory tract infection with episodes more than 6 weeks apart. 2 Frequent intermittent asthma: episodes less than 6 weeks apart but similar to infrequent intermittent asthma. 3 Persistent asthma (mild, moderate, severe): these children have symptoms of asthma at least weekly and experience night waking. They have the greatest number of hospitalisations and usually have asthma through to adulthood. In a typical asthmatic episode, the major complaints are cough, wheeze and shortness of breath. There may or may not have been signs of a preceding upper respiratory infection, such as rhinorrhoea (discharge of nasal mucus,
75%
20%
5%
Infrequent intermittent asthma (75%) Frequent intermittent asthma (20%) Persistent asthma (5%)
FIGURE 25.7
Classification of childhood asthma and their distribution. Infrequent, intermittent asthma is the most common type of childhood asthma.
PAEDIATRICS
Paediatrics and asthma
CHAPTER 25 Alterations of pulmonary function across the life span
often termed ‘runny’ nose) or low-grade fever. In children, about 70–80% of acute wheezing episodes are associated with viral respiratory infections. In infants and toddlers under 2 years old, the most common of these is respiratory syncytial virus. In older children and adults, the major viral trigger is rhinovirus (commonly referred to as the ‘common cold’ virus). On physical examination, there is an expiratory wheeze that is often described as high-pitched and musical, and exhalation is unusually longer than inhalation. Breath
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a progressive chronic disease characterised by irreversible obstruction of the airways. It is Australia’s fourth leading cause of death and third leading cause of disability.22 Moderate to severe COPD affects 7.5% of Australians over 40 years with prevalence rising rapidly with age; 29% of Australians over 75 years have COPD.23 Worldwide, COPD is the third leading cause of death.24 An economic report estimated the cost of COPD in Australia as $8 billion.25 This consisted of lost productivity ($6.8 billion), health system expenditure ($0.9 billion), patient expenses ($0.3 billion), and additional COPD-related welfare payments ($0.9 billion). People with COPD experience multiple clinical management problems related to airway, comorbidity, risk factors and self-management domains, and these problems have a major impact on health status. COPD is a preventable, chronic disease that is characterised by persistent respiratory symptoms and airflow limitation, which is due to airway or alveolar abnormalities, that are usually caused by significant exposure to noxious particles or gases, with the most common cause being cigarette smoking.26 The airflow limitation in COPD is largely irreversible. COPD can be characterised pathophysiologically by emphysema, chronic bronchitis (and bronchiolitis), or commonly the coexistence of both emphysema and chronic bronchitis. The airflow limitation is caused by damage to the small airways, as a result of two main diseases: chronic bronchitis, which consists of airway inflammation and remodelling, and emphysema, which consists of destruction of alveolar tissue, and a decrease in elastic recoil.26 COPD is associated with a range of immunological processes. In COPD neutrophils, macrophages and CD8+ T-lymphocytes play a major role in the airway inflammation and lung damage. Proinflammatory cytokines such as IL-6, IL-8, IL-1β and tumour necrosis factor alpha (TNF-α) are also released in the COPD airway. Eosinophilic airway inflammation occurs in approximately 30% of individuals with the disease.27 While COPD is primarily a pulmonary condition, it is now also recognised as a multi-system disease associated
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sounds may become faint when air movement is poor. The child may speak in short sentences or not at all because of dyspnoea (difficulty breathing). Ventilatory rate and heart rate are elevated to compensate for the low oxygen levels and increased work of breathing. Nasal flaring and use of accessory muscles with retractions in the substernal, subcostal, intercostal, suprasternal or sternocleidomastoid muscle areas are evident. The child may appear anxious or be diaphoretic (excessive sweating), which are often important signs of respiratory compromise.
with systemic consequences including systemic inflammation and complex chronic comorbidities.28 This results in significant and progressive functional impairment with reduced exercise capacity and increased exacerbations.29 (Fig. 25.8). COPD is diagnosed using spirometry, with a FEV1/FVC ratio of less 70% following administration of a bronchodilator.30 The ratio should be greater than 70% in individuals without airway obstruction lung pathophysiology: FEV1 × 100 = 70% or more in healthy airways FVC
This is combined with a thorough history including history of smoking (or exposure to other noxious inhalational agents). The disease is primarily caused by cigarette smoke (of any cigarette type) and both active and passive smoking have been implicated. This is the most important cause of COPD, and smokers demonstrate a steady decline in pulmonary function (see Fig. 25.9). The risk of developing COPD with continued long-term smoking, irrespective of cigarette type, is high. Other risks include inhaled noxious particles such as occupational exposure and air pollution. In the following sections we take a closer look at the two main conditions that result in COPD. CHRONIC BRONCHITIS
Chronic bronchitis is defined as hypersecretion of mucus and chronic productive cough for at least 3 months of the year (usually the winter months) for at least 2 consecutive years.26 It is almost always caused by cigarette smoking and by exposure to inhaled noxious particles. It differs from episodes of acute bronchitis, which are usually caused by infection and are reversible, whereas chronic bronchitis is an irreversible condition of progressive decline. PATHOPHYSIOLOGY
Inspired irritants result in airway inflammation with infiltration of neutrophils, macrophages and lymphocytes into the bronchial wall. Continual bronchial inflammation causes bronchial oedema and increases the size and
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Cigarette smoke
Normal ageing
Biomass fuel Peripheral lung inflammation
Physical activity Hypoxia
Skeletal muscle weakness Cachexia
Spill-over SYSTEMIC INFLAMMATION Cytokines, IL-1 , IL-6, IL-18, TNF Acute phase proteins: CRP
Cardiovascular – Coronary artery disease – Chronic heart failure – Hypertension
Metabolic diseases – Diabetes – Metabolic syndrome – Obesity
Depression
Bone disease Osteoporosis Osteopenia
FIGURE 25.8
COPD, systemic inflammation and comorbidities. Chronic inhalation of smoke leads to COPD and lung inflammation, which can lead to systemic inflammation. COPD also leads to a reduction in physical activity, which worsens systemic inflammation. The consequences of this chronic systemic inflammation can include cardiovascular, metabolic, and bone disorders, as well as depression.
number of mucous glands and goblet cells in the airway epithelium. Thick, tenacious mucus is produced and cannot be cleared because of impaired ciliary function. The defence mechanisms of the pulmonary system are compromised, increasing susceptibility to pulmonary infection and injury. Frequent infectious exacerbations are complicated by bronchospasm with dyspnoea and a productive cough. The pathophysiology of chronic bronchitis is shown in Fig. 25.10. Initially this process affects only the larger bronchi, but eventually all airways are involved. As the airways become increasingly narrowed, airway obstruction results (see Figs 25.11 and 25.12). The airways collapse early in expiration, trapping gas in the distal portions of the lung. Eventually ventilation–perfusion mismatching (see Chapter 24) and hypoxaemia occurs. Extensive air trapping puts the respiratory muscles at a mechanical disadvantage, resulting in hypoventilation and hypercapnia.
RESEARCH IN F CUS Coexisting asthma and COPD Asthma and COPD are most often considered distinct conditions with different diagnostic and management approaches. However, in practice, patients frequently exhibit features of more than one disease particularly in an older population. This is referred to as asthma-COPD overlap and refers to the coexistence of asthma, emphysema or chronic bronchitis; it is prevalent in over 50% of people over the age of 50 years, and people who have features of both diseases experience more frequent and severe exacerbations, increased symptom burden and worse health status. Traditionally people with features of both diseases have been excluded from clinical trials, and as a result the evidence base for management of asthma-COPD overlap is limited. This area is currently a focus of research.
CHAPTER 25 Alterations of pulmonary function across the life span
(% of value at age 25 years)
100
75
50
25
0
Never smoked or not susceptible to smoke Smoked regularly and susceptible to the effects
Stopped smoking at age 45 years
Onset of symptoms Stopped smoking at age 65 years
Severe disability Death 25
50
75
Age (years)
FIGURE 25.9
Time course of smoking and the changes with smoking cessation at 45 and 65 years of age. Notice that for the smoker who quit at age 45, the serious progression of COPD is much slower than that for the smoker who quit at age 65. In both cases, the disease progression is slower than for those who continue smoking.
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workload of breathing, so that late in the course of disease, many individuals will develop hypoventilation and hypercapnia. CLINICAL MANIFESTATIONS OF COPD
Table 25.3 lists the common clinical manifestations of COPD including chronic bronchitis. Acute exacerbations of COPD are a common feature which put the patient at immediate risk of distress, hospitalisation and even death. Acute exacerbations represent a significant contribution to the healthcare costs associated with these conditions.31 Acute exacerbations of COPD are not only a concern during the immediate time of that exacerbation; after recovery they can also have a negative effect on disease trajectory. In COPD the frequency of exacerbations is associated with an accelerated decline in lung function, accelerated decrease in health status and decreased survival (Fig. 25.14). Furthermore, recent evidence indicates that exacerbations cluster together in time and that after one exacerbation patients are at a heightened risk of a second.32 This is important given the detrimental effect recurrent exacerbations have on outcomes for people with COPD. EVALUATION AND MANAGEMENT OF COPD
EMPHYSEMA
Emphysema is abnormal permanent enlargement of gas-exchange airways accompanied by destruction of alveolar walls. Obstruction results from changes in lung tissues, rather than mucus production and inflammation as in chronic bronchitis. The major mechanism of airflow limitation is loss of elastic recoil (see Fig. 25.11). The major cause of emphysema is cigarette smoking, although air pollution and childhood respiratory infections are contributing factors. PATHOPHYSIOLOGY
Emphysema begins with destruction of alveolar septa, which eliminates portions of the pulmonary capillary bed and increases the volume of air in the alveoli (see Fig. 25.13). It is postulated that inhaled oxidants in tobacco smoke and air pollution stimulate inflammation, which over time causes alveolar destruction and loss of the normal elastic recoil of the bronchi (see Fig. 25.10). Alveolar destruction produces large air spaces within the lung tissue and air spaces adjacent to pleurae. These areas are not effective in gas exchange. The loss of alveolar tissue means a loss of the respiratory membrane where gases cross between air and the blood, resulting in a significant ventilation– perfusion mismatching and hypoxaemia. Expiration becomes difficult because loss of elastic recoil reduces the volume of air that can be expired passively and air is trapped in the lungs. Air trapping causes an increase in expansion of the chest, which puts the muscles of ventilation at a mechanical disadvantage. This results in increased
Under-diagnosis of COPD is common; rates of under-diagnosis have been reported as high as 78%.33 Disease-specific guidelines propose diagnostic criteria to assist clinicians in the diagnosis of COPD. In clinical practice, COPD is usually diagnosed based on a history of smoking, or exposure to other noxious agents and a FEV1/ FVC% (otherwise known as forced expiratory ratio (FER)) of less than 70%.30 The Australian and New Zealand guidelines for treatment are based on the spirometry severity grading scale.30 Other useful assessments in the evaluation include pulmonary function tests to measure lung volumes and gas diffusion, chest x-rays, blood gas analysis and physical examination. The goals of COPD management are to reduce the risk of exacerbation and minimise symptoms.30 This approach recommends short-acting bronchodilators and reduction of risk by stopping smoking, and by ensuring influenza vaccinations across all COPD severity grades. Additionally, pharmacotherapy including inhaled glucocorticosteroids and long-term oxygen therapy is recommended as severity, symptoms and exacerbation frequency increase. Pulmonary rehabilitation is recommended for COPD individuals who are symptomatic regardless of severity.30,34 CYSTIC FIBROSIS
Cystic fibrosis is the most common autosomal recessive inherited disease affecting Caucasians and results from defective epithelial chloride ion transport. The chromosomal mutation results in the abnormal expression of the protein, cystic fibrosis transmembrane conductance regulator, which is a chloride channel (it allows the diffusion of chloride
CONCEPT MAP
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Tobacco smoke Air pollution causes Inflammation of the airway epithelium leads to
Systemic effects (muscle weakness, weight loss)
Infiltration of inflammatory cells and release of cytokines causes (neutrophils, macrophages, lymphocytes, leukotrienes, interleukins) leads to
Continuous bronchial irritation and inflammation
Breakdown in lung elastic tissue
results in
results in
Chronic bronchitis (bronchial oedema, hypersecretion of mucus, bacterial colonisation of airways)
Emphysema (destruction of alveolar septa and loss of elastic recoil of bronchial walls) can result in
Airway obstruction Air trapping Loss of surface area for gas exchange Frequent exacerbations (infections, bronchospasm) evidenced by Dyspnoea Cough Hypoxaemia Hypercapnia Cor pulmonale
FIGURE 25.10
The pathophysiology of COPD. Chronic inhalation of smoke leads to inflammation of the lungs. This inflammation manifests as bronchial inflammation and mucus production, leading to chronic bronchitis, and also manifests as break down of alveolar tissue, leading to emphysema. Together, chronic bronchitis and emphysema lead to significant impairments in breathing, leading to symptoms that may be severe for the patient.
CHAPTER 25 Alterations of pulmonary function across the life span
Air movement during INSPIRATION
Air movement during EXPIRATION
Pulmonary artery Cartilage Submucosal gland
A Mast cell
Mucus plug
Muscle
Bronchial walls collapse
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Parasympathetic nerve Smooth muscle
Basement membrane
Bronchioles Epithelium Respiratory bronchioles
B
Alveolar walls
Goblet cell Alveoli Enlarged submucosal gland
Mucus accumulation
FIGURE 25.11
Mechanisms of air trapping in chronic obstructive pulmonary disease. During inspiration, the force of airflow is sufficient to overcome the mucus. However, during expiration, the airways partially collapse, and the mucus becomes sufficient to plug the airway to a much greater extent, causing difficulty exhaling.
out of the cell) present on the surface of many types of epithelial cells including the airways, bile ducts, pancreas, sweat ducts and vas deferens. In Australia, approximately 1 in 3630 people are born with cystic fibrosis, and about 1 in 25 are carriers who are not affected by the mutation.35 Cystic fibrosis has long been considered a disease of childhood; however, over time there have been significant improvements in the management and treatment options for people with cystic fibrosis, such that in the last four decades the survival has improved dramatically. Improved treatments and increased survival have consequently led to a significant increase in the number of adult patients with cystic fibrosis, such that cystic fibrosis can no longer be considered a paediatric disease alone. The number of cystic fibrosis patients over the age of 18 has increased significantly and the most recently published data from the Australian cystic fibrosis data register report that approximately half of patients are adults.35 PATHOPHYSIOLOGY
Although cystic fibrosis affects many organs (endocrine, gastrointestinal, renal and reproductive systems) the most important effects are on the lungs and in 90% of cases, chronic pulmonary infections eventually lead to
Mucus plug Inflammation of epithelium Hyperinflation of alveoli
FIGURE 25.12
Airway obstruction resulting from chronic bronchitis. A Normal lungs with clear airways. B Inflammation and airway thickening of mucous membrane with accumulation of mucus and pus leading to obstruction and characterised by a cough.
respiratory failure and death.36 The typical features of cystic fibrosis lung disease are mucus plugging, chronic inflammation and chronic infection. The mucus plugging seen in cystic fibrosis probably results from both increased production of mucus and altered chemical properties of the mucus. Mucus-secreting airway cells (goblet cells and submucosal glands) are increased in number and size. Cystic fibrosis mucus is dehydrated and viscous because of defective chloride secretion and excess sodium absorption — as a result, the mucus secretions are thick and sticky. This decreases the fluid volume on the airway surface, impairing the mobility of the cilia and thereby allowing mucus to adhere to the airway epithelium, along with bacteria and injurious byproducts from neutrophils. Chronic inflammation is believed to contribute to long-term lung damage and there is evidence that this
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A
B
FIGURE 25.13
The effects of emphysema on the gas exchange units. A Normal lung with many small alveoli. B Lung tissue affected by emphysema. Notice that the alveoli have merged into larger air spaces, reducing the surface area for gas exchange.
TABLE 25.3 Clinical manifestations of COPD BRONCHITIS
EMPHYSEMA
Age (years)
40–45
50–75
Infections
Common
Occasional
Dyspnoea
Mild, late in course
Severe, early in course
Productive cough
Classical sign
Late in course with infection
Wheezing
Intermittent
Common
History of smoking
Common
Common
Prolonged expiration
Always present
Always present
Cyanosis
Common
Uncommon
Chronic hypoventilation
Common
Late in course
Chest x-ray findings
Prominent vessels
Hyperinflation
General appearance
‘Blue bloater’
‘Pink puffer’
Barrel chest
Occasionally
Classic
process begins in infancy. Abnormal cytokine profiles promote a proinflammatory state. Individuals with cystic fibrosis have a propensity for chronic bronchial infection. It is likely that local factors in the cystic fibrosis airway microenvironment favour bacterial colonisation, because there is no systemic immune defect. Staphylococcus aureus and Pseudomonas aeruginosa are common, and Pseudomonas aeruginosa ultimately colonises airways in approximately 70% of adults between the ages of 18 and 29 and 82.3% of adults with cystic fibrosis over
Decline in quality of life with exacerbations
Quality of life
VARIABLES
Exacerbation
Progressive decline in lung function
Time
Death
FIGURE 25.14
Effect of exacerbations on lung function and quality of life in COPD. In the individual with COPD, there is a progressive decline in lung function. However, exacerbations can cause the decline to progress quicker, leading to a quicker decline in the quality of life.
the age of 30 years.37 Combined with chronic bacterial infection, these lead to microabscess formation, bronchiectasis, patchy consolidation and pneumonia, peribronchial fibrosis and cyst formation (see Fig. 25.15). There is a progressive decrease in the amount of available and functional lung tissue. The pathophysiology for these changes are outlined in Fig. 25.16. Over time, pulmonary
CHAPTER 25 Alterations of pulmonary function across the life span
RESEARCH IN F Nutrition and COPD
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CUS
Malnutrition is a major concern for individuals with COPD because they have increased energy expenditure, decreased energy intake and impaired oxygenation. The disproportionate muscle wasting is similar to that which occurs with other chronic diseases, such as cancer, heart failure and AIDS. Systemic inflammatory mediators may impair appetite and contribute to hypermetabolism. There are several detrimental effects of malnutrition: (1) adversely affects exercise tolerance by limiting skeletal and respiratory muscle strength and aerobic capacity; (2) limits surfactant production; (3) reduces cell-mediated immune responses; (4) reduces production of proteins (protein synthesis); and (5) increases morbidity and mortality. The goal of medical nutrition therapy is to maintain an acceptable and stable weight for the individual. This can be accomplished by including foods of high energy density, snacking frequently, choosing soft foods, having an adequate intake of fluids and providing assistance with shopping and meal preparation. Increasing omega-3 fatty acids and antioxidant intake may modulate the effects of systemic inflammation. Protein intake should be maintained at 1.0–1.5 g/kg of body weight, and a daily vitamin C supplement should be added to the diet if the individual is still smoking. On the other hand, obesity is observed at high rates of prevalence in COPD, and the prevalence is increasing. The rates of obesity in COPD have been reported at rates with an even higher prevalence than that seen in the general population. Obesity is usually associated with increased risk of all cause mortality in the general population, and is linked to metabolic syndrome. Discordantly, obesity in COPD is associated with improved survival and reduced lung function decline. The focus of current research is to define the best approach to the management of obesity in COPD populations.
vascular remodelling occurs because of localised hypoxia and arteriolar vasoconstriction, and pulmonary hypertension and cor pulmonale (right ventricular enlargement) may develop in the late stages of disease. CLINICAL MANIFESTATIONS
The most common presentations are respiratory or gastrointestinal. Respiratory symptoms include persistent cough or dyspnoea and recurrent or severe pulmonary infection. Lung function decreases in individuals with cystic fibrosis with increasing age. For instance, at 18 years, FEV1 is approximately 80% of predicted volumes.37 Physical signs that develop over time include barrel chest and digital clubbing. Over time, more serious pulmonary conditions may arise, such as haemoptysis and pneumothorax (see ‘Clinical manifestations of pulmonary alterations’). Classic gastrointestinal presentations include meconium ileus
FIGURE 25.15
The pathology of the lung in cystic fibrosis. Key features are widespread mucus impaction of airways and bronchiectasis (especially from upper lobe [U]), with haemorrhagic pneumonia in the lower lobe (L). Small cysts (C) are present at the apex of the lung.
(meconium blocking the bowel) at birth, which is indicative of cystic fibrosis. Approximately 80% of individuals with CF have pancreatic insufficiency leading to malabsorption, symptoms include frequent, loose and oily stools and, if not treated, either meconium ileus in infants or distal intestinal obstructive syndrome in adults develops. More subtle presentations include chronic sinusitis, nasal polyps and rectal prolapse. Complications of cystic fibrosis may include liver disease and cystic fibrosis related diabetes, each of which occurs in approximately one-quarter of adults. EVALUATION AND TREATMENT
In Australia and New Zealand, newborn infants are screened for cystic fibrosis. The blood test measures pancreatic enzyme levels and, if the levels are abnormal, genetic testing for the cystic fibrosis mutation is undertaken. However, the testing is not definitive: there are numerous cystic fibrosis-associated mutations and up to 5% of all tests will not be conclusive. Therefore, the definitive diagnosis is confirmed from a sweat test, which determines the level
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CONCEPT MAP
Chromosome 7 CFTR defect causes Defective chloride secretion leads to
impairs
Dehydrated mucus
Cilia movement
contributes to
contributes to
leads to Viscous mucus contributes to
Mucus plugs and impaired mucus clearance results in Bronchiectasis
Chronic bacterial infection leads to
Cyst formation
affects Pulmonary defence mechanisms results in (over time)
Chronic inflammation
FIGURE 25.16
The pathogenesis of bronchiectasis and cyst formation in cystic fibrosis. The altered chloride secretion leads to dehydrated, thick mucus, which cannot be moved easily by the impaired cilia. As a result, mucus accumulates and impairs normal pulmonary defence mechanisms, leading to infections and inflammation. CFTR = cystic fibrosis transmembrane regulator.
of sweat chloride concentration (indicative when in excess of 60 mmol/L). Treatment is primarily focused on pulmonary health and nutrition. Common pulmonary therapies include techniques to promote mucus clearance, such as chest physical therapy and positive pressure devices, bronchodilators, aerosolised DNase which liquefies mucus, and inhaled mucolytics such as hypertonic saline and mannitol. Inhaled maintenance antibiotics can be used to suppress Pseudomonas aeruginosa when it is present and this has a beneficial clinical impact. Oral antibiotics are used fairly liberally for minor pulmonary exacerbations. Intravenous antibiotics are used to treat more severe exacerbations of pulmonary infection. Lung transplantation is an option for selected individuals with end-stage lung disease from cystic fibrosis. Complications are usually related to infection or rejection and survival at 5 years posttransplant is approximately 67%.38 Approximately 80% of individuals with cystic fibrosis have pancreatic insufficiency and therefore need to take
pancreatic enzymes (for digestion of nutrients) before meals and snacks for their entire lifetime. Fat-soluble vitamins must be supplemented. Energy needs are high, especially with advancing lung disease and high-kilojoule supplements or even gastrostomy feeding may be warranted. Nutritional care for individuals with cystic fibrosis has become increasingly aggressive because of the documented link to better long-term outcomes. Fortunately, there have been major improvements in cystic fibrosis outcomes over the last few decades. These improvements are related to advances in treatment but of equal importance relate to the specialist multidisciplinary centres for children and adults with cystic fibrosis. Specialist centre care has been shown to be associated with improved clinical outcomes for children and adults; those treated in these centres have better nutritional status, chest x-ray scores and pulmonary function compared to other cystic fibrosis patients, and this approach is recommended as an essential component of management.
CHAPTER 25 Alterations of pulmonary function across the life span
RESEARCH IN F CUS New treatments for cystic fibrosis There have been recent advances in cystic fibrosis with the development of new therapies that target specific defects of the CFTR (cystic fibrosis transmembrane conductance regulator) function. The first CFTR modulator approved for use in cystic fibrosis is Ivacaftor. Ivacaftor targets the underlying protein defect in patients with the G551D mutation, and has been show to significantly improve lung function, exacerbations rates, weight and quality of life in adults. Lumacaftor/Ivacaftor combination is another targeted therapy that leads to improved lung function, exacerbations and nutrition in a subset of patients with cystic fibrosis. These treatments represent a new era of precision medicine in cystic fibrosis and emerging therapies are currently being developed and trialled.
BRONCHIECTASIS
Bronchiectasis is an abnormal permanent dilation and distortion of the bronchi and bronchioles, resulting from chronic inflammation of the airways, and leading to progressive destruction of the bronchial walls and lung tissue. Bronchiectasis has a distinctive appearance on x-rays (see Fig. 25.17) and chest computerised tomography (CT) scans. The prevalence of bronchiectasis among adults in Australia and New Zealand is largely uncertain due to lack of population studies and it is likely that any existing bronchiectasis prevalence rates are underestimated due to lack of diagnosis or misdiagnosis of the disease.
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Bronchiectasis is a debilitating illness in which individuals suffer significant respiratory morbidity and poor health-related quality of life. Exacerbations occur at rates of 1.5–6.5 per patient per year and are associated with an increased risk of admission and readmission to hospital, and high healthcare costs.39 Data estimating rates of hospital admissions, average length of stay and the economic burden of the disease give an indication as to the impact of this condition. The average annual age-adjusted rate of hospitalisations is 16.5 per 100 000 population,40 and an average annual increase of hospitalisation rates of 2.4% among men and 3.0% among women was identified between 1993 and 2006. These data highlight the need to optimise management of the disease. It is increasingly recognised that bronchiectasis may coexist with other common respiratory diseases such as COPD and asthma and that many of the clinical consequences may overlap. Literature reports up to 57% of people with COPD have coexisting bronchiectasis41 and 24.8% of people with severe persistent asthma have been shown to have coexisting bronchiectasis when examined with high resolution CT scan, despite being previously undiagnosed.42 Bronchiectasis is associated with multiple comorbidities that may alter the disease presentation, be a systemic consequence of the same pathophysiological process or act as confounding factors in the diagnosis and treatment of the disease. The symptoms of bronchiectasis may date back to a childhood illness or infection. The disease is commonly associated with recurrent lower respiratory tract infections and expectoration of large amounts of purulent sputum and haemoptysis are common. Pulmonary function studies show decreased vital capacity and expiratory flow rates. Bronchiectasis is often associated with bronchitis and atelectasis. Treatment of bronchiectasis involves avoidance and management of chest infections, antibiotics, airway clearance techniques, mucolytic agents and pulmonary rehabilitation in individuals who experience dyspnoea as part of their activities of daily living. FOCU S ON L EA RN IN G
1 Differentiate between the different components of COPD. 2 Discuss the anatomical and pathophysiological changes in chronic bronchitis. 3 Describe the changes in oxygenation and ventilation in individuals with emphysema. 4 Describe the pathogenesis of impaired mucus clearance and lung changes in cystic fibrosis.
Restrictive airway diseases FIGURE 25.17
Bronchiectasis on a chest x-ray. Note the dilated bronchi close to the midline (see arrows).
Restrictive airway diseases are not as prevalent as obstructive airway diseases in the Australian and New Zealand populations. They are fundamentally different from obstructive diseases, but many of the clinical manifestations
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are similar. Therefore, it is essential that you can differentiate between these two groups of disorders, such that clinical management can be directed appropriately. Restrictive lung diseases are characterised by decreased compliance (stretchiness) of the lung tissue, resulting in an increased work of breathing. Individuals with lung restriction complain of dyspnoea and have an increased ventilatory rate and decreased tidal volume — that is, they breathe fast but with smaller breath size. Pulmonary function testing reveals a decrease in FVC often accompanied with a reduction in FEV1. Therefore, the ratio of FEV1/FVC can be normal but usually increased — that is, about 80% of the forced expired air is expelled from the lungs in the first second — yet the overall amount of air forcibly exhaled is less than normal (see Fig. 25.18). Restrictive lung diseases commonly affect the alveolar–capillary membrane and cause decreased diffusion of oxygen from the alveoli into the blood, resulting in hypoxaemia. Some of the most common restrictive lung diseases in adults are acute respiratory distress syndrome, inhalational disorders, idiopathic pulmonary fibrosis and interstitial lung disease.
Acute respiratory distress syndrome
Acute respiratory distress syndrome is a dramatic life-threatening condition characterised by acute lung inflammation and diffuse alveolar capillary injury. It can affect all age groups. Individuals who progress to acute 8
Flow (L/s)
6
4
2
0 Volume (L) FIGURE 25.18
Flow volume loop — restrictive lung disease. These expiratory flow volume curves show pre- and postbronchodilator spirometry. The pre-bronchodilator effort is represented by the blue curve and the post-bronchodilator effort by the red curve. Note that there is a reduction in both FEV1 and FVC. Therefore, when calculated, the FEV1/FVC ratio is not different from that in healthy individuals; however, there is restriction throughout the entire expiratory phase.
respiratory distress syndrome typically are critically ill and require intensive care treatment. The mortality rate is high; however, advances in therapy have decreased mortality in people younger than 60 years. The most common predisposing factors are sepsis and multiple trauma; however, there are many other causes, including pneumonia, burns, aspiration, cardiopulmonary bypass surgery, pancreatitis, blood transfusions, drug overdose, high concentrations of supplemental oxygen and disseminated intravascular coagulation. PATHOPHYSIOLOGY
The hallmark of acute respiratory distress syndrome is lung inflammation. There is activation of the inflammatory response (see Fig. 25.19), including complement, cytokines, arachidonic acid metabolites and platelet-activating factor. All disorders causing acute respiratory distress syndrome cause massive pulmonary inflammation that injures the alveolar–capillary membrane and which produces severe pulmonary oedema and hypoxaemia. The damage can occur directly, as with the aspiration of highly acidic gastric contents or the inhalation of toxic gases, or indirectly from chemical mediators released in response to systemic disorders such as sepsis. Injury to the pulmonary capillary endothelium stimulates platelet aggregation (platelets sticking together) and intravascular thrombus formation. Endothelial damage also initiates the complement cascade, stimulating neutrophil and macrophage activity and the inflammatory response. Once activated, macrophages produce toxic mediators such as tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) (see Chapter 12). The role of neutrophils is central to the development of acute respiratory distress syndrome. Activated neutrophils release a battery of inflammatory mediators, including proteolytic enzymes (enzymes that break down proteins), toxic oxygen products, arachidonic acid metabolites (prostaglandins, thromboxanes, leukotrienes) and platelet-activating factor. These mediators extensively damage the alveolar–capillary membrane and greatly increase capillary membrane permeability. This allows fluids, proteins and various blood cells to leak from the capillary bed into the pulmonary interstitium and alveoli. The resulting pulmonary oedema severely reduces lung compliance and impairs alveolar ventilation. Mediators released by neutrophils and macrophages also cause pulmonary vasoconstriction, which leads to worsening of ventilation–perfusion mismatching and hypoxaemia. This vicious cycle continues and is difficult to halt. The initial lung injury also damages the alveolar epithelium. This cell injury increases alveolar capillary permeability, increases susceptibility to bacterial infection and pneumonia, and decreases surfactant production. Alveoli and respiratory bronchioles fill with fluid or collapse. The lungs become less compliant, ventilation of alveoli decreases and pulmonary blood flow is shunted right to left. The work of breathing increases. The end result is acute respiratory failure.
CHAPTER 25 Alterations of pulmonary function across the life span
731
results in Alveolar epithelial damage
Endothelial damage starts
affects Platelet aggregation causes Type II pneumocyte damage causes
Decreased surfactant production
leads to
Pneumonia
precipitates Neutrophil aggregation and release of mediators
can cause Bacterial infection
Release of neutrophil chemotactic factors
causes
Atelectasis and impaired lung compliance
Complement activation also Bacterial endotoxin release initiates Macrophage mobilisation causes contributes Release of cytokines (TNF, IL-1)
increases Alveolar-capillary membrane permeability
Vasoconstriction
allows Exudation of fluid, protein, RBCs into interstitium results in Pulmonary oedema and haemorrhage with severe impairment of alveolar ventilation
causes Decreased flow to selected areas causes Ventilation perfusion mismatching causes
Hypoxaemia
contributes to
Acute respiratory failure
contributes to
FIGURE 25.19
The proposed mechanism for the pathophysiological changes associated with acute respiratory distress syndrome. Damage to the alveoli leads to increased susceptibility to pneumonia and atelectasis. Damage to endothelial cells leads to activation of platelets and complement, which triggers a series of events that can result in pulmonary oedema and hypoxaemia. IL-1 = interleukin-1; RBCs = red blood cells; TNF = tumour necrosis factor.
CONCEPT MAP
Clinical lung injury
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The chemical mediators responsible for the alveolar capillary damage of acute respiratory distress syndrome often cause widespread inflammation, endothelial damage and capillary permeability throughout the body, resulting in the systemic inflammatory response syndrome, which then leads to multiple organ dysfunction syndrome. In fact, death may not be caused by respiratory failure alone but by multiple organ dysfunction syndrome associated with acute respiratory distress syndrome. (Multiple organ dysfunction syndrome is discussed in Chapter 23.) CLINICAL MANIFESTATIONS
Acute respiratory distress syndrome develops acutely after the initial insult, usually within 24 hours, though occasionally it is delayed up to a few days. The classic signs and symptoms of acute respiratory distress syndrome are marked dyspnoea, rapid shallow breathing, inspiratory crackles, respiratory alkalosis, decreased lung compliance, hypoxaemia unresponsive to oxygen therapy (called refractory hypoxaemia) and diffuse alveolar infiltrates seen on chest x-rays, without evidence of cardiac disease. EVALUATION AND TREATMENT
Diagnosis is based on physical examination, analysis of blood gases and radiological examination. Treatment for acute respiratory distress syndrome remains supportive in nature and the goals are to maintain adequate tissue oxygenation, minimise acute lung injury and avoid further pulmonary complications. Most individuals with acute respiratory distress syndrome require mechanical ventilation and often relatively high levels of positive end-expiratory pressure to promote alveolar ventilation and stabilisation and redistribution of alveolar oedema fluid into the interstitium.
Inhalation disorders EXPOSURE TO TOXIC GASES
Inhalation of gaseous irritants can cause significant respiratory dysfunction. Gases that are toxic to the pulmonary system include smoke, ammonia, hydrogen chloride, sulfur dioxide, chlorine and nitrogen dioxide. Inhalation of a toxic gas results in severe inflammation of the airways, alveolar and capillary damage and pulmonary oedema. Initial symptoms include burning of the eyes, nose and throat; coughing, chest tightness and dyspnoea. Hypoxaemia is common. Treatment includes supplemental oxygen, mechanical ventilation and support of the cardiovascular system due to hypotension. Most individuals respond quickly to therapy. Some, however, may improve initially then deteriorate as a result of bronchiectasis (persistent dilation of the bronchioles) or bronchiolitis (inflammation of the bronchioles). PNEUMOCONIOSIS
Pneumoconiosis represents any change in the lung caused by inhalation of inorganic dust particles, usually in the workplace. As in all cases of environmentally acquired lung
disease, the individual’s history of exposure is important in determining the diagnosis. Pneumoconiosis often occurs after years of exposure to the offending dust, with progressive fibrosis of lung tissue. Asbestosis, silicosis and coal worker’s pneumoconiosis are among the three most important dust-related diseases from occupational exposure in Australia, and recent local and international data suggest that there is a resurgence of coal worker’s pneumoconiosis.43 Asbestosis has the highest mortality of these three; though the risk of environmental exposure has been recognised for decades, it is to be hoped that with the controls now in place, exposure to asbestos will be limited in the future. However, there is also some concern remaining regarding exposure to asbestos, due to individuals undertaking their own home renovations, as the untrained renovator may disturb asbestos from numerous products that were used previously in home construction. Deposition of dusts from silica, asbestos and coal leads to chronic inflammation. In addition, scarring of the alveolar–capillary membrane leads to a build-up of connective tissue in the lung (termed pulmonary fibrosis). These dust deposits are permanent and lead to progressive pulmonary deterioration. Clinical manifestations with advancement of disease include cough, chronic sputum production, dyspnoea, decreased lung volumes and hypoxaemia. Diagnosis is confirmed by chest x-ray and CT scans. Treatment (such as pain control) is usually palliative (to reduce symptoms of the disease) and focuses on preventing further exposure, particularly in the workplace.
FOCU S ON L EA RN IN G
1 Describe the pathophysiology of acute respiratory distress syndrome. 2 Discuss the clinical manifestations of acute respiratory distress syndrome and how they progress differently from other lung diseases. 3 Differentiate between inhalational gas and particle exposure.
Infections of the pulmonary system Infections of the pulmonary system are some of the most common infections in humans. Symptoms of respiratory infection include increased sputum, cough, sore throat and fever; mild infections do not usually require medical intervention. Most of these infections — the common cold, pharyngitis (sore throat) and laryngitis — involve only the upper airways (i.e. the top part of the conducting airways). Although the lungs have direct contact with the atmosphere, they usually remain sterile as the upper airways filter and clear the inspired air of contaminants and thus more serious infections are prevented. Infections of the lower respiratory
CHAPTER 25 Alterations of pulmonary function across the life span
tract occur most often in individuals whose normal defence mechanisms are impaired and often provide more serious alterations to the pulmonary system, which can also have profound systemic effects, such as changes in cellular metabolism, affecting homeostasis. Of all the pulmonary infections in adults, pneumonia is the most serious and a leading cause of death in both males and females in Australia and New Zealand, especially in people older than 65 years of age.44 We now examine the pathophysiology of this serious infection.
Pneumonia
Pneumonia is infection of the lower respiratory tract caused by bacteria, viruses, fungi, protozoa or parasites. Risk factors for pneumonia include advanced age, individuals who are immunocompromised, underlying lung disease, alcoholism, altered consciousness, smoking, malnutrition and immobilisation. The causative microorganism influences how the individual presents clinically, how the pneumonia should be treated and the prognosis. Community-acquired pneumonia tends to be caused by different microorganisms compared to healthcare-acquired infections (healthcareacquired infections are discussed in Chapter 14). In addition, the characteristics of the individual are important in determining which microorganism is likely to infect them; for example, immunocompromised individuals tend to be susceptible to opportunistic infections (pathogens that cause infections but not in healthy individuals) that normally are uncommon in adults. In general, infections acquired within healthcare facilities and those affecting immunocompromised individuals have a higher mortality rate than communityacquired pneumonia. Some of the most common causal microorganisms are listed in Table 25.4. The most common community-acquired pneumonias are caused by bacteria, particularly those caused by Streptococcus pneumoniae (also known as the pneumococcus), which has a relatively high mortality rate in the elderly. Mycoplasma pneumoniae is a common cause of pneumonia in young people living in close contact, such as in dormitories. Influenza is the most common viral community-acquired pneumonia in adults and children; respiratory syncytial
733
virus and parainfluenza virus are common aetiological microorganisms. Legionella species is also an important cause of community-acquired pneumonia. Pseudomonas aeruginosa, other gram-negative microorganisms and Staphylococcus aureus are the most common aetiological agents in hospital-acquired pneumonia. Immunocompromised individuals (e.g. people with HIV or individuals who have undergone organ transplantation) are especially susceptible to Pneumocystis jiroveci, mycobacterial infections and fungal infections, such as aspergillus, of the respiratory tract. These infections can be difficult to treat and have a high mortality rate. PATHOPHYSIOLOGY
Aspiration of oropharyngeal secretions is the most common route of lower respiratory tract infection; thus, the nasopharynx and oropharynx constitute the first line of defence for most infectious agents. Another route of infection is through the inhalation of microorganisms that have been released into the air when an infected individual coughs, sneezes or talks, or from aerosolised water such as that from contaminated respiratory therapy equipment. This route of infection is most important in viral and mycobacterial pneumonias and in Legionella outbreaks. Pneumonia can also occur when bacteria are spread to the lungs in the blood from bacteraemia (bacteria within the blood) that can result from infection elsewhere in the body or from intravenous drug abuse. In healthy individuals, pathogens that reach the lungs are expelled or held in check by mechanisms of defence (see Chapters 12 and 13). If a microorganism gets past the upper airway defence mechanisms, such as the cough reflex and mucociliary escalator, the next line of defence is the alveolar macrophage (see Chapter 24 for details on pulmonary system defence mechanisms). This phagocyte is capable of removing most infectious agents without setting off significant inflammatory or immune responses. However, if the microorganism is virulent (small numbers can be pathogenic) or present in large enough numbers, it can overwhelm the alveolar macrophages. This results in a full-scale activation of the body’s defence mechanisms, including the release of multiple inflammatory mediators,
TABLE 25.4 Common microorganisms of pneumonia COMMUNITY-ACQUIRED PNEUMONIA
HEALTHCARE-ACQUIRED PNEUMONIA
IMMUNOCOMPROMISED INDIVIDUALS
Streptococcus pneumoniae
Pseudomonas aeruginosa
Pneumocystis jiroveci (Pneumocystis pneumonia)
Mycoplasma pneumoniae
Staphylococcus aureus
Mycobacterium tuberculosis
Haemophilus influenzae
Klebsiella pneumoniae
Atypical mycobacteria
Oral anaerobic bacteria
Escherichia coli
Fungi
Influenza virus
Respiratory viruses
Legionella pneumophilae
Protozoa
Chlamydia pneumoniae
Parasites
Moraxella catarrhalis
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cellular infiltration and immune activation. These inflammatory mediators and immune complexes can damage bronchial mucous membranes and alveolar–capillary membranes, causing the alveoli and terminal bronchioles to fill with infectious debris and exudate (fluid moving into a site of inflammation). In addition, some microorganisms release toxins from their cell walls that can cause further lung damage. The accumulation of exudate in the alveoli leads to dyspnoea, ventilation–perfusion mismatching and hypoxaemia. There are many viruses that can cause pneumonia, including influenza virus, respiratory syncytial virus, adenoviruses and parainfluenza virus. Viral pneumonia is the primary cause of pneumonia in children and older adults. Although viral pneumonia can be severe, it is usually mild and self-limiting. However, it can set the stage for a secondary bacterial infection by providing an ideal environment for bacterial growth and by damaging ciliated epithelial cells, which normally prevent pathogens from reaching the lower airways. Viral pneumonia can be a primary infection or a complication of another viral illness, such as chickenpox or measles (spread from the blood). The virus not only destroys the ciliated epithelial cells but also invades the goblet cells and bronchial mucous glands. Sloughing of destroyed bronchial epithelium occurs throughout the respiratory tract, preventing mucociliary clearance. Bronchial walls become oedematous and infiltrated with leucocytes. In severe cases, the alveoli are involved, with decreased compliance and increased work of breathing. CLINICAL MANIFESTATIONS
Many cases of pneumonia are preceded by an upper respiratory infection, which is often viral. Individuals then develop fever, chills, productive or dry cough, malaise, pleural pain and sometimes dyspnoea and haemoptysis (blood in the sputum). Physical examination may reveal signs of pulmonary consolidation, such as dullness to percussion (creation of vibrations, typically by tapping the chest) and inspiratory crackles. Individuals may also demonstrate symptoms and signs of underlying systemic disease or sepsis. EVALUATION AND TREATMENT
Diagnosis is made on the basis of the physical examination, white blood cell count, chest x-ray, stains and cultures of respiratory secretions, and blood cultures. The white blood cell count is usually elevated, although it may be low if the individual is debilitated or immunocompromised. Chest x-rays show infiltrates that may involve a single lobe of the lung or may be more diffuse (see Fig. 25.20). Once the diagnosis of pneumonia has been made, the pathogen is identified by means of sputum characteristics (gram stain; see Chapter 14 for details) and cultures or, if sputum is absent, blood cultures. Because many pathogens exist in the normal oropharyngeal flora, the specimen may be contaminated with pathogens from oral secretions. If sputum studies fail to identify the pathogen, the individual is immunocompromised or the individual’s condition worsens,
further diagnostic studies may include bronchoscopy (in which a scope with a camera is introduced into the lungs to visualise the airways) or lung biopsy. Positive identification of viruses can be difficult. Blood cultures often help to identify the virus if systemic disease is present. Antibiotics are used to treat bacterial pneumonia; however, resistant strains of pneumococcus are on the rise. Antibiotics are chosen based on the likely causative microorganism according to the clinical presentation and history. Viral pneumonia is usually treated with supportive therapy alone; however, antiviral medication may be needed in severe cases. Infections with opportunistic microorganisms may be polymicrobial (many species of microorganism) and require multiple drugs, including antifungals. Adequate hydration and good pulmonary hygiene (e.g. deep breathing, coughing, chest physiotherapy) are important aspects of treatment for all types of pneumonia.
Tuberculosis
Tuberculosis, commonly abbreviated to TB, is an infection caused by Mycobacterium tuberculosis, a bacterium that usually affects the lungs but may invade other body systems. Worldwide, tuberculosis is the leading cause of death from a curable infectious disease and was responsible for an estimated 1.8 million deaths in 2015.45 There are new cases of tuberculosis each year in Australia and New Zealand although the rates are very low compared with other developed countries. In 2012 there were 1317 cases of TB reported in Australia; these data represent a rate of 5.8 cases for every 100 000 people. Alarmingly the incidence rates of TB among the Indigenous population was five times that of the non-Indigenous Australian-born population in 2012 and 2013.45 PATHOPHYSIOLOGY
Tuberculosis (TB) is transmitted from person to person in airborne droplets. Microorganisms lodge in the lung periphery, usually in the upper lobe. Once the bacteria are inspired into the lung, they multiply and cause lung inflammation. Some bacteria migrate through the lymphatics and become lodged in the lymph nodes, where they encounter lymphocytes that initiate the immune response. The infection can either be active or latent. Inflammation in the lung causes activation of alveolar macrophages and neutrophils. These cells engulf the bacteria and begin the process by which the body’s defence mechanisms isolate and prevent their spread. The neutrophils and macrophages seal off the colonies of bacteria, forming granulomatous lesions called tubercles. Infected tissues within the tubercles die, forming cheese-like material that is necrotic (see Fig. 25.21).46 Scar tissue then grows around the tubercles, completing isolation of the bacteria. The immune response is complete after about 10 days, preventing further spread of the bacteria. Once immunity develops, tuberculosis may remain dormant for life.46 If the immune system is impaired or if live bacteria escape into the bronchi, active disease occurs
CHAPTER 25 Alterations of pulmonary function across the life span
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A
Lobar pneumonia
B
Bronchopneumonia FIGURE 25.20
Bacterial pneumonia seen in gross lung, chest x-ray and illustration. A Lobar pneumonia occurs when bacterial infection occurs in a portion of the lobe or the entire lobe. B Bronchopneumonia with patchy consolidation throughout the lung.
and may spread through the blood and lymphatics to other organs. CLINICAL MANIFESTATIONS
In people with active infection the most common clinical features of tuberculosis include chronic cough, sputum production, loss of appetite, weight loss, fever, night sweats, chest pain and haemoptysis. Individuals with latent infection are usually asymptomatic; however, they remain at risk of reactivation of tuberculosis in their lifetime. EVALUATION AND TREATMENT
Tuberculosis is usually diagnosed by a positive tuberculin skin test, sputum culture and chest x-rays. However, due to the high rate of false positives with the tuberculin skin test (meaning that the test reveals a positive tuberculosis result when the disease is not present), newer diagnostic tests have been developed. One such test, the interferon gamma release assay, measures interferon gamma that has been released from T cells of the immune system. The
recommendations of the Australian National Tuberculosis Advisory Committee are that tuberculin skin testing be used as the standard test for latent tuberculosis infection, with targeted use of interferon gamma release assays (Quantiferon Gold) when high specificity is desired.47 When an individual becomes infected with the pathogenic bacteria, Mycobacterium tuberculosis, the bacterial antigen is recognised by the immune system and T cells are sensitised. The T cells then release the cytokine, interferon gamma, which stimulates macrophages to phagocytose bacteria (see Chapter 13 for more details on immune responses). Treatment consists of antibiotic therapy to control active or latent tuberculosis infection and prevent transmission. Today, with the increased numbers of immunosuppressed individuals and drug-resistant bacteria, treatment is never single drug therapy as resistance appears rapidly; the recommended treatment includes a combination of drugs to which the organism is susceptible, including isoniazid, rifampin, pyrazinamide and ethambutol. Combination therapy is usually continued for 6 months.
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of the airways is usually caused by viruses, whereas the chronic airway inflammation is mainly caused by smoking. Acute bronchitis is likely to lead to a full recovery once the inflammation is resolved, whereas chronic bronchitis is irreversible. Many clinical manifestations of acute bronchitis are similar to those of pneumonia (fever, cough, chills and malaise — a general feeling of being unwell), but chest x-rays show no infiltrates. Individuals with viral bronchitis present with a non-productive cough that often occurs in paroxysms (sudden fits of coughing) and is aggravated by cold, dry or dusty air. In some cases, purulent sputum is produced. Chest pain often develops from the effort of coughing. Treatment consists of rest, aspirin, humidity and a cough suppressant, such as codeine.51 Bacterial bronchitis is rare in previously healthy adults except after viral infection but is common in patients with COPD. Although individuals with bronchitis do not have signs of pulmonary consolidation on physical examination (e.g. crackles), many will require chest x-ray evaluation to exclude the diagnosis of pneumonia. Bacterial bronchitis is treated with rest, antipyretics (fever-reducing drugs) and antibiotics.
Influenza
FIGURE 25.21
Tuberculosis in the lung. The grey-white areas represent the lesions formed from the bacteria.
In the past, individuals with active tuberculosis were isolated from the community. Today, individuals remain at home or, rarely, in hospital, until sputum cultures show that the active disease has been eliminated. Directly observed therapy short courses (DOTS) has been integral in the control of tuberculosis worldwide.48 DOTS involves five elements: political commitment; microscopy services; drug supplies; surveillance and monitoring systems and use of highly efficacious regimens; and direct observation of treatment.49 Building on this the World Health Organization has developed the END TB Strategy which aims to end the global tuberculosis epidemic.50
Acute bronchitis
Acute bronchitis is an acute infection or inflammation of the airways or bronchi and is usually self-limiting. In the vast majority of cases, it is caused by viruses.51 It differs from chronic bronchitis of COPD, in that acute inflammation
Influenza is a common respiratory viral infection that affects millions of people worldwide.1 The influenza virus can infect all age groups. There are a number of groups that are at a higher risk of influenza including the elderly; adults and children (aged 6 months and over) with chronic disorders of the pulmonary or circulatory systems, and nursing home and long-term-care residents. The virus can rapidly spread worldwide and has a seasonal variation that affects Australia and New Zealand predominately from June to September.44,52 PATHOPHYSIOLOGY
There are three main strains of influenza virus: type A, type B and type C. All three can cause influenza in humans, but type A is the most prevalent and is responsible for the yearly influenza known as ‘seasonal flu’. Type A has many different subtypes, which are classified using the letters ‘H’ and ‘N’, denoting two different surface proteins. For example, the most common virus causing infection in humans is type A (H1N1), which itself has many different subtypes. However, the virus can change — called antigenic drift, which means that mutations occur in the virus antigen such that the body’s antibodies cannot recognise the virus and hence it represents a new primary immune response. This is the primary reason why ‘new’ types of flu circulate each year. Antigenic drift has led to major pandemics that have resulted in massive mortality worldwide. Alarmingly, type A affects not only humans, but also horses, pigs, birds and aquatic birds. Avian and swine type A influenza have infected humans, and human-to-human transmission has occurred, leading to pandemics. The influenza virus enters the upper airways from airborne secretions of an infected individual. If the virus is
CHAPTER 25 Alterations of pulmonary function across the life span
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not immobilised by the inflammatory and immune systems, it invades the respiratory tract lining and proliferates. The triggered inflammatory mediators cause mucosal hyperaemia (redness to the mucosal lining), upper airway oedema and excess mucous secretion. The incubation period (until the appearance of symptoms) is up to 72 hours. CLINICAL MANIFESTATIONS
The classic signs and symptoms of cough and fever are usually indicative of influenza infection. They are often accompanied by generalised myalgia (muscle pain), headache and sore throat. The onset of the illness is abrupt and usually lasts between 3 and 5 days. Influenza infections can invade the lower respiratory tract and cause pneumonia, especially in children, the elderly and immunocompromised individuals (see Fig. 25.22). EVALUATION AND TREATMENT
Diagnosis of influenza is often difficult because of the rapid onset and relatively short duration. In addition, it is often hard to obtain isolation of the virus in specimens. The most effective treatment is prevention. Handwashing combined with pulmonary hygiene lowers the risk of acquiring the virus. In Australia and New Zealand, influenza vaccines are available for those at higher risk of attaining the virus, such as healthcare workers, those with chronic illnesses, infants and the elderly.
FIGURE 25.22
Chest x-ray changes in a patient with influenza pneumonia. The primary chest x-ray changes include small multifocal, patchy consolidations throughout both lungs, predominantly in the bases.
Respiratory infections are common in children and are a frequent cause of hospitalisations. Clinical presentation, the age of the child and the season of the year can often provide clues to the type of microorganism, even when the agent cannot be proven. Bronchiolitis Bronchiolitis is a rather common, viral-induced lower respiratory tract infection that occurs almost exclusively in infants and young toddlers. It has a seasonal, yearly incidence (May–October) and is the leading cause of hospitalisations for infants during the winter season. The most common associated pathogen is respiratory syncytial virus, which accounts for 50–80% of hospitalisations,53 but it may also be associated with human rhinovirus, adenoviruses, influenza, parainfluenza and mycoplasma. Healthy infants usually make a full recovery from respiratory syncytial virus bronchiolitis, but infants who were born premature with a birth weight of less than 2500 grams have a much higher risk for a more severe or even fatal course.
PATHOPHYSIOLOGY
Viral infection causes necrosis of the bronchial epithelium and destruction of ciliated epithelial cells. There is infiltration with lymphocytes around the bronchioles and a cell-mediated hypersensitivity to viral antigens with release of lymphokines causing inflammation, as well as activation of eosinophils, neutrophils and monocytes. The submucosa becomes oedematous and cellular debris and fibrin form plugs within the bronchioles. Oedema of the bronchiolar wall, accumulation of mucus and cellular debris and, perhaps, bronchospasm narrow many peripheral airways. Other airways become partially or completely occluded. Atelectasis (collapse of lung tissue) occurs in some areas of the lungs and hyperinflation in others. There is air trapping and functional residual capacity is greatly increased. Compliance is decreased because the lungs are already highly inflated and because airway resistance within the lungs is uneven and increased. The decrease in compliance and the increase in airway resistance result in a substantial Continued
PAEDIATRICS
Paediatrics and pulmonary infections
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increase in the work of breathing. Serious alterations in gas exchange occur because of airway obstruction and patchy atelectasis. Hypoxaemia develops because of ventilation–perfusion mismatch and hypercapnia may occur in severe cases. It has been suggested that children with acquired bronchiolitis may later develop asthma, but the relationship between these two respiratory disorders is unclear. CLINICAL MANIFESTATIONS
Symptoms usually begin with significant rhinorrhoea (runny nose) followed by a tight cough over the next few days, along with systemic signs of poor feeding, lethargy and fever. Infants typically have tachypnoea (increased ventilatory rate), variable degrees of respiratory distress and abnormal auscultatory findings of the chest. Wheezing is most common. EVALUATION AND TREATMENT
Diagnosis of bronchiolitis is made by a review of the signs and symptoms (e.g. rhinitis, cough, wheezing, chest retractions, tachypnoea) and chest x-ray findings.
F OCU S O N L E ARN IN G
1 Differentiate between different pneumonias. 2 Discuss the effects of tuberculosis on pulmonary structures. 3 Discuss why influenza virus is virulent and can lead to pandemics. 4 Describe the typical presentation of respiratory syncytial virus bronchiolitis.
Lung cancer Lung cancer arises from the epithelium of the respiratory tract. Therefore, the term lung cancer excludes other pulmonary tumours such as sarcomas, lymphomas, blastomas, haematomas and mesotheliomas. In 2010 more than 8000 people died from lung cancer in Australia.56 Of all the cancers, lung cancer is the leading cause of death in Australia.56 Since 2006 the number of lung cancer-related deaths has exceeded breast cancer, and while there has been a decline in mortality from most cancers between 1991 and 2010 the mortality rate from lung cancer in the female population has continued to rise.56 The incidence and mortality rates of lung cancer in the Indigenous population are approximately double those of the non-Indigenous population. Concomitantly, smoking rates in the Indigenous population are also greater.56 In New Zealand, lung cancer is the most common cause of cancer death for both males and females.57 Similarly in
Treatment is determined by the severity of the disease and the age of the child. Most cases are mild and usually require no specific treatment. Preventive treatment using pulmonary and hand hygiene combined with decreased exposure to people in the susceptible months decreases the risk of infection. Respiratory syncytial virus antibody is recommended for high-risk infants under 2 years old.54 Pertussis Pertussis is caused by the bacterium Bordetella pertussis. The symptoms are thick secretions, a chronic cough and spasm following coughing fits, which give a characteristic ‘whoop’ sound — hence the commonly used name ‘whooping cough’. The infection has an incubation period of 7–10 days and is highly contagious, but vaccination can prevent the infection. However, despite the availability of a vaccine, Australia and New Zealand experience periodic outbreaks of pertussis, with 11 863 cases reported in Australia in 2014.55 Pertussis is particularly lethal in newborns and infants who are too young to have received two or more doses of the vaccine (see Chapter 14 for immunisation schedules).
Australia, lung cancer incidence and mortality in females is projected to rise, while the rates for males are in decline. The most common cause of lung cancer is cigarette smoking, being linked to approximately 70% of cases in females and 90% in men. It has been shown that the number of cigarettes that people smoke and the number of years they smoke are directly related to the risk of developing lung cancer. There is an increased risk of developing lung cancer with advancing age, with a three times greater risk in people aged 65 years and older compared with their younger counterparts. This is evidenced by the fact that only 1% of lung cancers occur in people less than 40 years of age.56 In addition, second-hand (passive or environmental) smoke exposure is also a risk for lung cancer, so an individual exposed to the smoke from someone else’s cigarettes also has this increased risk. Smokers with obstructive airway disease (low FEV1) are at even greater risk. Genetic predisposition to developing lung cancer also plays a role in the pathophysiology. Other risk factors include occupational exposure to certain workplace toxins, radiation, air pollution and tuberculosis.
Types of lung cancer
Primary lung cancers arise from the bronchi within the lungs and are therefore called bronchogenic carcinomas. Although there are many types of lung cancer, lung cancer is divided into two major categories: non-small cell carcinoma (75–85% of all lung cancers) and small cell carcinoma (15–25% of all lung cancers). The category non-small cell carcinoma can be subdivided into three
CHAPTER 25 Alterations of pulmonary function across the life span
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TABLE 25.5 Characteristics of lung cancers TUMOUR TYPE
GROWTH RATE
METASTASIS
DIAGNOSIS
CLINICAL MANIFESTATIONS
Late; mostly to hilar lymph nodes
Biopsy, sputum analysis, bronchoscopy, electron microscopy
Cough, haemoptysis, sputum production, airway obstruction, hypercalcaemia
Adenocarcinoma Moderate
Early; to lymph nodes, pleura, bone, adrenal glands and brain
Radiography, fibreoptic bronchoscopy, electron microscopy
Pleural effusion
Large cell carcinoma
Early and widespread
Sputum analysis, bronchoscopy, electron microscopy (by exclusion of other cell types)
Chest wall pain, pleural effusion, cough, sputum production, haemoptysis, airway obstruction resulting in pneumonia
Very early; to mediastinum, lymph nodes, brain, bone marrow
Radiography, sputum analysis, bronchoscopy, electron microscopy
Cough, chest pain, dyspnoea, haemoptysis, localised wheezing, airway obstruction, signs and symptoms of excessive hormone secretion
Non-small cell carcinoma Squamous cell carcinoma
Slow
Rapid
Small cell carcinoma Very rapid
A
B
FIGURE 25.23
Squamous cell carcinoma. A Normal carina and bronchi of left upper lobe. B Carina of left lower lobe with swollen mucosa (thin dark line showing extent of swelling), white lesion (squamous cell cancer, bottom arrow) and haemorrhage on upper surface (top arrow).
common types of lung cancer: squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Characteristics of these tumours, including the clinical manifestations, are listed in Table 25.5. Many cancers that arise in other organs of the body metastasise to the lungs; however, these are not considered as lung cancers and are categorised by their primary site of origin.
Non-small cell carcinoma
Squamous cell carcinoma accounts for about 30% of bronchogenic carcinomas. These tumours are typically located near the hilum and project into the bronchi (see Fig. 25.23). Because of the location in the central bronchi, obstructive manifestations are nonspecific and include
non-productive cough or haemoptysis (which is the coughing up of blood in the sputum; see ‘Clinical manifestations of pulmonary alterations’ below). Pneumonia and atelectasis are often associated with squamous cell carcinoma. Chest pain is a late symptom associated with large tumours. These tumours can remain fairly well localised and tend not to metastasise until late in the course of the disease. The preferred treatment is surgical resection, although once metastasis (spread away from the original site) has taken place, total surgical resection is more difficult and survival rates decrease dramatically.58 Radiation therapy and chemotherapy improve outcomes in many individuals. Adenocarcinoma (meaning that the tumour arises from the glands) constitutes 35–40% of all bronchogenic carcinomas (see Fig. 25.24). The increase in incidence of adenocarcinoma has been ascribed to the increasing occurrence of lung cancer in females, environmental and occupational carcinogens, and changes in the histological criteria for diagnosis. These tumours, which are usually smaller than 4 cm, more commonly arise in the peripheral regions of the lung tissue. They may be asymptomatic and discovered by routine chest x-ray in the early stages or the individual may present with pleuritic chest pain and shortness of breath from pleural involvement by the tumour. Surgical resection is possible in a high proportion of cases, but because metastasis occurs early, the 5-year survival rate is low. Large cell carcinomas constitute 10–15% of bronchogenic carcinomas (see Fig. 25.25). This cell type has lost all evidence of differentiation and therefore is sometimes referred to as undifferentiated large cell anaplastic cancer (literally meaning that the cells revert back to an immature form). Because large cell carcinomas show none of the histological findings of squamous cell carcinoma or
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A
B
FIGURE 25.24
Adenocarcinoma. This gross lung lobe has a large white mass (carcinoma). The cancers are predominately on the peripheral aspects of the lung, not in the large airways.
adenocarcinoma, they are diagnosed by a process of exclusion. The cells are large and contain darkly stained nuclei. These tumours commonly arise centrally and can grow to distort the trachea and cause widening of the carina, which can result in breathing difficulties. Once metastasis has occurred, surgical therapy is limited to palliative procedures — meaning that care is for comfort only, as the individual cannot be cured.
Small cell carcinoma
Small cell carcinomas constitute 15–20% of bronchogenic carcinomas. Most of these tumours are central in origin (see Fig. 25.26). This cell type has the strongest correlation with cigarette smoking. Because these tumours show a rapid rate of growth and tend to metastasise early and widely, small cell carcinomas have the worst prognosis. Survival time for untreated small cell carcinoma is usually only 1–3 months. Approximately only 14% of treated individuals are alive 2 years after diagnosis. Small cell carcinoma is most often associated with ectopic hormone production, meaning that hormones are produced in tissues, in this case cancerous lung tissue, away from the usual glands. Neuroendocrine cells containing neurosecretory granules exist throughout the tracheobronchial tree and may be associated with small cell carcinoma. Ectopic hormone production is important to the clinician because resulting signs and symptoms may be the first manifestation
FIGURE 25.25
Large cell carcinoma. A Gross lung with a large white-grey mass on lower right margin. B Chest x-ray of a large cell carcinoma in the right lower lobe (red arrow).
of the underlying cancer. Small cell carcinomas most commonly produce antidiuretic hormone from associated neuroendocrine cells and develop the syndrome of inappropriate antidiuretic hormone secretion. Individuals with lung cancer secrete large quantities of steroids, leading to the development of an atypical Cushing’s syndrome (see Chapter 11). Signs and symptoms related to this condition include muscular weakness, facial oedema, hypokalaemia, alkalosis, hyperglycaemia, hypertension and increased pigmentation. Treatment of small cell carcinoma is usually palliative. More than 85% of tumours will have metastasised by the time of diagnosis. Chemotherapy and radiation can significantly prolong life and relieve symptoms, but relapse is inevitable in most individuals.59
CHAPTER 25 Alterations of pulmonary function across the life span
FIGURE 25.26
Small cell carcinoma. The cancer can be seen as the white growths.
PATHOPHYSIOLOGY
Tobacco smoke contains more than 30 carcinogens and is responsible for causing 80–90% of lung cancers. These carcinogens result in multiple genetic abnormalities in bronchial cells including deletions of chromosomes, activation of oncogenes and inactivation of tumour suppressor genes. The most common genetic abnormality associated with lung cancer is loss of the tumour suppressor gene p53; mutations in this gene have been found in 50–60% of non-small cell carcinomas and 90% of small cell carcinomas.60 Once lung cancer is initiated by these carcinogen-induced mutations, further tumour development is promoted by growth factors. Further cellular toxicity is enhanced through smoke-induced toxic free radical production. The bronchial mucosa suffers multiple carcinogenic ‘hits’ due to repetitive exposure to cigarette smoke and eventually epithelial cell changes begin to be visible on biopsy. These changes progress from metaplasia (changing from one cell type to another cell type) to carcinoma in situ and finally to invasive carcinoma. Further tumour progression includes invasion of surrounding tissues and finally metastasis to distant sites including the brain, bone marrow and liver. CLINICAL MANIFESTATIONS
There are many different signs and symptoms in individuals with lung cancer. It is somewhat dependent on the location of the cancer in the pulmonary system as to what clinical manifestations will arise. Table 25.5 summarises the characteristic clinical manifestations according to tumour type. By the time there are manifestations severe enough for the individual to notice them, the disease is usually advanced. EVALUATION AND TREATMENT
Diagnostic tests for the evaluation of lung cancer include chest x-ray, sputum cytology, chest-computed tomography, fibreoptic bronchoscopy and biopsy. Biopsy determines the
741
cell type, and the evaluation of lymph nodes and other organ systems is used to determine the stage of the cancer. The histological cell type and the stage of the disease are the major factors that influence the choice of therapy. The current accepted system for the staging of non-small cell carcinoma is the TNM classification. This system is a code in which T denotes the extent of the primary tumour, N indicates the lymph node involvement and M describes the extent of metastasis. Small cell carcinoma is so rapidly progressive that its staging system consists of only two stages: limited and extensive disease. The only proven way of reducing the risk for lung cancer is the cessation of smoking. To date, trials evaluating the use of various early screening modalities such as chest x-ray and CT scanning have not resulted in a decrease in lung cancer mortality.61 The management of lung cancer has been outlined here under each cell type, but it is generally chosen on the basis of tumour stage and patient functional status. Current modalities include combinations of surgical resection, chemotherapy and radiation; however, new genetic and immunological therapies are being explored (see ‘Research in Focus: Genetic and immunological therapies for lung cancer’).
RESEARCH IN F CUS Genetic and immunological therapies for lung cancer Although new chemotherapeutic agents have slightly improved outcomes in the management of lung cancer, overall survival rates remain poor and the toxicities of these regimens limit their use. New understandings of the genetic and immunological features of lung cancer cells have led to new treatments. Gene therapy is emerging as a way of restoring normal tumour suppressor gene function and increasing tumour responsiveness to chemotherapy and radiation therapy. Immunological therapies include antibodies to growth factor receptors and anti-angiogenesis drugs (those that prevent the growth of new blood vessels from the tumour). The effectiveness of these strategies is still being evaluated, but new knowledge is leading to new opportunities for treatment.
FOCU S ON L EA RN IN G
1 Describe the incidence and mortality of lung cancer and the differences between the sexes. 2 Discuss the pathological differences between non-small cell carcinoma and small cell carcinoma.
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Obstructive sleep apnoea
PATHOPHYSIOLOGY
Obstructive sleep apnoea generally results from upper airway obstruction recurring during sleep, with excessive snoring and multiple apnoeic episodes (periods were there is no breathing) that last at least 10 seconds but can last up to 60 seconds or more. Approximately 9–25% of the middle-aged population in Australia have obstructive sleep apnoea,62 and the prevalence in older people is likely to be higher as sleep complaints and disorders are more common in the elderley.63 In New Zealand, the prevalence of obstructive sleep apnoea has been estimated at 4.1% for males and 0.7% for females.64 Within Indigenous populations, the prevalence is higher for both males and females. Childhood obstructive sleep apnoea is also quite common, with an estimated prevalence of 1–10%.65 In children, unlike in adults, obstructive sleep apnoea occurs equally among girls and boys. There is an increased risk of death from cardiovascular disease associated with obstructive sleep apnoea.66 The exact reason for this is unknown; however, the repeated episodes of hypoxia related to apnoea during sleep are likely to impact on the cardiovascular system. It has also been shown that obstructive sleep apnoea is an independent risk factor for increased mortality from any cause.67 Other deleterious consequences of obstructive sleep apnoea include unrefreshing sleep, excessive daytime sleepiness and neurocognitive impairment.68
A
Anatomical and structural factors in the upper airway play a crucial role in the development of obstructive sleep apnoea. The tonsils, adenoids, tongue and soft tissue that surround the pharynx become enlarged, reducing the lumen (airway size). This is more pronounced in obese individuals who have a large neck circumference. Collectively, these factors predispose the individual to upper airway collapse during sleep.69 In children, the most pathophysiological reason for obstructive sleep apnoea is due to adenotonsillar hypertrophy; however, rates of childhood obesity are also likely to contribute to the rates of childhood sleep apnoea. When obstructive sleep apnoea is present, the pharyngeal tissue completely obstructs the airway, preventing ventilation. This causes a cycle of obstructive breathing during sleep when the airway repeatedly collapses, and this periodic breathing eventually produces arousal, which interrupts the sleep cycle, reducing total sleep time and producing sleep deprivation.69 The often sustained and repeated apnoeic periods result in hypoxaemia (inadequate oxygen levels in the blood), which, it has been proposed, influences neural control of the upper airway. Hypoxaemia is more pronounced during periods of rapid eye movement (REM) sleep. The reason for this is unknown, but it may explain the tiredness and insomnia reported by individuals with obstructive sleep apnoea. Sleep apnoea produces low oxygen saturation (see Fig. 25.27) and eventually leads to polycythaemia (a blood
100
SpO2 (%)
90 80 70 60 50
B
100
SpO2 (%)
90 80 70 60 50 11:00 pm
12 Midnight
1 am
2 am 3 am Time (clock)
4 am
5 am
6 am
FIGURE 25.27
Oxygen saturation levels during sleep apnoea. Oxygen saturation (SpO2) levels during sleep in A a healthy individual, and B an individual with severe obstructive sleep apnoea. In the healthy individual, oxygen saturation remains close to 100%. With the individual with sleep apnoea, the large reductions in oxygen saturation during sleep are due to the repeated apnoea episodes.
CHAPTER 25 Alterations of pulmonary function across the life span
disorder causing excessive red cell production), pulmonary hypertension, right-sided heart failure, liver congestion, cyanosis and peripheral oedema. Systemic hypertension may result from repeated episodes of apnoea and hypoxaemia. CLINICAL MANIFESTATIONS
Due to obstruction of the upper airway, snoring is the most common manifestation. There may be periods of increased ventilatory effort without an audible airflow. During the apnoeic periods, breathing can cease for 10 seconds up to 1 minute and these episodes can occur repeatedly throughout sleep.70 Therefore, sleep is often restless, and there is daytime tiredness and sleepiness. This chronic tiredness impacts on daytime cognitive and neurobehavioural performance. For instance, obstructive sleep apnoea has been associated with an increased mortality from traffic accidents.69 Cardiac arrhythmias during sleep apnoea are common, such as sinus pauses (temporary cessation of sinus node activity) and premature ventricular contractions.71 In children, bedwetting and chronic mouth breathing are associated with obstructive sleep apnoea. EVALUATION AND TREATMENT
There usually is a history of snoring and laboured breathing during sleep, which may be continuous or intermittent in individuals with obstructive sleep apnoea. Associated risk factors include advancing age, obesity, gender (males are more affected than females), genetic predisposition, smoking
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and alcohol consumption.69 The most accurate diagnosis of obstructive sleep apnoea is an overnight polysomnogram, also known as a sleep study.70 This test records brain activity (electroencephalogram), eye movement, muscle activity (electromyogram), heart rate, air flow and oxygen haemoglobin (SpO2) levels during sleep and collectively allows classification of the amount and duration of apnoeic periods, thereby permitting diagnosis of obstructive sleep apnoea. Treatments include nasal continuous positive airway pressure (CPAP) and dental devices, upper airway and jaw surgery in selected individuals, and management of obesity.70 In children, if obstructive sleep apnoea is documented or strongly suspected clinically, tonsillectomy and adenoidectomy are the treatments of choice. For severely affected children who do not respond to surgery or who have different problems, such as obesity, that cannot be remedied rapidly, CPAP, similar to adult management, may be required.
FOCU S ON L EA RN IN G
1 Describe the signs and symptoms suggestive of obstructive sleep apnoea in children and adults. 2 Discuss the effect of sleep apnoea on daytime activities.
There are some important childhood pulmonary disorders that need to be explored. In this section we examine some of the major childhood disorders, starting with croup. Croup Classic croup is an acute inflammation of the upper airways and almost always occurs in children between 3 months and 5 years of age.72 In 85% of cases, croup is caused by a virus, most commonly parainfluenza and in other instances by influenza A or respiratory syncytial virus, however bacteria and atypical agents have also been identified.72 The incidence of croup is higher in males and is most common during the winter months. PATHOPHYSIOLOGY
Airway obstruction occurs in the subglottic region of the trachea, just below the vocal cords. Contributory factors include mucosal oedema and secretions related to the viral infection. Anatomically, the subglottic region is slightly narrower than the rest of the trachea and in children the subglottic mucous membrane is more loosely attached and more vascular than in adults. These factors make the airway susceptible to compromise in children.
If there is significant narrowing of the airway in this area, work of breathing will increase and the excessive negative pressure generated may even cause the airway structures higher up to collapse with inspiration (see Fig. 25.28). The turbulent flow across this obstruction will cause stridor (an abnormal, harsh, high-pitched sound caused by turbulent flow in a partially obstructed upper airway) on inspiration and sometimes also on expiration (see Fig. 25.29). Croup tends to affect younger children more prominently because they have smaller airways that are therefore compromised more easily (see Fig. 25.30). CLINICAL MANIFESTATIONS
Typically, the child experiences rhinorrhoea, sore throat and low-grade fever for a few days, then develops a seallike barking cough. Most cases resolve spontaneously within 24–48 hours and do not warrant hospitalisation. However, the presence of inspiratory stridor or respiratory distress suggests a more severe situation. EVALUATION AND TREATMENT
The degree of symptoms determines the level of treatment. Treatment may include injected, oral or nebulised Continued
PAEDIATRICS
Paediatrics and pulmonary disorders
CONCEPT MAP
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Part 4 Alterations to body maintenance
Microorganism enters upper airway
Inflammation and oedema
initiates Inflammatory response in upper airway causes Snoring zone
if swelling enough causes Upper airway obstruction increases
Voice quality zone
Resistance to air flow
Cough quality zone
results in Increased intrathoracic negative pressure
Inspiratory stridor zone
Expiratory stridor zone
causes Collapse of upper airway
FIGURE 25.28
The formation of upper airway obstruction with croup. Entry of the microorganisms causes upper airway inflammation, leading to airway obstruction and collapse.
glucocorticoids to reduce the inflammation. The presence of stridor at rest, moderate or severe retractions of the chest or agitation suggests more severe disease and requires hospitalisation for observation and treatment. Severe obstruction requires emergency care to protect the airway. Respiratory distress syndrome of the newborn The name respiratory distress syndrome of the newborn refers to a lung disorder that remains a significant cause of neonatal morbidity and mortality.73 It occurs almost exclusively in premature infants. Respiratory distress syndrome occurs in 60% of infants born at less than 28 weeks gestation, in 30% of those born at 28–34 weeks and in fewer than 5% of those born after 34 weeks. The incidence and death rates have declined significantly since the introduction of antenatal steroid therapy and postnatal surfactant therapy.74 Risk factors include premature birth, caesarean delivery without labour, gender (male), diabetic mother and perinatal asphyxia. PATHOPHYSIOLOGY
Respiratory distress syndrome is caused by surfactant deficiency and also a deficiency in alveolar surface area for gas exchange. Surfactant is the material that lines the
FIGURE 25.29
Respiratory sounds and their anatomical location. Alterations in respiratory sounds inform about the airways in those respective anatomical locations.
A
B Epiglottis False cords True cords Subglottic tissue Trachea
FIGURE 25.30
The larynx and subglottic trachea. A Normal. B Narrowing and obstruction from oedema caused by croup.
alveoli and is required for maintaining their inflation. Without surfactant, which lowers surface tension, alveoli would tend to collapse at the end of each exhalation. Surfactant is not normally secreted by the alveolar cells until approximately 30 weeks gestation. In addition to the functional surfactant deficiency of the premature
CHAPTER 25 Alterations of pulmonary function across the life span
lung, structural immaturity is a problem. Premature infants are born with many underdeveloped and small alveoli that are difficult to inflate. In the most extreme premature infants, the ‘alveoli’ have thick walls and inadequate capillary blood supply such that gas exchange is significantly impaired. In addition, the chest wall is weak and highly compliant and the rib cage tends to collapse inwards with ventilatory effort. The net effect of all these adverse factors is atelectasis (collapsed alveoli), which is difficult for the neonate to overcome because
it requires a significant negative inspiratory pressure to open the alveoli with each breath. The infant uses more oxygen to sustain the work of breathing and becomes hypoxaemic and hypercapnic (low blood oxygen and high carbon dioxide, respectively). Hypoxia and atelectasis cause pulmonary vasoconstriction and increase intrapulmonary resistance. This results in hypoperfusion of the lung and a decrease in effective pulmonary blood flow. The pathogenesis of respiratory distress syndrome is summarised in Fig. 25.31.
Decreased number of alveoli
presents with
Poor lung compliance
Immature alveoli
results
results in
results
CONCEPT MAP
Premature birth Decreased surfactant production
Atelectasis
contributes to
causes
Inactivation of surfactant causes
leads to
Increased pulmonary vascular resistance leads to
results in Protein leak into airspaces
Impaired cellular metabolism
Inadequate alveolar ventilation
causes
worsens
Decreased expansion of alveoli
leads to
745
Pulmonary hypoperfusion
causes Hypoxaemia
manifest as
develops Hypoxic vasoconstriction causes
Hypercapnia
Ventilation-perfusion mismatch
results in
manifest as
Respiratory acidosis
Metabolic acidosis
leads to
Respiratory failure
leads to
FIGURE 25.31
The pathogenesis of respiratory distress syndrome of the newborn. Premature birth leads to insufficient production of surfactant, poor lung compliance, insufficient number of alveoli and immature alveoli. Together, these lead to a complex series of events including lung collapse (atelectasis), hypoxaemia and respiratory failure. Continued
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CLINICAL MANIFESTATIONS
Signs of respiratory distress syndrome appear within minutes of birth. Some neonates require immediate resuscitation because of asphyxia or severe respiratory distress. Characteristic signs are tachypnoea (respiratory rate over 60 breaths per minute), expiratory grunting, intercostal and subcostal retractions, nasal flaring and pale colour. The natural course is characterised by progressive hypoxaemia and dyspnoea. Apnoea and irregular respirations occur as the infant becomes fatigued from the difficulty of breathing. The typical chest x-ray shows diffuse, fine granular densities within the first 6 hours of life. In most cases the clinical manifestations reach a peak within 3 days, after which there is gradual improvement. EVALUATION AND TREATMENT
Diagnosis is made on the basis of prematurity or other risk factors and chest x-rays. The ultimate treatment for respiratory distress syndrome would be prevention of premature birth; however, this is not always possible and often not foreseeable. Antenatal treatments with glucocorticoids are given to women at 24–34 weeks gestation for those at risk of premature delivery, and in preterm labour, unless delivery is imminent. Glucocorticoids induce a significant and rapid acceleration of lung maturation and there is extensive evidence that maternal steroid therapy significantly reduces the incidence of respiratory distress syndrome and death.75 Surfactant therapy should be considered complementary to antenatal corticosteroids. Supportive care includes oxygen and often continuous positive airway pressure or mechanical ventilation. Most infants survive respiratory distress syndrome with treatment. In many cases, recovery may be complete within 10–14 days. However, the incidence of subsequent chronic lung disease is significant among very low birth weight infants. Sudden infant death syndrome Sudden infant death syndrome (SIDS) remains a disease of unknown cause.76 It is defined as ‘sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene and review of the clinical history’.77
FOCUS O N L E ARN IN G
1 Describe the pathophysiology of croup. 2 Discuss how the alveoli and capillaries are affected by respiratory distress syndrome of the newborn. 3 List the risk factors for sudden infant death syndrome.
The incidence of SIDS is low during the first month of life but sharply increases in the second month and peaks at 3–4 months of age, then gradually declines.76 It is more common in males (60%) than females (40%). It almost always seems to occur during night-time sleep, when infants are least likely to be observed. A seasonal variation has been noted, with higher frequencies during the winter months. This has been related to a higher rate of respiratory tract infections during these months and, in fact, such infections are often reported to have preceded the death. Clinical risk groups include babies who were preterm or low birth weight, who were one of simultaneous multiple births and who had siblings die of SIDS. Nevertheless, about three-quarters of all SIDS cases have no known predisposing clinical risk factor. Additional risk factors fall into the categories of socioeconomic or maternal factors and factors in the baby’s sleeping situation. Maternal factors that predict increased risk are maternal smoking, young maternal age (under 20 years), less prenatal care, poverty and illicit drug use. Risk factors that relate to the baby’s sleeping situation are prone positioning, sleeping on a soft surface and overheating.78 Prone sleeping has been concluded to be a major and modifiable risk factor. Infants should sleep on their backs, even in preference to side sleeping. Other avoidable risk factors include sleeping on top of any soft surface and loose bedding. Overwrapping the infant or over-heating the room also appears to increase risk, particularly if the infant is sleeping prone. The aetiology of SIDS remains unknown but probably involves a combination of predisposing factors and external stressors.76,77 Currently, the best strategies for reducing SIDS seem to be avoidance of all the controllable risk factors. In Australia, infant mortality from SIDS has fallen to now being extremely rare, with only three babies dying of SIDS in 2012.79 The dramatic reduction from several hundred deaths in previous years was attributed to a successful national health education campaign that raised awareness of the risk factors and promoted safe infant sleeping practices, such as positioning the baby on their back during sleeping.
Alterations of pulmonary blood flow and pressure Blood flow through the lungs can be disrupted by disorders that occlude the vessels, increase pulmonary vascular resistance or destroy the vascular bed. The effects of altered pulmonary blood flow and pressure range from insignificant
CHAPTER 25 Alterations of pulmonary function across the life span
dysfunction to severe and life-threatening changes in ventilation/perfusion ratios.
Pulmonary embolism
Pulmonary embolism is occlusion of a portion of the pulmonary vascular bed by an embolus (see Fig. 25.32), which can be a thrombus (blood clot), tissue fragment, lipids (fats), foreign body or an air bubble (air embolism). More than 90% of pulmonary emboli result from clots formed in the veins of the legs and pelvis. Risk factors for pulmonary thromboembolism, or the obstruction of a pulmonary vessel by a thrombus, include conditions and disorders that promote blood clotting as a result of venous stasis (slowing or stagnation of blood flow through the veins), hypercoagulability (increased tendency of the blood to form clots) and injuries to the endothelial cells that line the vessels. No matter the source, a blood clot becomes an embolus when all or part of it breaks away from the site of formation and begins to travel in the bloodstream. Thromboembolism or deep vein thrombus is described further in Chapter 23. Although the overall incidence of pulmonary embolism has declined (2 per 1000 people per year), it remains an important cause of death, especially in the elderly and hospitalised individuals. Trauma, especially head injuries and fractures of the lower extremities, spine or pelvis, confers a high risk for venous thromboembolism. PATHOPHYSIOLOGY
The impact or effect of the embolus depends on the extent of pulmonary blood flow obstruction, the size of the affected vessels, the nature of the embolus and the secondary effects. Pulmonary emboli can occur as any of the following: • massive occlusion: an embolus that occludes a major portion of the pulmonary circulation (i.e. main pulmonary artery embolus)
FIGURE 25.32
Pulmonary embolism. Large pulmonary embolus (arrow) lying in the pulmonary artery (retracted back for visualisation).
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• embolus with infarction: an embolus that is large enough to cause infarction (death) of a portion of lung tissue • embolus without infarction: an embolus that is not severe enough to cause permanent lung injury • multiple pulmonary emboli: may be chronic or recurrent. The pathogenesis of pulmonary embolism caused by a thrombus is summarised in Fig. 25.33. If the embolus does not cause infarction in the lung tissue that is not receiving blood, the clot will be dissolved by the fibrinolytic system (see Chapter 16) and pulmonary function will return to normal. If pulmonary infarction occurs, shrinking and scarring develops in the affected area of the lung. CLINICAL MANIFESTATIONS
In most cases, the clinical manifestations of pulmonary embolism are nonspecific, so evaluation of risk factors and predisposing factors is an important aspect of diagnosis. Although most emboli originate from clots in the lower extremities, specifically the iliac and femoral veins,80 deep vein thrombosis is often asymptomatic and clinical examination has low sensitivity for the presence of clot, especially in the thigh. An individual with pulmonary embolism usually presents with the sudden onset of chest pain, dyspnoea, tachypnoea, tachycardia and unexplained anxiety. Occasionally syncope (fainting) or haemoptysis occurs. With large emboli, a pleural friction rub, pleural effusion, fever and leucocytosis may be noted. Recurrent small emboli may not be detected until progressive incapacitation, precordial pain (stabbing chest pain), anxiety, dyspnoea and right ventricular enlargement are exhibited. Massive occlusion causes severe pulmonary hypertension, shock and sudden death. EVALUATION AND TREATMENT
Routine chest x-rays and pulmonary function tests are not definitive for pulmonary embolism. On chest x-rays, the infarcted portion of the lung appears as a nonspecific infiltrate in a classic wedge shape bordering the pleura. Arterial blood gas analyses usually demonstrate hypoxaemia and hyperventilation (leading to respiratory alkalosis). A ventilation–perfusion scan, in which lungs are scanned after injection and inhalation of a radioactive substance, may indicate embolism (see Fig. 25.34). Today, the diagnosis is made by measuring elevated levels of D-dimer in the blood (an indicator of fibrinolysis) in combination with spiral CT scanning.81 The ideal treatment for pulmonary embolism is prevention through elimination of predisposing factors for individuals at risk. Venous stasis in hospital patients is minimised by leg elevation, bed exercises, position changes, early postoperative ambulation and pneumatic calf compression. Clot formation is also prevented by prophylactic low-dose anticoagulant therapy usually with low-molecularweight heparin or warfarin. Anticoagulant therapy is the primary treatment for pulmonary embolism. Intravenous administration of heparin
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CONCEPT MAP
Venous stasis Vessel injury Hypercoagulability
Predisposing factors
Predispose e.g. DVT Thrombus formation dislogdes Formation of thrombus and occlusion of embolus
Portion of thrombus causes Occlusion of part of pulmonary circulation leads to Hypoxic vasoconstriction Decreased surfactant Release of neurohumoral and inflammatory substances Pulmonary oedema Atelectasis
Conditions arising from occlusion of pulmonary vasculature
manifest as Tachypnoea Dyspnoea Chest pain Increased dead space Ventilation–perfusion imbalances Decreased PaO2 Pulmonary infarction Pulmonary hypertension Decreased cardiac output Systemic hypotension Shock
Signs and symptoms of pulmonary embolism
FIGURE 25.33
The pathogenesis of massive pulmonary embolism caused by a thrombus (venous thromboembolism). A thrombus can form in another vessel, usually a deep vein thrombosis in the leg. From this, a fragment can dislodge and travel through the blood to the lungs, where it forms a pulmonary embolism. This blockage to the pulmonary vessel may lead to severe complications including severe impairment of gas exchange, pulmonary oedema and hypertension, and shock.
is begun immediately and is followed by oral doses of warfarin. Studies suggest that low-molecular-weight heparins (e.g. enoxaparin) are as safe and effective as standard heparin but are easier to administer.82 If a massive life-threatening embolism occurs, a fibrinolytic agent is sometimes used and some individuals will require surgical thrombectomy.
Cor pulmonale
Cor pulmonale consists of right ventricular enlargement (hypertrophy or dilation, or both) and failure. It is most commonly caused by pulmonary hypertension.
PATHOPHYSIOLOGY
Cor pulmonale develops as pulmonary hypertension and creates chronic pressure overload in the right ventricle, similar to that created in the left ventricle by systemic hypertension. (Hypertension is discussed in Chapter 23.) Pressure overload increases the work of the right ventricle and first causes hypertrophy of the normally thin-walled heart muscle, but eventually leads to dilation and failure of the ventricle. Acute hypoxaemia, as with pneumonia, can exaggerate pulmonary hypertension and dilate the ventricle as well. The right ventricle usually fails when pulmonary artery pressure equals systemic blood pressure.
CHAPTER 25 Alterations of pulmonary function across the life span
A
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B
FIGURE 25.34
Ventilation–perfusion scan. A Normal study with no defects visible. B Defects in scan showing lack of radioactive tracer uptake indicative of pulmonary embolism.
CLINICAL MANIFESTATIONS
The clinical manifestations of cor pulmonale may be obscured by primary respiratory disease and appear only during exercise testing. The heart may appear normal at rest, but with exercise, cardiac output falls. The electrocardiogram may show right ventricular hypertrophy. Increased pressures in the systemic venous circulation can cause jugular venous distension, hepatosplenomegaly (enlarged liver and spleen due to venous engorgement) and peripheral oedema. EVALUATION AND TREATMENT
Diagnosis is based on physical examination, radiological examination, electrocardiogram and echocardiography. The goal of treatment for cor pulmonale is to decrease the workload of the right ventricle by lowering pulmonary artery pressure. Treatment success depends on reversal of the underlying lung disease. F O CUS O N L E A R N IN G
1 Describe how thrombus formation can lead to pulmonary embolism. 2 Describe cor pulmonale and the clinical manifestations.
Clinical manifestations of pulmonary alterations So far in this chapter we have explored the pathophysiology of the major pulmonary system disorders. In the following sections we look at the manifestations of these disorders — the conditions that result from pulmonary system
alterations and their signs and symptoms. You should be familiar with the diseases and now need to consolidate your knowledge with an understanding of the clinical manifestations that individuals with pulmonary system alterations will exhibit.
Conditions caused by pulmonary alterations Pulmonary oedema
One of the most serious conditions resulting from alterations to either the pulmonary system or the cardiovascular system is pulmonary oedema. Simply, pulmonary oedema is excess water in the lungs. The normal lungs are kept free from excess water by lymphatic drainage and a balance among capillary hydrostatic pressure, capillary oncotic pressure and capillary permeability (see Chapter 22). In addition, surfactant lining the alveoli repels water, keeping fluid from entering the alveoli. Predisposing factors for pulmonary oedema include heart disease, acute respiratory distress syndrome and inhalation of toxic gases. The pathogenesis of pulmonary oedema is shown in Fig. 25.35. The most common cause of pulmonary oedema is heart disease. When the left ventricle fails, filling pressures on the left side of the heart increase and vascular volume redistributes into the lungs, subsequently causing an increase in pulmonary capillary hydrostatic pressure and a back-tracking of excess fluid into the lungs. When the hydrostatic pressure exceeds oncotic pressure (which holds fluid in the capillary), fluid moves out into the interstitial spaces (the spaces within the alveolar septum between the alveolus and capillary). When the flow of fluid out of the capillaries exceeds the lymphatic system’s ability to remove it, pulmonary oedema develops.
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CONCEPT MAP
Valvular dysfunction Coronary artery disease Left ventricular dysfunction
Injury to capillary endothelium causes
Blockage of lymphatic vessels
causes
can cause Increased left atrial pressure leads to Increased pulmonary capillary hydrostatic pressure
Increased capillary permeability and disruption of surfactant production by alveoli leads to Movement of fluid and plasma proteins from capillary to interstitial space (alveolar septum) and alveoli results in
results in
Inability to remove excess fluid from interstitial space leads to Accumulation of fluid in interstitial space
results in
Pulmonary oedema
FIGURE 25.35
The pathogenesis of pulmonary oedema. Pulmonary oedema can arise from increased pulmonary blood pressure, increased capillary permeability, or blockage of the lymphatic drainage.
Another cause of pulmonary oedema is capillary injury that increases capillary permeability, as in cases of acute respiratory distress syndrome. Capillary injury causes water and plasma proteins to leak out of the capillary and move into the interstitial spaces, increasing interstitial oncotic pressure, which is usually very low. As the interstitial oncotic pressure begins to equal capillary oncotic pressure, water moves out of the capillary and into the lungs. (This phenomenon is discussed in Chapter 22). Clinical manifestations of pulmonary oedema include dyspnoea, hypoxaemia and increased work of breathing. Patients may also experience orthopnoea and paroxysmal nocturnal dyspnoea. Physical examination may reveal inspiratory crackles and dullness to percussion over the lung bases. In severe pulmonary oedema, pink frothy sputum is expectorated (coughed up) and oxygen levels decrease, while carbon dioxide levels increase, due to inadequate gas exchange. The mainstay of therapy is supplemental oxygen. Individuals with pulmonary oedema usually require the delivery of a higher concentration of oxygen. The treatment of pulmonary oedema depends on its cause. If the oedema is caused by increased hydrostatic pressure that results from heart failure, therapy is geared towards improving cardiac output with diuretics (to reduce fluid volume), vasodilators (to redistribute blood to other areas of the body) and drugs that improve the contraction of the heart muscle (to allow normal blood flow throughout the systemic circulation).
If oedema is the result of increased capillary permeability resulting from injury, the treatment is focused on removing the offending agent and supportive therapy to maintain adequate ventilation and circulation. When oxygen therapy alone is inadequate to meet metabolic demand, positivepressure mechanical ventilation may be needed to improve ventilation and oxygenation. HYPOXAEMIA
Hypoxaemia, or reduced oxygenation of arterial blood (reduced PaO2), is caused by respiratory alterations, whereas hypoxia, or reduced oxygenation of cells in tissues, may be caused by alterations of other systems as well. Although hypoxaemia can lead to tissue hypoxia, tissue hypoxia can result from other abnormalities unrelated to alterations of pulmonary function, such as low cardiac output.83 Hypoxaemia results from problems with one or more of the major mechanisms of oxygenation: • oxygen delivery to the alveoli a oxygen content of the inspired air ventilation of the alveoli b • diffusion of oxygen from the alveoli into the blood a balance between alveolar ventilation and perfusion diffusion of oxygen across the alveolar–capillary b barrier • perfusion of pulmonary capillaries.
CHAPTER 25 Alterations of pulmonary function across the life span
The amount of oxygen in the alveoli is dependent on two factors. The first factor is the presence of adequate oxygen content in the inspired air. The amount of oxygen in inspired air is expressed as the percentage or fraction of air that is composed of oxygen. Anything that decreases the oxygen content of inspired air (such as high altitude) decreases oxygen in the alveoli. The second factor is the amount of alveolar minute volume (see Chapter 24 for alveolar ventilation). Hypoventilation results in an increased alveolar carbon dioxide and decreased oxygen such that diffusion across the alveoli is impacted. This type of hypoxaemia can be completely corrected if alveolar ventilation is improved by increasing the rate and depth of breathing. Hypoventilation causes hypoxaemia in unconscious individuals; in those with neurological, muscular or bone diseases that restrict chest expansion; and in individuals who have COPD. Diffusion of oxygen from the alveoli into the blood is also dependent on two factors. The first is the balance between the amount of air getting into the alveoli and the amount of blood perfusing the capillaries around the alveoli. Normally, alveolar capillary lung units receive almost equal amounts of ventilation and perfusion. The normal ventilation/perfusion ratio is 0.8 : 0.9 because perfusion is
Normal ventilation–perfusion From pulmonary artery
somewhat greater than ventilation in the lung bases and because some blood is normally distributed to the bronchial circulation. An abnormal ventilation/perfusion ratio is the most common cause of hypoxaemia (see Fig. 25.36). This is referred to as a ventilation–perfusion mismatch (clinically abbreviated to V̇ /Q̇ mismatch). Hypoxaemia can be caused by inadequate ventilation of well-perfused areas of the lung (low ventilation–perfusion). Mismatching of this type occurs in atelectasis, in asthma as a result of bronchoconstriction and in pulmonary oedema and pneumonia when alveoli are filled with fluid. When blood passes through portions of the pulmonary capillary bed that receive no ventilation, blood is not oxygenated, resulting in hypoxaemia. Hypoxaemia can also be caused by poor perfusion of well-ventilated portions of the lung (high ventilation– perfusion), resulting in wasted ventilation. The most common cause of high ventilation–perfusion mismatching is a pulmonary embolus that impairs blood flow to a segment of the lung. An area where alveoli are ventilated but not perfused is termed alveolar dead space. The second factor affecting diffusion of oxygen from the alveoli into the blood is the alveolar–capillary barrier. Diffusion of oxygen through the alveolar–capillary membrane is impaired if the membrane is thickened or the surface
Low ventilation–perfusion
Airway
Impaired ventilation
Alveolus
Alveolocapillary membrane
To pulmonary vein
Shunt (very low) ventilation–perfusion Blocked ventilation Collapsed alveolus
Hypoxaemia
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Hypoxaemia High ventilation–perfusion Impaired perfusion Alveolar dead space
Hypoxaemia
FIGURE 25.36
Ventilation–perfusion abnormalities. Normal ventilation–perfusion occurs when ventilation and perfusion are both ideal at the alveoli. Low ventilation–perfusion occurs due to impairments in ventilation. High ventilation–perfusion occurs due to impairments in perfusion.
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area available for diffusion is decreased. Thickened alveolar– capillary membranes, as occur with oedema (tissue swelling) and fibrosis (formation of fibrous lesions), increase the time required for oxygen to diffuse from the alveoli into the capillaries. If diffusion is slowed enough, the oxygen in the alveoli and capillary blood do not have time to equilibrate and hence oxygenation of the blood is limited.
Hypercapnia
Hypercapnia, or increased carbon dioxide in the arterial blood, is caused by hypoventilation of the alveoli. As discussed in Chapter 24, carbon dioxide is easily diffused from the blood into the alveolar space; thus, minute volume (ventilation rate × tidal volume) determines not only alveolar ventilation but also carbon dioxide levels in the blood. There are many causes of hypercapnia. Most are a result of decreased drive to breathe or an inadequate ability to respond to ventilatory stimulation. Some of these causes include: (1) depression of the respiratory centre in the brainstem by drugs such as morphine and heroin; (2) diseases of the medulla, including infections of the central nervous system or trauma; (3) abnormalities of the spinal conducting pathways, as in spinal cord disruption; (4) diseases of the neuromuscular junction or of the respiratory muscles themselves, as in myasthenia gravis or muscular dystrophy; (5) thoracic cage abnormalities, as in chest injury or congenital deformity; (6) large airway obstruction, as in tumours or sleep apnoea; and (7) increased work of breathing or physiological dead space, as in emphysema.
Acute respiratory failure
Respiratory failure is defined as inadequate gas exchange such that arterial oxygen levels are less than 50 mmHg or arterial carbon dioxide levels are greater than 50 mmHg with pH less than 7.25. Respiratory failure can result from direct injury to the lungs, airways or chest wall, or indirectly because of injury to another body system, such as the brain or spinal cord. It can occur in individuals who have an otherwise normal pulmonary system or in those with underlying chronic pulmonary disease. Most pulmonary diseases can cause episodes of acute respiratory failure. If the respiratory failure is primarily hypercapnic (i.e. due to high carbon dioxide levels), it is the result of inadequate alveolar ventilation. If the respiratory failure is primarily hypoxaemic (i.e. due to low oxygen levels), it is the result of inadequate exchange of oxygen between the alveoli and the capillaries. Many individuals will have combined hypercapnic and hypoxaemic respiratory failure.
Atelectasis
Atelectasis is the collapse of lung tissue. It can occur due to lack of lung expansion, such as that experienced after surgery. There are two types of atelectasis: 1 Compression atelectasis is caused by external pressure exerted by tumour, fluid or air in pleural space or by abdominal distension pressing on a portion of lung, causing alveoli to collapse.
Absorption atelectasis results from removal of air from obstructed or hypoventilated alveoli or from inhalation of concentrated oxygen or anaesthetic agents (see Fig. 25.37). Clinical manifestations of atelectasis are similar to those of pulmonary infection including dyspnoea, cough and fever. Atelectasis tends to occur after surgery. Postoperative patients may have received supplemental oxygen or inhaled anaesthetics and they are usually in pain, shallow breathe, are reluctant to change position and produce thick secretions that tend to pool in dependent portions of the lungs. Prevention and treatment of postoperative atelectasis usually include deep breathing, frequent position changes and early ambulation. Deep breathing opens connections between patent and collapsed alveoli, called pores of Kohn. This allows air to flow into the collapsed alveoli (collateral ventilation) and aids in the expulsion of intrabronchial obstructions.
2
Pneumothorax
Pneumothorax is the presence of air or gas in the pleural space caused by a rupture in the visceral pleura (which surrounds the lungs) or the parietal pleura and chest wall. As air separates the visceral and parietal pleurae, it destroys the negative pressure of the pleural space and disrupts the equilibrium between the elastic recoil forces of the lung and chest wall. The lung then tends to recoil by collapsing towards the hilum (see Fig. 25.38). Pneumothorax can occur spontaneously or secondary to trauma. The most common presentation of spontaneous pneumothorax occurs unexpectedly in healthy males aged 20–40 years. Secondary pneumothorax can result from rib fractures, COPD or chest stabbings or shootings.
Absorption
Compression
FIGURE 25.37
Different forms of atelectasis. Lung collapse can occur by absorption, usually from decreased air flow through the lung, or from compression from outside of the lung.
CHAPTER 25 Alterations of pulmonary function across the life span
Outside air enters because of disruption of chest wall and parietal pleura
Normal lung Chest wall
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Mediastinum
Lung air enters because of disruption of visceral pleura
Pleural space Diaphragm
FIGURE 25.38
Pneumothorax. Air in the pleural space causes the lung to collapse around the hilus and may push mediastinal contents (heart and great vessels) towards the other lung.
Both spontaneous and secondary pneumothorax can present as either open or tension. In open pneumothorax, air pressure in the pleural space equals barometric pressure because air that is drawn into the pleural space during inspiration (through the damaged chest wall and parietal pleura or through the lungs and damaged visceral pleura) is forced back out during expiration. In tension pneumothorax, however, the site of pleural rupture acts as a one-way valve, permitting air to enter on inspiration but preventing its escape by closing up during expiration. As more and more air enters the pleural space, air pressure in the pneumothorax begins to exceed barometric pressure. Tension pneumothorax is life-threatening. Air pressure in the pleural space pushes against the already recoiled lung, causing compression atelectasis and against the mediastinum, compressing and displacing the heart and great vessels. Clinical manifestations of spontaneous or secondary pneumothorax begin with sudden pleural pain, tachypnoea and dyspnoea (rapid breathing and difficulty breathing, respectively). The manifestations depend on the size of the pneumothorax. Physical examination may reveal absent or decreased breath sounds. Tension pneumothorax may be complicated by severe hypoxaemia, tracheal deviation away from the affected lung and hypotension (low blood pressure). Deterioration occurs rapidly and immediate treatment is required. Diagnosis of pneumothorax is made with chest x-rays and CT scans. Pneumothorax is treated with insertion of a chest tube that is attached to a water-seal drainage system with suction, such that negative pressure is restored. After the pneumothorax
re-expands and the pleural rupture is healed, the chest tube is removed.
Pleural effusion
Pleural effusion is the presence of excess fluid in the pleural space. The most common mechanism of pleural effusion is migration of fluids and other blood components through the walls of intact capillaries bordering the pleura. Pleural effusions that enter the pleural space from the intact blood vessels can be transudative (watery) or exudative (high in concentrations of white blood cells and plasma proteins). Mechanisms of pleural effusion are summarised in Table 25.6. Small collections of fluid normally can be drained away by the lymphatics. Dyspnoea, compression atelectasis with impaired ventilation and mediastinal shift occur with large effusions. Pleural pain is present if the pleura are inflamed and cardiovascular manifestations occur in a large, rapidly developing effusion. Diagnosis is confirmed by chest x-ray (see Fig. 25.39) and thoracentesis (needle aspiration), which can determine the type of effusion and provide symptomatic relief. If the effusion is large, drainage usually requires the placement of a chest tube.
Empyema
Empyema (infected pleural effusion) is the presence of pus in the pleural space. It is thought to develop when the pulmonary lymphatics become blocked, leading to an outpouring of contaminated lymphatic fluid into the pleural space. Empyema occurs most commonly in older adults
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TABLE 25.6 Mechanisms of pleural effusion TYPE OF FLUID/ EFFUSION
SOURCE OF ACCUMULATION
PRIMARY OR ASSOCIATED DISORDER
Transudate (hydrothorax)
Watery fluid that diffuses out of capillaries beneath the pleura (i.e. capillaries in the lungs or chest wall)
Cardiovascular disease that causes high pulmonary capillary pressures; liver or kidney disease that disrupts plasma protein production, causing hypoproteinaemia (decreased oncotic pressure in the blood vessels)
Exudate
Fluid rich in cells and proteins (leucocytes, plasma Infection, inflammation or malignancy of the pleura that proteins of all kinds; see Chapter 13) that migrates stimulates mast cells to release biochemical mediators out of the capillaries that increase capillary permeability
Pus (empyema)
Debris of infection (microorganisms, leucocytes, cellular debris) dumped into the pleural space by blocked lymphatic vessels
Pulmonary infections, such as pneumonia; lung abscesses; infected wounds
Blood (haemothorax)
Haemorrhage into the pleural space
Traumatic injury, surgery, rupture or malignancy that damages blood vessels
Chyle (chylothorax) Chyle (milky fluid containing lymph and fat droplets) that is dumped by lymphatic vessels into the pleural space instead of passing from the gastrointestinal tract to the thoracic duct
FIGURE 25.39
Chest x-ray of a right-side pleural effusion. Note the arrows highlighting the extent of the effusion. This angle should be sharp and this blunting is due to fluid formation.
and children and usually develops as a complication of pneumonia, surgery, trauma or bronchial obstruction from a tumour. Individuals with empyema present clinically with cyanosis, fever, tachycardia (rapid heart rate), cough and pleural pain. Diagnosis is made by chest x-rays, thoracentesis and sputum culture. The treatment for empyema includes the administration of appropriate antimicrobials and drainage of the pleural space with a chest tube.
Aspiration
Aspiration is the inhalation of fluid and solid particles into the lung. It tends to occur in children between the ages of
Traumatic injury, infection or disorder that disrupts lymphatic transport
1 and 3 years or in individuals whose normal swallowing mechanism and cough reflex are impaired by central or peripheral nervous system abnormalities. Predisposing factors include an altered level of consciousness caused by substance abuse, sedation or anaesthesia; seizure disorders; cerebrovascular accident; and neuromuscular disorders that cause dysphagia (see Chapter 27). The right lung, particularly the right lower lobe, is more susceptible to aspiration than the left lung because the branching angle of the right main stem bronchus is straighter than the branching angle of the left main stem bronchus (see Chapter 24). Foreign bodies lodged in the larynx or upper trachea cause cough, stridor, hoarseness or inability to speak, respiratory distress and agitation or panic. The presentation is often dramatic and frightening. Aspiration of acidic gastric fluid (pH of less than 2.5) may cause lung inflammation. Bronchial damage includes inflammation, loss of ciliary function and bronchospasm. In the alveoli, acidic gastric fluid damages the alveolar– capillary membrane, allowing plasma and blood cells to move from the capillaries into the alveoli. The lung becomes stiff and non-compliant as surfactant production is disrupted, leading to further oedema and collapse. Preventive measures for individuals at risk are more effective than treatment of known aspiration. The most important preventive measures include the semi-recumbent position, the surveillance of enteral feeding and the avoidance of excessive sedation. Nasogastric tubes, which are often used to remove stomach contents, are used to prevent aspiration but can also cause aspiration if fluid and particulate matter are regurgitated as the tube is being placed. Treatment of aspiration of foreign bodies may include bronchoscopy to remove the foreign body, if sneezing and coughing does not displace the object. More serious aspirations with either stomach contents or ingestion of
CHAPTER 25 Alterations of pulmonary function across the life span
solids or fluids into the lungs may necessitate supplemental oxygen, mechanical ventilation, fluid restriction and steroids. Bacterial pneumonia may develop as a complication of aspiration and must be treated with broad-spectrum antimicrobials.
FOCUS O N L E A R N IN G
1 Describe pulmonary oedema and list two causes. 2 Discuss the mechanisms that produce hypoxaemia and hypercapnia. 3 Differentiate the different levels of hypoxaemia and hypercapnia in acute respiratory failure. 4 Compare and contrast the two forms of atelectasis. 5 Compare and contrast open and tension pneumothorax. 6 Describe how pneumothorax differs from pleural effusion. 7 List causes of empyema. 8 Provide a list of 5 different causes of aspiration.
Signs and symptoms of pulmonary alterations Dyspnoea
Dyspnoea is the subjective sensation of uncomfortable breathing, the feeling of not being able to get enough air. It is often described as breathlessness, air hunger, shortness of breath and laboured breathing. Everyone experiences dyspnoea at some stage. One of the most common non-pathological reasons is when you exercise heavily and become short of breath — that is dyspnoea. Our discussion here concerns dyspnoea that occurs at rest and is due to pulmonary system pathophysiology. Dyspnoea can be caused by many pulmonary disorders. Disturbances of ventilation, gas exchange or ventilation– perfusion relationships can cause dyspnoea, as can increased work of breathing or any disease that damages lung tissue. One proposed mechanism for dyspnoea is a mismatch between sensory and motor input from the respiratory centre in the brainstem such that there is more urge to breathe than there is response by the respiratory muscles. Other causes of dyspnoea include stimulation of central and peripheral chemoreceptors and stimulation of afferent receptors in the lungs and chest wall. The signs of dyspnoea include flaring of the nostrils, use of accessory muscles of ventilation and retraction (pulling back) of the intercostal spaces. In dyspnoea caused by lung tissue disease (e.g. pneumonia), retractions of tissue between the ribs may be observed, although retractions are more common in children than in adults. Dyspnoea can be quantified using scales (such as the Borg Dyspnoea Scale,84 the Medical Research Council (MRC) Dyspnoea Score85 and the Dyspnoea-12)86 and is frequently associated with significant anxiety.87
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Dyspnoea can occur transiently or can become chronic. One cause of dyspnoea is pulmonary congestion usually resulting from heart disease. Pulmonary congestion tends to cause dyspnoea when the individual is lying down (orthopnoea). The horizontal position redistributes body water, causes the abdominal contents to exert pressure on the diaphragm and decreases the efficiency of the respiratory muscles. Sitting up in a forward-leaning posture or supporting the upper body on several pillows generally relieves orthopnoea. Some individuals with pulmonary or cardiac disease wake up at night gasping for air and have to sit up or stand to relieve the dyspnoea (paroxysmal nocturnal dyspnoea).
Cough
A cough is a protective reflex that cleanses the lower airways by an explosive expiration. Inhaled particles, accumulated mucus, inflammation or the presence of a foreign body initiates the cough reflex by stimulating the irritant receptors in the airways. There are only few of these receptors in the most distal bronchi and the alveoli, thus it is possible for significant amounts of secretions to accumulate in the distal respiratory tree without cough being initiated. The cough consists of inspiration, closure of the glottis and vocal cords, contraction of the expiratory muscles and reopening of the glottis, causing a sudden, forceful expiration that removes the offending matter. The effectiveness of the cough depends on the depth of the inspiration and the degree to which the airways narrow, increasing the velocity of expiratory gas flow. Acute cough is cough that resolves within 2–4 weeks of the onset of illness or resolves with treatment of the underlying condition. It is most commonly the result of upper respiratory infections, acute bronchitis, pneumonia, heart failure, pulmonary embolus or aspiration. Chronic cough is defined as cough that has persisted for more than 4 weeks in children and 8 weeks in adults. In non-smoking adults, the most common cause of chronic cough is rhinosinusitis, asthma or gastro-oesophageal reflux disease, in children it is asthma and protracted bacterial bronchitis.88,89 In smokers, chronic bronchitis is the most common cause of cough, although lung cancer must always be considered. Approximately 5–10% of Australians suffer from chronic cough and 20% of patients who take angiotensin-converting enzyme (ACE) inhibitors (see Chapter 23) develop a persistent dry cough, with some patients experiencing severe cough that requires the drug to be discontinued. Management of chronic cough involves addressing the common issues of environmental exposures and the concerns of the patient and parents, then the institution of specific therapy.88,90
Hypoventilation and hyperventilation
Hypoventilation is inadequate alveolar ventilation in relation to metabolic demand. Hypoventilation occurs when minute volume (tidal volume × ventilatory rate) is reduced. It is
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caused by alterations in pulmonary mechanics or in the neurological control of breathing. When alveolar ventilation is normal, carbon dioxide is removed from the lungs at the same rate as that produced by cellular metabolism; therefore, arterial and alveolar carbon dioxide values remain at normal levels (between 35 and 45 mmHg). With hypoventilation, carbon dioxide removal does not keep up with carbon dioxide production and the level of carbon dioxide in the arterial blood increases, causing hypercapnia (a carbon dioxide level more than 45 mmHg). This results in respiratory acidosis (pH less than 7.35), which can affect the function of many tissues throughout the body. Blood gas analysis (i.e. measurement of the arterial carbon dioxide level) reveals hypoventilation. Hyperventilation is alveolar ventilation exceeding metabolic demands. The lungs remove carbon dioxide faster than it is produced by cellular metabolism, resulting in decreased carbon dioxide levels in the blood, or hypocapnia (a carbon dioxide level less than 35 mmHg). Hypocapnia results in respiratory alkalosis (pH greater than 7.45), which also can interfere with tissue function. Like hypoventilation, hyperventilation can be determined by arterial blood gas analysis. Increased respiratory rate or tidal volume can occur with severe anxiety, acute head injury, pain and in response to conditions that cause insufficient oxygenation of the blood.
Abnormal breathing patterns
Normal breathing (eupnoea) is rhythmic and effortless. The resting ventilatory rate in adults is usually between 8 and 16 breaths per minute and tidal volume (the amount of air in each breath) ranges from 400–800 mL. A short expiratory pause occurs with each breath and the expiratory phase is longer than inspiration, usually in a ratio of 1:2 (for inspiration time: expiration time). Disease states can alter this ratio. Laboured breathing occurs whenever there is an increased work of breathing, especially if the airways are obstructed. If the large airways are obstructed, a slow ventilatory rate, large tidal volume, increased effort, prolonged inspiration and expiration, and stridor or audible wheezing (depending on the site of obstruction) are typical. In small airway obstruction like that seen in asthma and COPD, a rapid ventilatory rate, small tidal volume, increased effort and prolonged expiration are often present. Strenuous exercise or metabolic acidosis induces Kussmaul breathing (slow deep breathing), or hyperpnoea (excessive breathing), which is characterised by an increased ventilatory rate, very large tidal volumes and no expiratory pause. Another abnormal breathing pattern is Cheyne-Stokes breathing, characterised by alternating periods of deep and shallow breathing. Apnoea lasting from 15 to 60 seconds is followed by breaths that increase in volume until a peak is reached; then breathing decreases again to apnoea. Cheyne-Stokes breathing results from any condition that slows the blood flow to the brainstem, which in turn slows impulses sending information to the respiratory centres of the brainstem. Neurological impairment above
the brainstem is also a contributing factor. CheyneStokes breathing indicates that severe pathophysiological disturbances have occurred and often is present immediately before death.
Haemoptysis
Haemoptysis is the coughing up of blood or bloody secretions. This should not be confused with haematemesis, which is the vomiting of blood. Blood that is coughed up is usually bright red, has an alkaline pH and may be mixed with frothy sputum, whereas blood that is vomited is dark, has an acidic pH and is mixed with food particles. However, both are serious conditions. Haemoptysis indicates a localised abnormality, usually infection or inflammation that damages the bronchi, such as bronchiectasis, or the lung tissue, such as tuberculosis and cancer. Bronchoscopy, combined with chest CT scans, is used to confirm the site of bleeding.
Cyanosis
Cyanosis is a bluish discolouration of the skin and mucous membranes caused by increasing amounts of desaturated or reduced haemoglobin (which is bluish) in the blood. It generally develops when 5 g of haemoglobin is desaturated, regardless of haemoglobin concentration. Cyanosis can be caused by decreased arterial oxygenation, ventilation–perfusion inequalities, decreased cardiac output, a cold environment or anxiety. In adults, cyanosis is not evident until severe hypoxaemia is present and therefore is an insensitive indication of respiratory failure. Severe anaemia (inadequate haemoglobin concentration) can cause inadequate oxygenation of tissues without causing cyanosis. However, individuals with polycythaemia (an abnormal increase in the numbers of red blood cells) may have cyanosis when oxygenation is adequate. Therefore, cyanosis must be interpreted in relation to the underlying pathophysiology. If cyanosis is suggested, the oxygen levels in the blood should be measured. Central cyanosis (decreased oxygen saturation of haemoglobin in arterial blood) is best seen in buccal (cheek) mucous membranes and lips. Peripheral cyanosis (slow blood circulation in fingers and toes) is best seen in nail beds.
FOCU S ON L EA RN IN G
1 List the primary signs and symptoms of pulmonary disease. 2 Discuss reasons why individuals may experience dyspnoea. 3 Differentiate between acute and chronic cough. 4 Differentiate between hypoventilation and hyperventilation. 5 Indicate reasons for haemoptysis. 6 Describe causes of cyanosis.
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chapter SUMMARY Disorders of the pulmonary system • Obstructive airway diseases are characterised by airway obstruction. Obstructive airway diseases can be acute or chronic in nature and include asthma and COPD. • In asthma, the mechanisms causing airway obstruction include bronchoconstriction, bronchial inflammation, mucosal oedema and increased mucus production. • Asthma control severity and control are used to determine therapy. • Asthma is a common and important problem in children, adults and the elderly. Its origins are multifactorial, including genetic, allergic and viral-triggered mechanisms. Effective management is aimed at decreasing chronic inflammation in the lungs, eliminating known triggers from the environment, and early recognition and treatment of acute symptoms. Best practice asthma management includes effective pharmacotherapy, self-management education, the provision of a written asthma action plan and regular medical review. • Childhood asthma is best classified by clinical patterns to support the spirometry results; different patterns of wheezing may be observed. Childhood asthma may be infrequent, frequent or persistent that progresses into adulthood. Viral infections are common triggers for childhood asthma. • Chronic obstructive pulmonary disease (COPD) is an obstructive airway disease which involves the occurrence and the coexistence of chronic bronchitis and emphysema. Asthma COPD overlap is common particularly in older populations. • COPD is an important cause of hypoxaemic and hypercapnic respiratory failure. • Chronic bronchitis causes airway obstruction resulting from bronchial smooth muscle hypertrophy and production of thick, tenacious mucus. • In emphysema, destruction of the alveolar septa and loss of passive elastic recoil lead to airway collapse and obstruct gas flow during expiration. • Acute respiratory distress syndrome results from an acute diffuse injury to the alveolar–capillary membrane and decreased surfactant production, which increases membrane permeability and causes oedema and atelectasis. There is progressive respiratory distress with severe hypoxaemia and respiratory failure. • Inhalation of noxious gases or prolonged exposure to high concentrations of oxygen can damage the bronchial mucosa or alveolar–capillary membrane and cause inflammation or acute respiratory failure.
• Pneumoconiosis, which is caused by inhalation of dust particles in the workplace, can cause pulmonary fibrosis, susceptibility to lower airway infection and cancers. • Cystic fibrosis is an autosomal recessive genetic disease that affects many organ systems, especially the lungs and digestive system. Airway secretions are particularly thick and tenacious and the airways develop chronic bacterial infection with pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. Chronic infection, plugged airways and severe inflammation cause longterm lung damage and ultimately death. However, the prognosis is improving and most patients with cystic fibrosis now survive to adulthood. • Bronchiectasis is an abnormal permanent dilation and distortion of the bronchi and bronchioles, resulting from chronic inflammation of the airways, and leading to progressive destruction of the bronchial walls and lung tissue.
Infections of the pulmonary system • Upper respiratory tract infections are the most common cause of short-term disability in Australia and New Zealand. • Serious lower respiratory tract infections occur most often in the elderly and in individuals with impaired immunity or underlying disease. • Viral pneumonia can be severe, but is more often an acute self-limiting lung infection usually caused by the influenza virus. • Tuberculosis is a lung infection caused by Mycobacterium tuberculosis. • In tuberculosis, the inflammatory response proceeds to isolate colonies of bacterium by enclosing them in tubercles and surrounding the tubercles with scar tissue. These may remain dormant within the tubercles for life or, if the immune system breaks down, cause recurrence of active disease. • Influenza is a common viral infection that affects large proportions of the population. This form is seasonal; however, more pathogenic forms of influenza involving mutations with avian and swine influenza have infected humans and may cause serious pandemics in the future.
Paediatrics and pulmonary infections • Bronchiolitis is the inflammatory obstruction of small airways. It is most common in children.
Lung cancer • Lung cancer, the most common cause of cancer death in Australia and New Zealand, is commonly caused by cigarette smoking.
Continued
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• Cancer cell types include non-small cell carcinoma (squamous cell, adenocarcinoma and large cell) and small cell carcinoma. Each type arises in a characteristic site or type of tissue, causes distinctive clinical manifestations and differs in likelihood of metastasis and prognosis.
Obstructive sleep apnoea • Obstructive sleep apnoea syndrome is defined by partial or complete upper airway obstruction during sleep with disruption of normal ventilation and normal sleep patterns. It affects a large percentage of adult males (typically middle-aged and older) and children. • Risk factors for adults are obesity, age, smoking and gender; in children the most common cause is adenotonsillar hypertrophy.
Paediatrics and pulmonary disorders • Croup is an acute respiratory illness of young children, usually caused by parainfluenza virus. This infection causes swelling of the upper trachea. The typical sign is a seal-like barking cough, which appears after a few days of rhinorrhoea, sore throat and low-grade fever. • Respiratory distress syndrome of the newborn usually occurs in premature infants who are born before surfactant production and alveolar capillary development are complete. Atelectasis and hypoventilation cause hypoxaemia and hypercapnia. Prenatal steroids and postnatal surfactant are beneficial therapies. • Sudden infant death syndrome (SIDS) is the leading cause of postnatal death for infants outside of the hospital setting and is associated with low birth weight, a prone sleeping position and other environmental factors. Some risk factors are modifiable — the prime example is the profound reduction in SIDS since widespread adoption of recommendations for supine positioning of infants during sleep.
•
• • •
•
•
• • • •
Alterations of pulmonary blood flow and pressure
•
• Pulmonary vascular diseases are caused by embolism or hypertension in the pulmonary circulation. • Pulmonary embolism is occlusion of a portion of the pulmonary vascular bed by a thrombus (most common), tissue fragment or air bubble. Depending on its size and location, the embolus can cause hypoxic vasoconstriction, pulmonary oedema, atelectasis, pulmonary hypertension, shock and even death. • Cor pulmonale is right ventricular enlargement caused by chronic pulmonary hypertension. Cor pulmonale progresses to right ventricular failure if the pulmonary hypertension is not reversed.
•
Clinical manifestations of pulmonary alterations • Pulmonary oedema is excess water in the lungs caused by disturbances of capillary hydrostatic pressure,
•
•
capillary oncotic pressure or capillary permeability. A common cause is left heart failure, which increases the hydrostatic pressure in the pulmonary circulation. Hypoxaemia is a reduced oxygen level in the blood caused by (1) decreased oxygen content of inspired gas, (2) hypoventilation, (3) diffusion abnormality or (4) ventilation–perfusion mismatch. Hypercapnia is an increased carbon dioxide level in the blood caused by hypoventilation. Atelectasis is the collapse of alveoli resulting from compression of lung tissue or absorption of gas from obstructed alveoli. Pneumothorax is the accumulation of air in the pleural space. It can be caused by spontaneous rupture of weakened pleural areas or it can be secondary to pleural damage caused by disease or trauma. Pneumothorax can be open, which means that the lung only partially collapses, or tension, which means that pressure builds up in the pleural space and can compress both the affected lung and the mediastinum. Pleural effusion is the accumulation of fluid in the pleural space, usually resulting from disorders that promote transudation or exudation from capillaries underlying the pleura but occasionally resulting from blockage or injury that causes lymphatic vessels to drain into the pleural space. Empyema (infected pleural effusion) is the presence of pus in the pleural space. Dyspnoea is the feeling of breathlessness and increased respiratory effort. It is a common pulmonary disorder symptom. Coughing is a protective reflex that expels secretions and irritants from the lower airways. Hypoventilation is decreased alveolar ventilation caused by airway obstruction, chest wall restriction or altered neurological control of breathing. Hypoventilation causes increased carbon dioxide levels. Hyperventilation is increased alveolar ventilation produced by anxiety, head injury or severe hypoxaemia. Hyperventilation causes decreased carbon dioxide levels. Abnormal breathing patterns are adjustments made by the body to minimise the work of the respiratory muscles. They include Kussmaul and Cheyne-Stokes breathing. Haemoptysis is expectoration of bloody mucus, which can be caused by bronchitis, tuberculosis, abscess, neoplasms and other conditions that cause haemorrhage from damaged vessels. Cyanosis is a bluish discolouration of the skin caused by desaturation of haemoglobin, polycythaemia or peripheral vasoconstriction.
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CASE STUDY
ADU LT Craig is 57 years old and has just been diagnosed with squamous cell lung cancer. Although he admits that he was well aware that lung cancer was a risk of smoking, he was not expecting such devastating news until he was much older. A large growth was found in the left primary bronchus, and metastasis has already occurred to another location within the lung tissue. His symptoms include cough and haemoptysis; it was haemoptysis which led to his diagnosis of cancer.
1 2 3 4 5
Compare the main features of the different types of lung cancer. Explain the likely clinical progression of Craig’s condition. Describe the relationship between cigarette smoking and the p53 gene. Discuss the potential reasons for encouraging Craig to quit smoking, given that he already has lung cancer. Lung cancer has a very high incidence and mortality in Australia and New Zealand. Outline possible reasons why we do not have national lung cancer screening programs in our countries.
CASE STUDY
AGEING John is 73 years old with COPD. He is prescribed tiotropium bromide daily and salbutamol 2 puffs as required. He uses his salbutamol several times per day and his tiotropium as prescribed. His wife died 5 years ago and since then he has not been taking care of himself very well; he is no longer active and doesn’t like to go out too much. He presented to hospital with his daughter as she was concerned about him. She states that over the last 8 days he has experienced an increase in his symptoms; he had a fever, was increasingly breathless, and was coughing up green phlegm. She states that he had been increasingly irritable and not attending to his meals or personal care as he was too breathless. He had seen his doctor 4 days ago who had started oral amoxicillin for 7 days and had advised him to return if it did not get any better. The doctor also indicated that he should return once he was better for his influenza vaccine. She reported that this was the third time in the last 12 months that she needed to take her dad to the doctor or emergency department because of a flare-up of his breathing. Physical examination revealed decreased breath sounds throughout both lung fields with bibasal crackles, tachypnoea
(ventilatory rate: 32 breaths per minute) with accessory muscle use, temperature 37.9°C, pursed lip breathing, tachycardia (heart rate: 116 beats per minute), oxygen saturations of 84% and anxiety. Spirometry was performed in the emergency department; his FEV1was 44% of predicted, his FVC was 106% of predicted and his FEV1/VC ratio was 0.41. An urgent arterial blood gas was performed, which revealed mild hypercapnia PaCO2 (48 mmHg pH 7.35) and hypoxaemia (PaO2 78 mmHg). Oxygen prongs were applied at a flow of 2 L/ min and he was administered prednisolone and salbutamol via the pressurised metered dose inhaler and large volume spacer. 1 Describe the most probable reasons for John’s acute exacerbation. 2 Describe why the arterial blood gas revealed respiratory acidosis as it relates to COPD. 3 Explain the results of his spirometry test and the implications of these results. 4 Based on the history discuss the impact of his previous exacerbations. 5 Differentiate between the pathophysiology of upper respiratory tract infections and asthma.
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REVIEW QUESTIONS 1 Using changes in airflow characteristics, differentiate between obstructive and restrictive lung diseases. 2 Describe how smoking affects pulmonary function and how it contributes to the development of chronic obstructive pulmonary disease. 3 Differentiate between an upper respiratory tract infection and a lower respiratory tract infection. Provide examples to supplement your answer. 4 Compare the different types of bronchogenic lung cancer and the signs and symptoms that arise. 5 Provide a pathophysiological outline of the development of obstructive sleep apnoea.
6 Explain the pathogenesis of cystic fibrosis and why individuals develop clinical manifestations in other body systems. 7 Explain why pulmonary embolism is a potentially fatal condition. 8 Discuss how pulmonary oedema can arise and what treatment options are available. 9 Provide explanations outlining the differences between pneumothorax, pleural effusion and empyema. 10 Suggest why dyspnoea and cough are common symptoms of many pulmonary conditions.
Key terms ampulla of Vater, 785 bile, 779 bilirubin, 784 brush border, 775 caecum, 787 cholecystokinin, 772 chyme, 771 colon, 787 defecation reflex, 788 duodenum, 774 enteric nervous system, 764 enterohepatic circulation, 780 exocrine, 785 external anal sphincter, 787 gallbladder, 785 gastric emptying, 772 gastrin, 772 gastrointestinal tract, 762 haustra, 788 hepatic portal vein, 777 hepatocytes, 779 ileum, 774 internal anal sphincter, 787 jejunum, 774 large intestine, 787 liver, 779 liver lobules, 779 mesentery, 775 metabolic detoxification, 784 microvilli, 775 motilin, 772 mouth, 767 mucosa, 763 muscularis, 764 oesophagus, 768 omenta, 775 pancreas, 785 peristalsis, 765 peritoneal cavity, 775 peritoneum, 775 pharynx, 768 rectum, 788 saliva, 768 salivary amylase, 770 salivary glands, 768 secretin, 772 segmentation, 765 serosa, 764 small intestine, 774 splanchnic blood flow, 765 stomach, 771 submucosa, 764 vermiform appendix, 787 villi, 775
CHAPTER
The structure and function of the digestive system
26
Kulmira Nurgali Chapter outline Introduction, 762 An overview of the digestive system, 762 The gastrointestinal tract and accessory organs, 762 Layers of the gastrointestinal tract, 763 Neural control of the digestive system, 764 Motility, 764 Splanchnic blood flow, 765 The main nutrients, 766 The mouth, pharynx and oesophagus, 767 Anatomy and physiology of the mouth, pharynx and oesophagus, 767 Digestion in the mouth, pharynx and oesophagus, 770 The stomach, 771 Anatomy and physiology of the stomach, 771 Digestion in the stomach, 774 Absorption from the stomach, 774
The small intestine, 774 Anatomy and physiology of the small intestine, 774 Intestinal motility, 775 Digestion in the small intestine, 777 Absorption from the small intestine, 777 Accessory organs of digestion, 777 The liver, 779 The gallbladder, 785 The pancreas, 785 The large intestine, 787 Anatomy and physiology of the large intestine, 787 Digestion in the large intestine, 788 Absorption in the large intestine, 790 Fluid movements in the digestive system, 790 An overview of nutrition, 791 Ageing and the digestive system, 793
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Introduction The digestive system breaks down ingested food, prepares it for uptake by the body’s cells, provides body water and eliminates wastes. The system consists of (a) the gastrointestinal tract and (b) the accessory organs of digestion. The adjective gastric refers to the stomach; hence the name ‘gastrointestinal tract’ reflects its main components, the stomach and intestines. Food breakdown begins in the mouth with chewing and continues in the stomach, where food is churned and mixed with acid, mucus, enzymes and other secretions. From the stomach, the partially digested food passes into the small intestine, where biochemical agents and enzymes secreted by the liver and pancreas break it down into absorbable components of proteins, carbohydrates and fats. These nutrients are absorbed as they pass through the walls of the small intestine into blood vessels and lymphatics, which carry them to the liver for storage or further processing. Ingested substances and secretions that are not absorbed in the small intestine pass into the large intestine, where fluid continues to be absorbed. Fluid wastes travel through the bloodstream to the kidneys and are eliminated in the urine. Solid wastes pass into the rectum and are eliminated from the body through the anus. Except for chewing, swallowing and defecation of solid wastes, the movements of the digestive system (gastrointestinal motility) are all controlled by hormones and the autonomic nervous system. Autonomic innervation, both sympathetic and parasympathetic, is controlled by centres in the brain and by local stimuli that are mediated at enteric plexuses (networks of neurons and nerve fibres) within the gastrointestinal walls.
An overview of the digestive system The gastrointestinal tract and accessory organs
The gastrointestinal tract (also known as the gut or alimentary canal) is essentially a long tube, extending from the mouth to the anus, which is divided into different organs (see Fig. 26.1): • mouth • pharynx • oesophagus • stomach • small intestine • large intestine. The upper digestive tract consists of structures from the mouth to the stomach, while the intestines form the lower digestive tract. The specific structures and functions differ substantially at each organ. A number of sphincters are located between the different organs and these have an
Mouth Oesophagus
Liver Gallbladder Duodenum Transverse colon Ascending colon Caecum Appendix Anal sphincters
Parotid gland Sublingual gland Submandibular gland Pharynx Upper oesophageal sphincter Lower oesophageal sphincter Stomach Pyloric sphincter Pancreas Large intestine Jejunum Descending colon Small intestine Ileum Ileocaecal sphincter Anus
FIGURE 26.1
The gastrointestinal tract. The main organs of the gastrointestinal tract are the mouth, pharynx, oesophagus, stomach, small intestine, and large intestine. The accessory organs are the salivary glands, liver, gallbladder and pancreas.
important role in controlling the passage of food. The sphincters of the gastrointestinal tract are as follows: • upper oesophageal sphincter • lower oesophageal sphincter • pyloric sphincter • ileocaecal sphincter • anal sphincters (see Fig. 26.1). Sphincters are formed by a specialised ring of circular muscle — when contracted, food cannot progress through the sphincter. A number of accessory organs are anatomically close to the gastrointestinal tract and these secrete substances that are vital for normal gastrointestinal function. The main accessory structures are the salivary glands, liver, gallbladder and pancreas. Sphincters are located where the accessory organs empty into the gastrointestinal tract and these must be relaxed to allow secretions to enter the gut. The main digestive processes performed by the digestive system are: 1 ingestion of food (food enters the lumen of the gastrointestinal tract, usually via the mouth)
CHAPTER 26 The structure and function of the digestive system
2
propulsion of food and wastes from the mouth towards the anus 3 secretion of mucus, water and enzymes 4 mechanical digestion of food particles (physical breakdown of food into smaller particles) 5 chemical digestion of food particles (chemical breakdown of food into smaller particles) 6 absorption of digested food from the gastrointestinal tract into the bloodstream 7 elimination of waste products by defecation. Chemical digestion mainly occurs with the action of enzymes, which are molecules produced and secreted by the digestive system. The function of enzymes is to speed up chemical reactions, and in the digestive system they help to break food down quickly. Usually, enzyme names end in ‘-ase’, so this will help you to recognise them easily (Table 26.1). It is only when food is broken down into small components that it can be absorbed into the bloodstream.
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From here, the small molecules from the food are able to travel through the blood and become available for use by all body cells (see Fig. 26.2). Throughout this chapter, you will learn the details of how this works.
Layers of the gastrointestinal tract
The gastrointestinal tract consists of four distinct layers. From the lumen outwards, they are the mucosa, the submucosa, the muscularis and the serosa. These concentric layers vary in thickness and each layer has sublayers (see Fig. 26.3). • The mucosa consists of simple columnar epithelium, which lines the lumen and is therefore in direct contact with food. Scattered among this epithelial layer are goblet cells, which have the important function of secreting mucus that allows for lubrication during the passage of food. The proportion of goblet cells varies in some organs, depending on the requirement for mucus secretion. The lamina propria lies underneath the epithelium and
TABLE 26.1 Major digestive enzymes ORGAN WHERE ENZYME PRODUCED
ORGAN WHERE ENZYME ACTS
SUBSTANCE BEING DIGESTED
— salivary amylase
Salivary glands
Mouth
Starch, glycogen
— pancreatic amylase
Pancreas
Small intestine
Starch, glycogen
Disaccharidases
Small intestine
Small intestine
Maltose, disaccharides
Monosaccharides
Glucoamylase
Small intestine
Small intestine
Maltose
Glucose
Small intestine
Small intestine
Sucrose
Glucose and fructose
Maltose
Glucose
ENZYME
Carbohydrate digestion
SUBSTANCE DIGESTED INTO
Amylases: Maltose, smaller polysaccharides Maltose, disaccharides
Carbohydrases: — Sucrase — Maltase — Lactase
Lactose
Glucose and galactose
Pancreas
Small intestine
Lipids
Fatty acids, glycerol, glycerides
— Pepsin
Stomach
Stomach
Proteins
Polypeptides
— Trypsin
Pancreas
Small intestine
Peptides
Smaller polypeptides
— Chymotrypsin
Pancreas
Small intestine
Peptides
Smaller polypeptides
Pancreas
Small intestine
Amino acids
Small intestine
Small intestine
Smaller polypeptides
Nucleases
Pancreas
Small intestine
Nucleic acids
Nucleotides and components
Nucleosidases and phosphatases
Small intestine
Small intestine
Nucleotides
Sugars, bases, phosphates
Fat digestion
Lipase
Protein digestion
Proteases:
Peptidases: — Pancreatic carboxypeptidase — Dipeptidases, carboxypaptidase, aminopeptidase Nucleic acid digestion
Small peptides
Amino acids
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Neural control of the digestive system
Absorption of small molecules into the blood
FIGURE 26.2
An overview of digestive system function. After food is eaten, it travels through the digestive system where it is progressively broken down into smaller components. These small molecules must cross over the gut wall and into the nearby bloodstream, where they become available to body cells. Any molecules that are not absorbed exit the body in the faeces.
consists of connective tissue; it provides the capillaries for the epithelial layer. A thin layer of smooth muscle called the muscularis mucosae provides the muscular activity for local movements. Some glands are also formed by the mucosal layer in some organs. • The submucosa is essentially connective tissue containing large blood vessels, nerves and secretory glands. • The muscularis, as its name suggests, consists of muscle and has two sublayers: • an inner circular muscle layer, in which the cells are oriented in a circular direction, around the circumference of the gastrointestinal tract • an outer longitudinal muscle layer, where the smooth muscle cells are aligned along the length of the gastrointestinal tract. • The outermost layer of connective tissue is the serosa, which contains and supports the gastrointestinal tract.
A network of intrinsic nerves called the enteric nervous system controls digestive function and is located solely within the layers of the digestive tract (see Fig. 26.4). It consists of the following: 1 The submucosal plexus (or Meissner’s plexus) is located in the submucosal layer. This controls small or localised functions, such as local blood flow and absorption and secretion from the digestive tract into the bloodstream. 2 The myenteric plexus (or Auerbach’s plexus) is located between the circular and longitudinal muscle layers. This collection of neurons has the important function of controlling the movement of gastrointestinal tract. Interestingly, not only does the enteric nervous system control digestive activity using efferent signals (outflow from neurons to target cells), but there is also an important role for sensory neurons in this system. Specialised neurons are able to sense the local environment within the digestive system (such as within the contents of the stomach) and can relay afferent signals into the enteric nervous system. In particular, there are chemoreceptors to sense chemicals such as toxins in food, mechanoreceptors that can sense the mechanical forces of gut activity and stretch, and nociceptors to detect pain (refer to Chapter 6 for receptor types). On receiving information about the environment within the gut, the enteric nervous system can alter function accordingly. For example, if food that contains a high amount of bacterial toxins reaches the intestines, the appropriate response may be increased contractions, leading to diarrhoea, in order to remove the toxins from the body. Also, sensory information from mechanoreceptors can detect when the stomach is stretched, which is vital in limiting further food intake temporarily. In addition to the enteric nervous system, the gastrointestinal system is also controlled by the well-known branches of the autonomic nervous system: the parasympathetic and sympathetic divisions. Parasympathetic activity increases the function of the digestive system, such as increasing secretions and motility, and causes relaxation of sphincters, thereby allowing food to progress through the system. Most parasympathetic innervation of the gastrointestinal system is via the vagus nerves (cranial nerve X). In contrast, the sympathetic nervous system, which coordinates the body’s response to stress (fight or flight response), decreases digestive processes and constricts sphincters. The sympathetic innervation of the digestive system is via the splanchnic nerves.
Motility
The majority of motility (or movement) in the digestive system is under involuntary control. Some voluntary control occurs at the mouth, pharynx and anus (and is discussed fully in the relevant sections). Gastrointestinal motility is a complex process involving coordination
CHAPTER 26 The structure and function of the digestive system
Mesentery
Nerve
Blood vessels
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Serosa Connective tissue layer Peritoneum Myenteric plexus Submucosal plexus
Enteric plexus Submucosa Gland in submucosa Duct from gland Mucosa Mucous epithelium Lamina propria Muscularis mucosae
Muscularis Circular muscle layer Longitudinal muscle layer
Lymph nodule
FIGURE 26.3
The wall of the gastrointestinal tract. The wall of the gastrointestinal tract is made up of four layers with a network of nerves between the layers. This generalised diagram shows a segment of the gastrointestinal tract. Note that the serosa is continuous with a fold of serous membrane called a mesentery. Note also that digestive glands may empty their products into the lumen of the gastrointestinal tract by way of ducts.
between the smooth muscle cells of the gut wall, the enteric neurons (the neurons of the gut), and interstitial cells of Cajal. These are specialised pacemaker cells with rhythmic activity, and facilitate the integration and communication between the neurons and smooth muscle cells — this results in rhythmic and coordinated contractions.1 This results in various motor patterns, including the two main types of movement: peristalsis and segmentation.2,3 • Peristalsis (see Fig. 26.5A): peristaltic contractions move the food along the gastrointestinal tract, in a direction from the mouth to the anus. The circular muscle contracts (like the action of a sphincter) immediately behind the food, so that it cannot travel in a reverse direction. Circular muscle relaxes ahead of the food, allowing a wide diameter for the food to progress along. The longitudinal muscle contracts as the food enters that region, which has the effect of decreasing the length that the food needs to travel through. • Segmentation (see Fig. 26.5B): these movements do not progress the food along, but instead allow it to move slightly forwards and backwards a number of times. This is particularly important to allow the food to mix well with digestive secretions, as well as assisting with mechanical digestion. The circular muscle contracts in a number of places, preventing food from travelling a substantial distance, and coordinated contraction
TABLE 26.2 Splanchnic blood flow to the digestive organs MAIN ARTERY
MAIN ORGANS SUPPLIED
Coeliac
Liver, spleen, lower oesophagus, stomach, parts of duodenum and pancreas
Superior mesenteric
Small intestine, caecum, ascending colon, most of transverse colon, parts of duodenum and pancreas
Inferior mesenteric
Descending and sigmoid colon, parts of transverse colon and rectum
and relaxation allows mixing of food while it stays in approximately the same place.
Splanchnic blood flow
Splanchnic blood flow provides blood to the oesophagus, stomach, small and large intestines, liver, gallbladder, pancreas and spleen (see Fig. 26.6). The three major arteries, coeliac, superior mesenteric and inferior mesenteric, give rise to smaller arteries that branch extensively providing blood supply to splanchnic organs (Table 26.2). The splanchnic blood flow is controlled by both intrinsic and extrinsic factors. Intrinsic mechanisms include the enteric nervous system, and locally produced vasoactive
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Part 4 Alterations to body maintenance Extrinsic innervation:
Intrinsic innervation (enteric nervous system):
Primary afferent sensory neurons
Intrinsic primary afferent neurons Interneuron
Parasympathetic sensory neurons
Excitatory motor neuron Inhibitory motor neuron
Sympathetic motor neurons From brain (brainstem and hypothalamus)
Parasympathetic neurons transmit signals from the brain to the enteric nervous system. This results in increased peristalsis, secretions and vasodilation.
Villi
Vagus nerve (X) Sympathetic neurons transmit signals from the brain to the enteric nervous system. This results in decreases in peristalsis, secretions and causes vasoconstriction.
Mucosa
Spinal cord (thoracic region)
Submucosa
Muscularis mucosae
Submucosal plexus within the submucosal layer (controls secretion)
Primary afferent neurons send sensory signals to the spinal cord, brainstem and cerebral cortex Primary afferent sensory neuron Spinal cord Splanchnic (sacral nerve region) Parasympathetic neurons
Circular muscle Longitudinal muscle Myenteric plexus between the circular and longitudinal muscle layers (controls motility)
Pelvic nerve Inhibitory motor neurons
Excitatory motor neurons
Intrinsic primary afferent neuron
FIGURE 26.4
Neural control of the gut wall. The main control is by the millions of neurons in the enteric nervous system, which also communicates with the sympathetic and parasympathetic nervous system branches. Afferent or sensory information travels through the gut wall towards the central nervous system, while efferent or motor information travels from the central nervous system towards the gut.
substances. Extrinsic factors include sympathetic and parasympathetic nervous system activity, systemic conditions of the cardiovascular system, and circulating neurohumoral agents. The principal functions of this vascular bed are to transport absorbed nutrients to the liver and systemic circulation, as well as serving as a reservoir of blood volume to return the blood to the heart when needed. Changes in metabolic activity after meal ingestion, gastrointestinal hormones and neuropeptides released from parasympathetic nerve terminals increase the blood flow in the gastrointestinal
tract. Noradrenaline released from the activated sympathetic nervous system and circulating vasoconstricting hormones, such as antidiuretic hormone and angiotensin II, account for the reduction in splanchnic blood flow to mobilise blood to the systemic circulation during periods of whole body stress.
The main nutrients
The energy from the food we eat comes from the three main nutrient groups: proteins, fats and carbohydrates. You will
CHAPTER 26 The structure and function of the digestive system
Contraction
A
Bolus
B
the same region of tissue, a few moments later
Contraction
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Bolus
the same region of tissue, a few moments later
FIGURE 26.5
Peristalsis and segmentation. A Peristalsis is a progressive type of movement in which food is propelled from point to point along the gastrointestinal tract. The ring of contraction moves like a wave along the tract to push the food forward. B Segmentation is a back-and-forth action that breaks apart chunks of food and mixes in digestive juices. Ring-like regions of contraction occur at intervals along the gastrointestinal tract. Previously contracted regions relax and adjacent regions contract, effectively ‘chopping’ the contents of each segment into smaller chunks, resulting in effective mixing.
Heart
Cardiac output (7000)
Hepatic vein (2080) Liver Hepatic portal vein (1500)
Hepatic artery (580) Stomach Spleen Pancreas
Small intestine Proximal colon Distal colon Rectum
Abdominal aorta (4500) Coeliac artery (800)
notice that these are the main molecules of the body that we examined in Chapter 1. These are the nutrients that will receive most of our attention in this chapter. Small amounts of vitamins (organic molecules) and minerals (inorganic molecules) are also essential for the human body and we briefly look at those as well. FOCU S ON L EA RN IN G
1 List the main organs of the digestive system (in the order that food normally passes through). 2 Name the accessory organs of the digestive system.
Superior mesenteric artery (800)
3 Name the main digestive enzymes and their functions.
Inferior mesenteric artery (480)
6 Explain the innervation of the digestive system.
4 Compare and contrast mechanical digestion and chemical digestion. 5 Describe the layers of the gastrointestinal tract wall. 7 Discuss the 2 different types of motility in the digestive system. 8 List the main nutrient groups for the human body.
FIGURE 26.6
The major blood vessels and organs supplied with blood in the splanchnic circulation. Numbers in parentheses reflect approximate blood flow values (mL/min) for each major vessel in an 80 kg resting adult human. Arrows indicate the direction of blood flow.
The mouth, pharynx and oesophagus Anatomy and physiology of the mouth, pharynx and oesophagus
The mouth (oral cavity or buccal cavity) is a reservoir for the chewing and mixing of food with saliva (see Fig. 26.7).
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Soft palate Nasal cavity
Pharyngeal tonsil Nasopharynx
Hard palate
Uvula Oropharynx
C2
Epiglottis Vocal cords
C5
Larynx
Mouth (oral cavity) Tongue Palatine tonsils Lingual tonsils Hyoid bone
Sublingual ducts Submandibular duct Sublingual gland
Parotid gland
Submandibular gland
FIGURE 26.8
C7
Laryngopharynx Trachea Thyroid cartilage Oesophagus
FIGURE 26.7
Structures associated with the mouth, pharynx and oesophagus. Main structures of this region include the oral cavity, tonsils, soft palate and uvula, and the epiglottis which closes over the trachea to prevent food entering the respiratory system.
As food particles become smaller and move around in the mouth, the taste buds (or chemoreceptors) and olfactory nerves are continuously stimulated, adding to the enjoyment of eating. The tongue’s surface contains thousands of taste buds, which can distinguish salty, sour, bitter and sweet tastes. Food tastes and odours help to initiate salivation and the secretion of gastric juice in the stomach. There are 32 permanent teeth in the adult mouth and they are important for speech and mastication (chewing). The pharynx is the region posterior to the mouth and nose and leads into the oesophagus. It consists of three regions: nasopharynx, oropharynx and laryngopharynx (see Fig. 26.7). The oesophagus is a hollow, muscular tube approximately 25 cm long that conducts substances from the oropharynx, through the thoracic cavity and into the stomach. Each end of the oesophagus is opened and closed by a sphincter. The upper oesophageal sphincter keeps air from entering the oesophagus during respiration; and the lower oesophageal sphincter (also known as the cardiac sphincter or gastro-oesophageal sphincter) prevents regurgitation from the stomach back into the oesophagus.
Salivation
Parotid duct
There are three pairs of salivary glands: the left and right submandibular, sublingual and parotid glands (see Fig. 26.8). These glands secrete approximately 1.5 L of saliva into the mouth per day, via a duct with the same name
Salivary glands from the left lateral aspect. The parotid, submandibular and sublingual glands empty in to the mouth via their corresponding ducts.
as the gland itself (e.g. the parotid gland empties into the mouth via the parotid duct). Saliva consists mostly of water with mucus, as well as ions including sodium, bicarbonate, chloride and potassium. Another important component of saliva, salivary amylase, is discussed later in ‘Digestion in the mouth, pharynx and oesophagus’ below. The composition of saliva depends on the rate of secretion. The bicarbonate concentration of saliva sustains a pH of about 7.4, which neutralises bacterial acids and prevents tooth decay. Saliva also contains antimicrobial substances (such as lysosyme and immunoglobulin A, IgA), which help prevent infection. Fluoride is also secreted in the saliva, providing protection against tooth decay; this is enhanced by the addition of fluoride into drinking water. Saliva is secreted at a relatively constant rate, keeping the mouth moist and facilitating speech and swallowing. The amount of saliva is increased in response to nervous system activity. You will recall that control centres for vital body functions are located in the brainstem (such as the cardiac and respiratory control centres) — this is also true for the salivary control centre, which is located in the medulla. It is the parasympathetic nervous system that is mainly responsible for increased secretions (see Fig. 26.9). Sensory receptors in the mouth sense the presence of particular tastes (such as sour or acid), and mechanoreceptors sense the physical presence of objects in the mouth. Interestingly, the pressure receptors are activated whether the object in the mouth is food or not — for example, if you continue sucking the stick from an ice-block after the ice-block has been eaten, the mechanoreceptors will continue to be activated. Inputs (action potentials) from these sensory neurons reach the salivary control centre in the medulla, which results in an increase in salivary secretions (mediated by outputs from the parasympathetic nervous system). The higher centres of the brain can also stimulate secretion of
CHAPTER 26 The structure and function of the digestive system
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Gustatory cortex (in insula)
3
Thalamus Parotid duct Medulla oblongata in the brainstem
Glossopharyngeal nerve (IX)
2
Sensory fibres
Parotid salivary gland
5 4
Vagus nerve (X)
Parasympathetic Parasympath Paras fibres fib bre
Sublingual salivary gland
Facial nerve (VII)
Submandibular salivary gland
Glossopharyngeal nerve (IX) Vagus nerve (X)
Facial nerve (VII)
6 Stomach
1
Chemoreceptors C hem mo buds) and ((taste (ta (t at b aste mechanoreceptors m (sense pressure (s e and an n touch)
FIGURE 26.9
Control of saliva secretion. 1 Activation of receptors in mouth induces action potentials in nerve fibres sending information to the medulla in the brainstem, thalamus and the cerebral cortex. 2 Taste impulses initiate reflexes involved in digestion via activation of parasympathetic neurons in the medulla (brainstem). 3 Taste impulses reach gustatory cortex (in insula) which controls taste perception. 4 Activated parasympathetic neurons send action potentials along their fibres (nerves) to salivary glands and stomach. 5 Glossopharyngeal nerve (IX) and facial nerve (VII) increase salivary secretion. 6 Vagus nerve (X) increases secretion of gastric juice into the stomach.
saliva, such as the conscious thought of food in the cerebral cortex — this too results in action potentials reaching the salivary control centre and increased salivation.
Swallowing
Swallowing (or deglutition) occurs when food mixed with saliva, now known as a bolus, moves onwards from the mouth. The upper third of the oesophagus contains striated muscle (voluntary) that is directly innervated by motor
neurons. The lower two-thirds contain smooth muscle (involuntary) that is innervated by the parasympathetic nervous system. Peristalsis is stimulated when afferent fibres distributed along the length of the oesophagus sense changes in wall tension caused by stretching as food passes. The greater the tension, the greater the intensity of oesophageal contraction. Occasionally, intense contractions cause pain similar to ‘heartburn’ or angina. (Heartburn is chest pain associated with the oesophagus.)
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Part 4 Alterations to body maintenance
Swallowing is coordinated primarily by the swallowing control centre in the medulla. During the oropharyngeal (voluntary) phase, the following steps occur (see Fig. 26.10A–C): 1 Food is formed into a bolus by the tongue and forced posteriorly towards the pharynx. 2 The soft palate and uvula are raised and the superior muscles of the pharynx contract — this prevents food from entering the nasopharynx. 3 The bolus of food causes the epiglottis to slide down, to prevent food from entering the larynx and trachea. Breathing is momentarily inhibited. This entire sequence of moving food from the mouth through the pharynx takes place in less than 1 second. The oesophageal phase of swallowing proceeds as follows (see Fig. 26.10D–E): 1 The bolus enters the oesophagus. 2 Peristalsis (sequential waves of muscular contractions) transports the bolus to the lower oesophageal sphincter, which is relaxed at that point. 3 The bolus enters the stomach, and the sphincter muscles return to their contracted state. This phase takes about 5–10 seconds because the lower oesophageal sphincter is normally constricted and serves as a barrier between the stomach and oesophagus. Peristalsis that immediately follows the oropharyngeal phase of swallowing is called primary peristalsis. If a bolus becomes stuck in the oesophagus, secondary peristalsis — a wave of contraction and relaxation independent of voluntary swallowing — occurs. This is in response to stretch receptors in the oesophagus, which increase impulses from the swallowing centre of the brain.
ORAL STAGE
Thyroid cartilage
A A
Skeletal (striated) muscle
PHARYNGEAL STAGE
BB
CC
OESOPHAGEAL STAGE
Digestion in the mouth, pharynx and oesophagus
The mouth is the first site of mechanical digestion, whereby the chewing action of the teeth causes physical breakdown of food into smaller particles. Once the food is small enough (and has been adequately moistened with saliva), it is ready to be swallowed. There is no further mechanical digestion in the pharynx or oesophagus. Saliva contains salivary amylase, which is an enzyme that initiates carbohydrate digestion — this is the only enzyme involved in chemical digestion in the mouth. Carbohydrate digestion by salivary amylase may continue when the bolus (mixed with enzyme) continues into the stomach. After the enzyme mixes with the acidic environment of the stomach, it becomes inactivated. None of the main nutrient groups (carbohydrates, proteins and fats) are digested sufficiently to be absorbed into the bloodstream from the mouth, pharynx or oesophagus. However, some drugs are administered in the mouth to be absorbed directly into the bloodstream from salivary glands, as this allows the drugs to enter the bloodstream quickly. Examples include glyceryl trinitrate
DD
EE
FIGURE 26.10
Deglutition (swallowing). A–C Oropharyngeal stage. A During this stage of swallowing, a bolus of food is voluntarily formed on the tongue and pushed against the palate and into the oropharynx. Notice that the soft palate and uvula prevent food from entering the nasopharynx. B After the bolus enters the oropharynx, involuntary reflexes push the bolus down towards the oesophagus. C The upward movement of the larynx and downward movement of the bolus close the epiglottis and thus prevent food from entering the lower respiratory tract. D–E Oesophageal stage. D Involuntary reflexes of skeletal and smooth muscle in the wall of the oesophagus move the bolus through the oesophagus towards the stomach. E After the bolus has passed, the epiglottis moves upwards, opening the larynx and trachea to respiration.
CHAPTER 26 The structure and function of the digestive system
(for the treatment of angina pectoris, discussed previously in Chapter 23) and fetanyl (for the immediate treatment of cancer pain). F O CUS O N L E A R N IN G
1 Describe the anatomy of the mouth, pharynx and oesophagus. 2 Discuss the roles of saliva and explain how salivation secretion is controlled. 3 Explain the steps involved in swallowing. 4 Describe the digestion and absorption of substances in the mouth, pharynx and oesophagus.
The stomach Anatomy and physiology of the stomach
The stomach is a muscular organ just inferior to the diaphragm that stores food during eating, secretes digestive juices, mixes food with these juices and propels partially digested food, now called chyme, into the small intestine. The anatomy of the stomach is shown in Fig. 26.11. Its major anatomical boundaries are the lower oesophageal sphincter, where food passes into the stomach; the greater and lesser curvatures; and the pyloric sphincter, which relaxes as food is propelled through the pylorus into
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the duodenum. Functional areas are the fundus (upper portion), body (middle portion) and antrum (lower portion). The muscularis layer has an inner circular muscle layer and an outer longitudinal layer, as described earlier. An additional sublayer of oblique muscle occurs in the stomach and it is the most prominent, lying between the submucosa and the circular muscle layer. Extrinsic innervation of the stomach is provided by (1) parasympathetic (cholinergic) fibres of the gastric branches of the vagus nerve, (2) sympathetic (adrenergic) fibres of the splanchnic nerves, and (3) sensory afferent fibres within these vagal and sympathetic nerves. Intrinsic innervation of the stomach is provided by the myenteric plexus located between circular and longitudinal muscle layers and submucosal plexus located between the submucosa and the circular muscle layer. Both extrinsic and intrinsic cholinergic innervation stimulates secretion and peristaltic movements inducing mixing, digestion and evacuation of food. The adrenergic fibres provide innervation to sphincters and blood vessels inducing their constriction. Sensory nerve endings of enteric neurons and sensory afferent fibres project to the epithelium where they detect changes in chemical environment, mechanical stretching and irritation of the stomach. Sensory impulses are sent to motor and secretory neurons of the enteric nervous system, to the spinal cord via sympathetic afferent fibres and to the brainstem via vagal afferent fibres. The vagal afferent fibres are involved in mediating satiety (feeling of fullness) and, therefore, regulating appetite.
Oesophagus Fundus
Gastro-oesophageal opening Lower oesophageal sphincter
Duodenal bulb
tu r
e
Serosa Longitudinal muscle layer Muscularis Circular muscle layer
va
Pyloric sphincter Pylorus
Body
u Lesser c
r
Oblique muscle layer Mucosa Submucosa e
Duodenum
at
ur
Antrum
Rugae
G re
ate
u rc
rv
FIGURE 26.11
The stomach. A portion of the anterior wall has been cut away to reveal the muscle layers of the stomach wall. Note that the mucosa lining the stomach forms folds called rugae. The dotted lines distinguish the fundus, body and antrum of the stomach.
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Part 4 Alterations to body maintenance
Gastric motility
In the resting state, the stomach is small and contains about only 50 mL of fluid. However, the stomach has a tremendous capacity and can expand to hold up to 4 L. Swallowing causes the fundus to relax to receive a bolus from the oesophagus. Relaxation is facilitated by gastrin and cholecystokinin — two hormones secreted by the gastrointestinal mucosa (the actions of digestive hormones are summarised in Table 26.3). Gastric motility increases with the initiation of peristaltic waves, which sweep over the body of the stomach towards the antrum. The rate of peristaltic contractions is approximately 3 per minute and is influenced by neural and hormonal activity. Gastrin, motilin (an intestinal hormone) and the activation of the parasympathetic nervous system (travelling via the vagus nerve) increase contraction. Sympathetic activity and secretin (another intestinal hormone) are inhibitory and decrease the rate of contractions. The rate of peristalsis is mediated by pacemaker cells that initiate a wave of depolarisation (basic electrical rhythm), which moves from the upper part of the stomach to the pylorus. The mixing and emptying of food from the stomach takes several hours. Mixing occurs as food is propelled towards the antrum. As food approaches the pylorus, the velocity of the peristaltic wave increases, forcing the contents back towards the body of the stomach. This retropulsion effectively mixes food with digestive juices and the oscillating motion breaks down large food particles. With each peristaltic wave, a small portion of the gastric contents (chyme) passes through the pylorus and into the duodenum,
as the pyloric sphincter opens only slightly to regulate the rate of entry into the duodenum (see Fig. 26.12). The rate of gastric emptying (movement of gastric contents into the duodenum) depends on the volume, osmotic pressure and chemical composition of the gastric contents. Larger volumes of food increase gastric pressure, peristalsis and rate of emptying. Food remains in the stomach for up to 4 hours, although a further 2 hours may be required for fatty meals. Products of fat digestion, which are formed in the duodenum by the action of bile from the liver and enzymes from the pancreas, stimulate the secretion of cholecystokinin. This hormone inhibits gastric motility and decreases gastric emptying so that fats are not emptied into the duodenum at a rate that exceeds the rate of bile and enzyme secretion. Osmoreceptors in the wall of the duodenum are sensitive to the osmotic pressure of duodenal contents. The arrival of hypertonic or hypotonic gastric contents activates the osmoreceptors, which delay gastric emptying so that the duodenum can receive the contents. (This is why sports drinks are often formulated to be ‘isotonic’. Review ‘tonicity’ in Chapter 3.) The rate at which acid enters the duodenum also influences gastric emptying. Secretions from the pancreas, liver and duodenal mucosa neutralise gastric acid in the duodenum. The rate of emptying is adjusted to the duodenum’s ability to neutralise the incoming acidity.
Gastric secretion
Stimulated by eating, the stomach secretes large volumes of gastric juices (or gastric secretions) directly into the lumen. These include mucus, acid, enzymes, intrinsic factor
TABLE 26.3 Selected hormones (and peptides) of the digestive system SOURCE
HORMONE
STIMULUS FOR SECRETION
ACTION
Mucosa of the stomach
Gastrin
Presence of partially digested proteins in the stomach
Stimulates gastric glands to secrete hydrochloric acid and pepsinogen; growth of gastric mucosa
Histamine
Gastrin
Stimulates acid secretion
Acetylcholine
Vagus and local nerves in stomach
Stimulates release of pepsinogen and acid secretion
Motilin
Presence of acid and fat in the duodenum
Increases gastrointestinal motility
Secretin
Presence of chyme (acid, partially digested proteins, fats) in the duodenum
Stimulates pancreas to secrete alkaline pancreatic juice and liver to secrete bile; decreases gastrointestinal motility; inhibits gastrin and gastric acid secretion
Cholecystokinin
Presence of chyme (acid, partially digested proteins, fats) in the duodenum
Stimulates gallbladder to eject bile and pancreas to secrete alkaline fluid; decreases gastric motility; constricts pyloric sphincter; inhibits gastrin
Pancreatic polypeptide
Protein, fat and glucose in small intestine
Decreases pancreatic bicarbonate and enzyme secretion
Vasoactive intestinal peptide
Intestinal mucosa and muscle
Relaxes intestinal smooth muscle
Mucosa of the small intestine
Note: the digestive hormones are not secreted into the gastrointestinal lumen but rather into the bloodstream, in which they travel to target tissues.
CHAPTER 26 The structure and function of the digestive system
Oesophagus
773
A Surface mucous cells
Gastric pit
Lamina propria Stomach Peristaltic contraction
Pyloric sphincter
Gastric glands: Mucous neck cell Chief cell
Mucosa
Parietal cell
Duodenum
Endocrine cell
Chyme Muscularis mucosae Retropulsion Propulsion
Stronger peristaltic contractions
Submucosa
Blood vessels Oblique muscle layer Circular muscle layer Longitudinal muscle layer
Muscularis
Serosa Connective tissue Visceral peritoneum
FIGURE 26.12
Stomach mechanical events. Mixing actions in the stomach include both propulsion (forward movement) and retropulsion (backward movement). As peristaltic contractions become stronger, some of the liquid chyme squirts past the pyloric sphincter (which has relaxed slightly) and into the duodenum. The stomach continues to mix the chyme as it is gradually released into the duodenum.
and gastroferrin. Intrinsic factor is necessary for subsequent intestinal absorption of vitamin B12 and gastroferrin facilitates small intestinal absorption of iron. The stomach also secretes some hormones into the bloodstream, including gastrin and histamine, which stimulate the gastric glands. The gastric pits and gastric glands are the main secretory units of the stomach (see Fig. 26.13A). From the stomach lumen down to the depths of the glands, the cell types are the mucous neck cells, chief cells, parietal cells and finally the enteroendocrine cells (which secrete hormones into the bloodstream). The rate of gastric secretions varies with the time of day. Generally, the rate and volume of secretion are lowest in the morning and highest in the afternoon and evening. Gastric secretions are increased by parasympathetic nervous system activity, while the sympathetic nervous
FIGURE 26.13
A Gastric pits and gastric glands.
Gastric pits are depressions in the epithelial lining of the stomach. At the bottom of each pit is one or more tubular gastric glands. Chief cells produce the enzymes of gastric juice (such as pepsinogen), parietal cells produce stomach acid, and G cells produce the hormone gastrin. B Pepsin activation. Pepsinogen secreted by chief cells becomes activated to pepsin in the presence of hydrochloric acid (HCl).
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system decreases secretions. Unpleasant odours and tastes or strong emotions alter the relative sympathetic and parasympathetic nervous system control and can therefore alter secretions. ACID
A high concentration of hydrochloric acid allows the stomach pH to be as low as 2 or 3 (a low pH is due to a high amount of acid). The major functions of gastric acid are to dissolve food fibres, act as a bactericide (kill bacteria) against swallowed microorganisms and convert pepsinogen to pepsin. The production of acid is by the parietal cells of the gastric glands. The main stimulants of acid secretion are gastrin, histamine and acetylcholine, with others including ghrelin and motilin. One main inhibitor of acid secretion is somatostatin.4 PEPSIN
Acetylcholine, gastrin and secretin stimulate the chief cells to release pepsinogen during eating. Pepsinogen is quickly converted to pepsin in the acid gastric environment (see Fig. 26.13B). Pepsin is a proteolytic enzyme — that is, it breaks down protein into smaller components known as polypeptides in the stomach. Once chyme enters the duodenum, the alkaline environment of the duodenum inactivates pepsin. MUCUS
The gastric mucosa is protected from the digestive actions of acid and pepsin by a coating of alkaline (bicarbonate-rich) mucus called the mucosal barrier. Mucus is produced in large quantities in the stomach by the mucus neck cells of the gastric glands. The stomach has two layers of mucus produced by the superficial epithelium: the inner layer is attached to the epithelium and the outer layer is less dense and unattached to the epithelium. The inner mucus layer acts as a barrier for hydrochloric acid, it is impervious to bacteria and is renewed every hour.5 The quality and quantity of mucus and the tight junctions between epithelial cells make gastric mucosa relatively impermeable to acid. Prostaglandins protect the mucosal barrier by stimulating the secretion of mucus and bicarbonate and by inhibiting the secretion of acid. Mucosal blood flow is important to maintaining mucosal protective functions. If epithelial cells lining the stomach are damaged, they are replaced quickly to protect underlying tissues. PHASES OF GASTRIC SECRETION
The secretion of gastric juice is influenced by numerous stimuli that together facilitate the process of digestion. There are three phases of gastric secretion: the cephalic phase, the gastric phase and the intestinal phase. Briefly, the cephalic phase actually occurs before food enters the stomach. The phase is activated by the thought, smell, sight and taste of food. These sensory inputs travel to the hypothalamus and then the medulla, which stimulates the stomach via the vagus nerve. The gastric phase is initiated once food enters
the stomach, as it causes distension or stretch of the stomach. Most of the gastric juices are secreted in this phase. The hormone gastrin is released, due to chemoreceptor stimulation from the chyme, and this stimulates parietal cells to release hydrochloric acid. This lowers the pH and protein digestion occurs. The last phase, the intestinal phase, occurs when chyme starts to enter the duodenum, which causes the release of more acid and also triggers the release of secretin and cholecystokinin, hormones that chemically prepare the duodenum.
Digestion in the stomach
The main digestive process in the stomach is mechanical digestion by the strong muscular layers, whereby larger food particles are ground and churned into smaller particles. Chemical digestion also occurs, whereby hydrochloric acid and the enzyme pepsin break down proteins into smaller molecules.
Absorption from the stomach
Absorption from the stomach is limited: none of the main nutrients are absorbed here. However, both alcohol and aspirin can easily pass through the stomach’s mucosal lining and into the bloodstream. Excessive amounts of these substances can be irritating to the stomach mucosa and therefore it is advisable to have food in the stomach at the same time that alcohol or aspirin (and other anti-inflammatory drugs) are consumed, to help protect the mucus lining. FOCU S ON L EA RN IN G
1 Discuss the anatomy of the stomach. 2 Describe the motility of the stomach, including the relevant hormones, nervous system control and gastric emptying. 3 Outline the gastric secretions, including where the substances are produced and their functions. 4 Explain the digestion and absorption of substances in the stomach.
The small intestine Anatomy and physiology of the small intestine
The small intestine (or small bowel) is named ‘small’ due to its relatively small diameter of approximately 2.5 cm. It is about 5 m long and is functionally divided into three segments: the duodenum, the jejunum and the ileum (see Figs 26.1 and 26.14). These structures are not grossly different, but the jejunum has a slightly larger lumen. At the distal end, the ileocaecal valve, or sphincter, controls the flow of digested material from the ileum into the large intestine and prevents reflux into the small intestine.
CHAPTER 26 The structure and function of the digestive system
FIGURE 26.14
Small and large intestines. The proximal part of the small intestine (white arrow) and all of the large intestine (red arrow) are shown on this image.
The peritoneum is the serous membrane surrounding the organs of the abdomen and pelvic cavity. It is analogous to the pericardium and pleura, which surround the heart and lungs, respectively. The visceral peritoneum lies over the organs and the parietal peritoneum lines the wall of the abdominal cavity. The space between these two layers is called the peritoneal cavity and normally contains just enough fluid to lubricate the two layers and prevent friction during organ movement. Associated with the anterior part of the peritoneal membranes is the omenta (plural; singular = omentum). The greater omentum drapes from the inferior part of the stomach over the intestinal fold and contains a considerable amount of fat. As fat builds up around the waist area, an increase in storage of fat within the greater omentum occurs. The lesser omentum is a much smaller membrane, located between the liver and stomach. We consider the storage of fat in greater detail in Chapter 35. The duodenum lies behind the peritoneum (retro-peritoneal) and is attached to the posterior abdominal wall. The ileum and jejunum are suspended in loose folds from the posterior abdominal wall by a peritoneal membrane called the mesentery. The mesentery facilitates intestinal motility and supports blood vessels, nerves and lymphatics. There are important structural specialisations of the small intestine that force food to move through quite slowly — this
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is important as a large amount of digestion and absorption occurs here. Mucosal folds within the small intestine slow the passage of food, thereby providing more time for digestion and absorption (see Fig. 26.15). The folds are most numerous and prominent in the jejunum and upper ileum. Absorption occurs through villi (plural; singular = villus), which cover the mucosal folds and are the functional units of the intestine. Each villus (see Fig. 26.15A–B) secretes some of the enzymes necessary for digestion and absorbs nutrients. A villus is composed of absorptive columnar cells and mucus-secreting goblet cells of the mucosal epithelium. The small intestine has only one layer of the surface mucus which is unattached to the epithelium and easy to remove.5 Near the surface, columnar cells closely adhere to each other at sites called tight junctions (literally, close together). Water and electrolytes are absorbed through these inter-cellular spaces. The surface of each columnar epithelial cell contains tiny projections called microvilli (see Fig. 26.15C–D). Together the microvilli create a mucosal surface known as the brush border. The villi and microvilli greatly increase the surface area available for absorption. Coating the brush border is an ‘unstirred’ layer of fluid that is important for the absorption of substances other than water and electrolytes. The lamina propria (a connective tissue layer of the mucous membrane) lies beneath the epithelial cells of the villi and contains lymphocytes and macrophages, involved in inflammation and immune functions. Aggregated lymphoid follicles, known as Peyer’s patches, can be found in the lamina propria throughout the ileum. Isolated and aggregated immune cells form a complex network known as gut-associated lymphoid tissue (GALT) which provides a functional protective barrier and contains up to 70% of the immune cells of the whole human body.6 Central arterioles ascend within each villus and branch into a capillary array that extends around the base of the columnar cells and cascades down to the venules that lead to the portal circulation (see Fig. 26.15B). A central lacteal, or lymphatic channel is also contained within each villus and is important for the absorption and transport of fat molecules. Contents of the lacteals flow to regional lymph nodes and channels that eventually drain into the thoracic duct. The entire epithelial population is replaced about every 4–7 days. Many factors can influence this process of cellular proliferation. Starvation, vitamin B12 deficiency, inflammation, chemotherapy (cytotoxic drugs) and irradiation suppress cell division and shorten the villi. The decreased absorption that results can cause diarrhoea and malnutrition.
Intestinal motility
The movements of the small intestine facilitate both digestion and absorption. Chyme coming from the stomach stimulates intestinal movements that mix in secretions from the liver, pancreas and intestinal glands. A churning motion brings the luminal contents into contact with the absorbing cells of the villi. The propulsive movements of peristalsis then advance the chyme towards the large intestine.
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A Mesentery Serosa
Longitudinal muscle Circular muscle
Muscularis Submucosa Mucosa
Magnification of jejunal mucosal wall
Plica (fold) Segment of jejunum
Lymph nodule
Epithelium
Single villus
B C
D
Microvilli
Goblet cell
Mucosal villi
Tight junctions between cells
Epithelium Microvilli Mucosa
Epithelial cell
Lacteal (lymph capillary) Artery and vein
Two cells of the villus epithelium showing brush border (microvilli)
FIGURE 26.15
The wall of the small intestine. A The folds of mucosa are covered with villi. B Each villus is covered with epithelium. C The epithelial cells have microvilli, which increase the surface area for absorption of food. D A microscope image of the epithelial cells of the small intestine, showing the microvilli. Note that a goblet cell containing mucus can also be seen.
Neural reflexes along the length of the small intestine facilitate motility, digestion and absorption. The ileogastric reflex inhibits gastric motility when the ileum becomes distended. This prevents the continued emptying of chyme into an already distended intestine. The intestinointestinal
reflex inhibits intestinal motility when one part of the intestine is overdistended. Both of these reflexes require extrinsic innervation. The gastroileal reflex, which is activated by an increase in gastric motility and secretion, stimulates an increase in ileal motility and relaxation of the ileocaecal
CHAPTER 26 The structure and function of the digestive system
Ascending colon
1 Colon
Terminal ileum (small intestine) Caecum
3 Appendix
the action of pancreatic enzymes, intestinal enzymes and bile salts. There carbohydrates are broken down to monosaccharides and disaccharides; proteins are degraded further to amino acids and peptides; and fats are emulsified and reduced to fatty acids and monoglycerides (see Fig. 26.17).
Absorption from the small intestine
Valve
4
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Ileocaecal sphincter
2
FIGURE 26.16
Emptying at the ileocaecal sphincter. 1 Chyme moves down the small intestine at the rate of about 1 cm/min, so will reach the terminal ileum in 3–5 hours. It stays there until the next meal which will activate gastroileal reflex by an increase in gastric motility and secretion leading to stimulation of ileal motility. 2 Increased pressure and chemical irritation in the terminal ileum will cause relaxation of ileocaecal sphincter and excite peristalsis forcing chyme through the sphincter. 3 Increased pressure or chemical irritation in the caecum will cause constriction of the sphincter and inhibition of peristalsis of the ileum. 4 The food will be pushed up the ascending colon and past the entrance of the ileum. The ileocaecal sphincter protrudes into the caecum, thus increased caecal pressure will cause occlusion of the sphincter to prevent reflux of faecal contents into the small intestine.
The majority of all absorption occurs in the small intestine. The small molecules of the main nutrient groups (simple sugars, amino acids and fatty acids), along with water, vitamins and electrolytes, are absorbed across the intestinal mucosa by active transport, diffusion or facilitated diffusion. Products of carbohydrate, protein and lipid breakdown move into capillaries (of the villi) and then travel to the liver through the hepatic portal vein. Some types of digested fats cross into the lacteals (lymphatic capillaries in the villi) and therefore travel through the lymphatic system and do not go through the liver. The lacteals join into larger lymphatic vessels carrying the contents towards the thoracic duct, and the lymphatics empty into the systemic venous circulation near the heart — at this point, those lipids reach the bloodstream. Intestinal motility exposes nutrients to a large mucosal surface area by mixing chyme and moving it through the lumen. Different segments of the gastrointestinal tract absorb different nutrients. Sites of absorption are shown in Fig. 26.18. Box 26.1 outlines the major processes involved in nutrient absorption.
FOCU S ON L EA RN IN G
sphincter. This empties the ileum and prepares it to receive more chyme. During prolonged fasting or between meals, particularly overnight, slow waves sweep along the entire length of the intestinal tract from the stomach to the terminal ileum. This action appears to propel residual gastric and intestinal contents into the colon. The ileocaecal sphincter marks the junction between the terminal ileum and the large intestine. This sphincter (or valve) is normally closed. The arrival of peristaltic waves from the last few centimetres of the ileum causes the ileocaecal sphincter to open, allowing a small amount of chyme to pass through. Distension of the upper large intestine causes the sphincter to constrict, preventing further distension, as well as avoiding retrograde flow of intestinal contents (see Fig. 26.16).
Digestion in the small intestine
The chyme that passes into the duodenum is a liquid with small particles of undigested food. Importantly, the secretions from the accessory organs — the liver, gallbladder and pancreas — all empty into the duodenum. Digestion continues in the proximal portion of the small intestine by
1 Describe the anatomy of the small intestine, peritoneal cavity, omenta and mesentery. 2 Discuss the anatomical features that slow down the rate of progression of chyme through the small intestine. Discuss the anatomical features that increase the surface area for absorption in the small intestine. 3 Explain the motility of the small intestine. 4 Describe the digestion and absorption of substances in the small intestine.
Accessory organs of digestion The liver, gallbladder and pancreas all secrete substances necessary for the digestion of chyme. These secretions are delivered to the duodenum through ducts. The liver produces bile, which contains salts necessary for fat digestion and absorption. Between meals, bile is stored in the gallbladder. The pancreas produces (1) enzymes needed for the complete digestion of carbohydrates, proteins and fats, and (2) an
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Action
Main nutrients
Enzymes/source
Site of action
Salivary amylase
Mouth
Starch
Dextrins, oligosaccharides Carbohydrate digestion and absorption
Pancreatic amylase Lactose
Maltose
Sucrose
Galactose
Glucose
Fructose
Brush-border enzymes (lactase, maltase, sucrase)
Small intestine
Pepsin in presence of hydrochloric acid
Stomach
Absorbed by capillaries in the villi and transported to the liver by hepatic portal vein Proteins
Proteases, peptones
Protein digestion and absorption
Pancreatic enzymes (trypsin, chymotrypsin, carboxypeptidase)
Small polypeptides, dipeptides
Amino acids
Small intestine
Brush-border enzymes (aminopeptidases and dipeptidases)
Small intestine
Emulsifying agents (bile salts, fatty acids, monoglycerides, lecithin, cholesterol and protein)
Small intestine
Pancreatic lipases
Small intestine
Absorbed by capillaries in the villi and transported to the liver by hepatic portal vein Unemulsified fats
Fat digestion and absorption
Monoglycerides and fatty acids
Absorbed by lacteals in the villi and transported in the lymphatic system to the thoracic duct, and then into the systemic venous circulation
Glycerol and fatty acids
Absorbed by capillaries in the villi and transported to the liver by the hepatic portal vein
FIGURE 26.17
Digestion and absorption of foods. Each main nutrient group, carbohydrates, proteins, and fats, is digested from the mouth to the small intestine; most absorption occurs at the small intestine.
CHAPTER 26 The structure and function of the digestive system
the diaphragm. The liver is covered by the Glisson capsule, which contains blood vessels, lymphatics and nerves. When the liver is diseased or swollen, distension of the capsule causes pain, and the lymphatics may ooze fluid into the peritoneal space. The liver’s blood supply is unusual, in that there are two inward sources (see Fig. 26.20):
STOMACH Alcohol (20% of total) SMALL INTESTINE Calcium, magnesium, iron
Glucose Water-soluble vitamins Alcohol (80% of total) Sodium, potassium
Fat-soluble vitamins Amino acids Fats Water 90%
Vitamin B12
Bile
COLON Sodium, potassium Water 9%
Acids and bases
RECTUM
Faeces FIGURE 26.18
Absorption sites in the digestive tract. The size of the arrow at each site indicates the relative amount of absorption of a particular substance at that site. Notice that most absorption occurs in the intestines, particularly the small intestine.
alkaline fluid that neutralises chyme, creating a duodenal pH that supports enzymatic action.
The liver
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The liver weighs 1200–1600 grams. It is located under the right side of the diaphragm and is divided into right and left lobes (see Fig. 26.19). The falciform ligament separates the right and left lobes and attaches the liver to the anterior abdominal wall. The round ligament (ligamentum teres) extends along the free edge of the falciform ligament, extending from the umbilicus to the inferior surface of the liver. The coronary ligament branches from the falciform ligament and extends over the superior surface of the right and left lobes, binding the liver to the inferior surface of
• the hepatic artery branches from the abdominal aorta and provides a substantial amount of oxygenated blood at the rate of 400–500 mL/min (about 25% of cardiac output); and • the hepatic portal vein receives deoxygenated blood from the inferior and superior mesenteric veins and the splenic vein, and delivers about 1000–1200 mL/min to the liver. This portal venous blood constitutes 70% of the blood supply to the liver. The blood in the hepatic portal vein contains all the substances that have been absorbed from the digestive tract, including nutrients, water and other substances such as toxins, drugs and bacteria. The liver receives the nutrients absorbed by the small intestine and metabolises them for use by the body’s cells. It then releases the nutrients into the bloodstream or stores them for later use. Within the liver lobes are multiple, smaller anatomical units called liver lobules (see Fig. 26.21). They are formed of plates of hepatocytes (literally ‘liver cells’), which are the functional cells of the liver. These cells can regenerate. In fact, an individual can survive even if more than half of the liver is removed, as the liver will grow back to its original size. Small channels (bile canaliculi) conduct bile, which is produced by the hepatocytes, outwards to the bile ducts and eventually drain into the common bile duct (see Fig. 26.21). This duct empties bile into the duodenum through an opening called the hepatopancreatic sphincter (sphincter of Oddi; see Fig. 26.22). Small capillaries, or sinusoids (leaky capillaries), are located between the plates of hepatocytes. They receive a mixture of blood from branches of the hepatic artery and hepatic portal vein. The liver has a pivotal function in processing the nutrient-rich blood from the digestive tract and therefore the hepatocytes have very rich access to the blood from these sinusoids. Blood from the sinusoids drains to a central vein in the middle of each liver lobule. Venous blood from all the lobules then flows into the hepatic vein, which empties blood away from the liver into the inferior vena cava. The sinusoids of the liver lobules are lined with highly permeable endothelium. This permeability enhances the transport of nutrients from the sinusoids into the hepatocytes, where they are metabolised. Between the endothelial lining of the sinusoid and the hepatocyte is the Dissé space, which drains interstitial fluid into the hepatic lymph system. The sinusoids are also lined with phagocytic Kupffer cells (tissue macrophages), which are part of the mononuclear phagocyte system. They remove foreign substances from the blood and trap bacteria. Hepatic stellate cells are vitamin A-storing cells located in the Dissé space. These cells regulate the contractility of sinusoids. In response
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BOX 26.1
Major nutrients absorbed in the small intestine
Water and electrolytes • Approximately 90% of the water that enters the gastrointestinal tract is absorbed in the small intestine. • Sodium is actively transported across cell membranes; sodium absorption is enhanced by glucose transport. • Potassium is absorbed passively. Carbohydrates • Salivary and pancreatic amylases break down starches to smaller carbohydrates (sucrose, maltose, lactose) in the stomach and duodenum; brush-border enzymes digest them further in the small intestine so they can be absorbed by diffusion. • The simple carbohydrates, glucose, galactose and fructose, are absorbed into the bloodstream. • Undigestible carbohydrates (fibre) stimulate large intestine motility. Proteins • Approximately 95% of protein is absorbed; major digestion is accomplished in the small intestine by the pancreatic enzymes trypsin, chymotrypsin and carboxypeptidase. • Brush-border enzymes break down proteins into smaller peptides and amino acids that can cross cell membranes. Fats • Emulsification prevents the small fat particles from reforming into fat droplets, while lipolysis breaks them down into diglycerides, monoglycerides, free fatty acids and glycerol. • The small fatty molecules are organised into micelles (lipid aggregates dispersed in aqueous solution), which can then be absorbed through the intestinal epithelium. • Triglycerides and phospholipids become chylomicrons (small lipoprotein particles), which eventually enter the systemic circulation. Minerals • Calcium is absorbed primarily in the duodenum. • Magnesium is absorbed in the jejunum and ileum. • Phosphate is absorbed in the small intestine. • Iron is absorbed in the duodenum and jejunum; vitamin C facilitates. Vitamins • Vitamins are absorbed mainly by active transport, with vitamin B12 bound to intrinsic factor and absorbed in the terminal ileum.
to injury, they proliferate and secrete proteins inducing hepatic fibrosis which leads to increased intrahepatic resistance to blood flow resulting into portal hypertension (refer to Chapter 27).7 The healthy adult liver contains large populations of resident immune cells which play important roles in liver regeneration, maintain organ and systemic homeostasis, and mobilise inflammatory mechanisms to protect against infection, metastasis and tissue damage.8
Secretion of bile
The liver hepatocytes assist intestinal digestion by producing and secreting 700–1200 mL of bile per day. Bile is an alkaline (bicarbonate-rich), bitter-tasting, yellowish green fluid that contains bile salts, cholesterol, bilirubin, electrolytes and water. It is formed by hepatocytes and secreted into the canaliculi. Bile salts, which are produced from cholesterol, are required for the intestinal emulsification of fats into small spheres known as micelles. These micelles can then be absorbed into the lacteals of the lymphatic
system and then into the systemic blood circulation (see below). Having facilitated fat emulsification and absorption, most bile salts are actively absorbed in the terminal ileum and returned to the liver through the portal circulation for resecretion. The recycling of bile salts is termed the enterohepatic circulation (see Fig. 26.23). The cycle of hepatic secretion, intestinal absorption and hepatic resecretion of bile salts completes the enterohepatic circulation.
Vascular and haematological functions
Because of its extensive vascular network, the liver can store a large volume of blood. The amount stored at any one time depends on pressure relationships in the arteries and veins. The liver can also release blood to maintain systemic circulatory volume in the event of haemorrhage. Kupffer cells in the sinusoids of the liver remove bacteria and foreign particles from the hepatic portal blood. Because the liver receives all the venous blood from the
CHAPTER 26 The structure and function of the digestive system
A A
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Inferior vena cava
Left lobe Right lobe
Falciform ligament
B
Inferior vena cava
Caudate lobe
Round ligament Gallbladder
Left lobe
Right lobe proper
Falciform ligament Hepatic artery Hepatic portal vein Common hepatic duct Quadrate lobe
Gallbladder
FIGURE 26.19
Gross structure of the liver. A Anterior view. B Inferior view.
gastrointestinal tract, Kupffer cells play an important role in destroying bacteria and preventing infections from the intestines reaching the rest of the body. Kupffer cells play an important role in the clearance of senescent and damaged erythrocytes. They also store haemosiderin, an iron-containing pigment from the haemoglobin of disintegrated red blood cells. The liver also has haemostatic functions, in that it produces clotting factors necessary for coagulation — namely prothrombin, fibrinogen and clotting factors I, II, VII, IX and X (see Chapter 16). Vitamin K is a fat-soluble vitamin essential for the production of clotting factors. Because bile salts are needed for the absorption of fats, vitamin K absorption depends on adequate bile production in the liver. In this way, normal liver function is necessary for adequate absorption of vitamin K to allow adequate circulating levels of clotting factors.
Metabolism of nutrients FATS
Some fatty molecules are absorbed into the lacteals (lymphatic capillaries in the intestinal villi) and carried via the lymphatic system and then emptied directly into the bloodstream (near the heart) to travel around the circulation. Almost all substances other than fats, including proteins, carbohydrates, water, vitamins, minerals, drugs
and contaminants, are absorbed from the small intestine to the blood, which is processed by the liver before reaching the rest of the circulation. After being absorbed by lacteals in the intestinal villi, the fats enter the liver through the lymphatics, primarily as triglycerides. These can be used to produce metabolic energy (adenosine triphosphate, ATP) or they can be released into the bloodstream as lipoproteins (lipids bound to proteins). Blood carries the lipoproteins to adipose cells for storage. The liver also produces phospholipids and cholesterol, which are needed for the hepatic production of bile salts, steroid hormones, components of cell membranes and other special molecules. Fats can also be produced from carbohydrate and protein, primarily in the liver. The role of lipids in the body is summarised in Table 26.4. PROTEINS
Protein production (synthesis) requires the presence of all the essential amino acids — obtained only from food — as well as nonessential amino acids (those that can be produced by the body). Proteins perform many important roles in the body; these are summarised in Table 26.4. Amino acids can be used for energy but first ammonia needs to be removed within the liver (known as deamination). Ammonia is toxic to the body and needs to be removed. It is converted
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Sinusoid Central veins Plates of hepatic cells
Bile duct
Hepatic artery
Branch of portal vein Branch of hepatic artery
Hepatocytes Bile canaliculi
FIGURE 26.21 FIGURE 26.20
Hepatic circulation. Substances are absorbed from the digestive tract into capillaries, which lead into the hepatic portal vein. This nutrient-rich blood enters the liver to be filtered. The other blood supply to the liver is via the hepatic artery, bringing oxygenated blood from the heart. All blood empties from the liver into the hepatic vein, which drains to the vena cava. Note that some small fatty molecules are absorbed into the lacteals to reach the lymphatic system, which does not travel through the hepatic portal circulation. Instead, the contents of lymphatic ducts empty directly into the bloodstream near the vena cava.
Diagrammatic representation of a liver lobule. A central vein is located in the centre of the lobule with plates of hepatic cells disposed radially. Branches of the portal vein and hepatic artery are located on the periphery of the lobule, and blood from both perfuses the sinusoids. Peripherally located bile ducts drain the bile canaliculi that run between the hepatocytes.
Right hepatic duct
to urea by the liver and passes into the blood to be excreted by the kidneys. Depending on the need, proteins may be converted to fatty acids for fat production and storage or used to provide energy for the liver cells. The plasma proteins, including albumins and globulins (which are important proteins involved in transport, enzyme and fluid regulation) are produced by the liver. They play an important role in maintaining blood volume and pressure by maintaining plasma oncotic pressure (see Chapter 22 for more details). The liver also produces several nonessential amino acids and serum enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP). Common tests of liver function are listed in Table 26.5. When there is suspected damage to the liver or metabolic processes are altered (discussed in Chapter 27), liver function tests are often performed. These tests measure a broad range of hepatocyte and biliary functions to provide an overview of liver function. CARBOHYDRATES
The liver contributes to the stability of blood glucose levels by releasing glucose during hypoglycaemia (low blood glucose) and taking up glucose during hyperglycaemia (high
Left hepatic duct Common hepatic duct
Cystic duct Gallbladder
Common bile duct
Pancreatic duct Portion of descending duodenum
Hepatopancreatic sphincter (sphincter of Oddi)
FIGURE 26.22
Gallbladder and extrahepatic biliary ducts. Bile that is produced by the liver travels through the common hepatic duct and reaches the gallbladder for storage. When released from the gallbladder, bile travels through the cystic duct, common bile duct, and the hepatopancreatic sphincter (sphincter of Oddi) to reach the small intestine.
CHAPTER 26 The structure and function of the digestive system
783
Liver and are returned to
secretes Bile
Hepatic portal vein
which is stored in
which drain into the
Gallbladder until needed, then secreted into the
Bile salts absorbed into capillary absorbed (with other nutrients) into capillaries
Duodenum
FIGURE 26.23
The enterohepatic circulation. Components of bile are absorbed into the circulation and returned to the liver, and are then recycled in the subsequent formation of bile.
TABLE 26.4 The importance of proteins, carbohydrates and fats in the body PROTEINS
• Contraction of muscle (actin and myosin are proteins) • Energy (proteins can be metabolised for energy) • Fluid balance (the protein albumin is a major source of plasma oncotic pressure) • Protection (antibodies and complement are proteins associated with immunity) • Regulation (enzymes regulate chemical reactions, while hormones regulate many physiological processes) • Structure (collagen fibres provide structural support to many parts of the body; keratin strengthens skin) • Transport (haemoglobin and plasma proteins are transport molecules, while proteins in cell membranes control movement of materials into and out of cells) CARBOHYDRATES
• Energy (glucose is the main energy source for most body cells; neurons and red blood cells are dependent on glucose) • Storage (energy stores in the liver are released into the bloodstream when needed) FATS
• Structure (cell membranes are predominantly made of lipid molecules) • Insulation (myelination of neurons consists of lipids, while fat stores under the skin provide insulation from heat loss) • Protection (fatty deposits around soft tissues provide physical protection) • Storage (energy is stored in lipid molecules)
blood glucose) and storing it as glycogen (glyconeogenesis) or converting it to fat. When glucose needs to be released into the blood to increase blood glucose levels, the two main options are: 1 glycogenolysis — the breakdown of glycogen stores to release glucose 2 gluconeogenesis (the creation of new glucose) — when all glycogen stores have been used, the liver can convert amino acids and glycerol to glucose. The roles of carbohydrates are summarised in Table 26.4.
Storage of minerals and vitamins
The liver stores certain vitamins and minerals, including iron and copper, in times of excessive intake and releases them in times of need. The liver can store vitamins B12 and D for several months and vitamin A for several years. The liver also stores vitamins E and K. The liver is critical for maintaining iron homeostasis, and hepatocytes are the main storage site of iron in the body.9 Iron is stored in the liver as ferritin, an iron–protein complex, and is released as required for red blood cell
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TABLE 26.5 Selected tests of liver function TEST
NORMAL VALUE
CLINICAL SIGNIFICANCE
Alkaline phosphatase (ALP)
25–100 U/L
Increases with biliary obstruction and cholestatic hepatitis
Aspartate aminotransferase (AST)
0–40 U/L
Increases with hepatocellular injury
Alanine aminotransferase (ALT)
0–35 U/L
Increases with hepatocellular injury
Lactic dehydrogenase (LDH)
110–230 U/L
Elevated with hypoxic and primary liver injury
Gamma glutamyl transferase (GGT)
Females 0–30 U/L Elevated with alcohol consumption (and cholestatic disease)
Serum enzymes
Males 0–50 U/L
Bilirubin metabolism Serum bilirubin total
0–20 µmol/L
Increases with biliary obstruction, hepatocellular injury or obstruction, haemolysis (lysis of red blood cells)
Albumin
32–45 g/L
Reduced with hepatocellular injury
Globulin
25–35 g/L
Increases with hepatitis
Prothrombin time (PT)
10–14 sec
Increases with chronic liver disease (cirrhosis) or vitamin K deficiency
Activated partial thromboplastin time (aPTT)
25–40 sec
Increases with severe liver disease or heparin therapy
Serum proteins
Blood-clotting functions
production. In addition, hepatocytes produce transferrin and ceruloplasmin, the main proteins involved in iron metabolism. Kupffer cells are the primary site of iron recycling for erythropoiesis. The liver also plays an important role in copper homeostasis. Copper is utilised by the liver to produce cuproproteins; excess levels of copper are physiologically secreted from the liver to the biliary system.9
Metabolism of bilirubin
Bilirubin is a byproduct of the destruction of aged red blood cells. It gives bile a greenish-black colour, and in large amounts produces the yellow tinge of the skin and eyes due to jaundice (a yellowish colour due to deposition of bilirubin). Aged red blood cells are taken up and destroyed by macrophages of the mononuclear phagocyte system, primarily in the spleen and liver (by the Kupffer cells). Within these cells, haemoglobin is separated into its component parts: haem and globin. The globin component is further degraded into its constituent amino acids, which are recycled to form new protein. The iron from the haem component can be recycled — by being either stored in the liver until required or used by the bone marrow to make new red blood cells. Another product derived from haem is bilirubin. The liver metabolises this bilirubin and secretes the waste products, which form the pigments of the bile. It is important to distinguish between bile salts, which assist fat digestion, and bile pigments, which contain the wastes of bilirubin. After being secreted by the bile into the duodenum, the bilirubin reaches the ileum and colon, where it is further
processed by bacteria and converted to urobilinogen. Most of the urobilinogen is absorbed into the bloodstream and then excreted in the urine, and a small amount is eliminated in faeces.
Metabolic detoxification
The liver metabolises substances produced by the body (such as hormones), as well as those that have been taken into the body (such as drugs), to make them less toxic or less biologically active. This process, called metabolic detoxification (or biotransformation), facilitates their intestinal and renal excretion. In this way alcohol, barbiturates, amphetamines, steroids and hormones (including oestrogens, aldosterone, antidiuretic hormone and testosterone) are metabolised or detoxified, preventing excessive accumulation and adverse effects. Although metabolic detoxification is usually protective, sometimes the end products become toxins. For example, the end products of alcohol metabolism are acetaldehyde and hydrogen. Excessive intake of alcohol over a prolonged period causes these end products to damage hepatocytes. Acetaldehyde damages cellular mitochondria and the excess hydrogen promotes fat accumulation. Therefore, alcohol impairs the liver’s ability to function (discussed further in Chapter 27). LIVER IMMUNITY
The healthy adult liver contains a diverse range of resident immune cells that play essential roles in immune regulation, tissue repair and liver regeneration. Kupffer cells, which are
CHAPTER 26 The structure and function of the digestive system
specialised tissue macrophages, account for 80% to 90% of the total population of fixed macrophages in the body. These cells secrete a variety of toxic and vasoactive substances that are involved in host defence. Kupffer cells play a central role in liver regeneration via release of inflammatory mediators such as IL-6 and TNFα, which promote hepatocyte proliferation. Other cells are also involved in liver immunity. Star-shaped hepatic stellate cells are important sources in maintaining homeostasis of the hepatic sinusoids, particularly in response to liver injury. Intrahepatic lymphocytes, including natural killer cells of the liver, have anti-tumour activity. There are also other subpopulations of lymphocytes, including some T cells, that reside in the liver. The liver is constantly exposed to dietary and gut-derived bacterial products resulting in a persistent, regulated immune response, that is essential to maintain liver homeostasis. The liver protects the rest of the body from excessive immune activation by providing detoxification of blood from the gut as well as immunosurveillance for pathogenic infections and malignant cells. Failure to clear such dangerous stimuli and resolve inflammation leads to disrupted tissue homeostasis, chronic infection, or pathological inflammation which can progress to fibrosis, cirrhosis, tumour growth and liver failure.8
The gallbladder
The gallbladder is a sac-like organ on the inferior surface of the liver. Its primary function is to store and concentrate bile between meals. Bile flows from the liver through the right or left hepatic duct into the common hepatic duct to the closed sphincter of Oddi (see Fig. 26.22); this controls flow into the duodenum and prevents backflow of duodenal contents into the pancreatobiliary system. Bile then flows through the cystic duct into the gallbladder, where it is concentrated and stored. The mucosa of the gallbladder wall readily absorbs water and electrolytes, leaving a high concentration of bile salts, bile pigments and cholesterol. The gallbladder holds about 90 mL of bile. Bile salts play a key role in fat digestion by emulsification (breaking down into microscopic droplets) of lipids. This makes the lipids available for digestion by enzyme lipases (using lipolysis or lipid hydrolysis). The products of lipolysis form water-soluble aggregates known as micelles. Lipids such as fatty acids, cholesterol and monoglycerides form the core of the micelle, and the bile salts form the outer shell. Micelles readily diffuse through the aqueous brush border of the intestine; the fat products then absorbed by the intestinal mucosa, while the bile salts are absorbed into the blood circulation and returned to the liver. Bile salts are also critical for absorption of the fat-soluble vitamins. Within 30 minutes after eating, the gallbladder begins to contract and the sphincter of Oddi relaxes, forcing bile into the duodenum. During the cephalic and gastric phases of digestion, gallbladder contraction is facilitated by the parasympathetic nervous system (via branches of the vagus
785
nerve). Hormonal regulation of gallbladder contraction is derived from the release of cholecystokinin and motilin secreted by the duodenal mucosa in the presence of fat. Vasoactive intestinal peptide, pancreatic polypeptide and sympathetic nerve stimulation relax the gallbladder.
The pancreas
The pancreas is approximately 20 cm long, with its head tucked into the curve of the duodenum and its tail touching the spleen. The body of the pancreas lies deep in the abdomen, behind the stomach (see Fig. 26.24). The pancreas is unique in that it has both endocrine and exocrine functions. The endocrine function is to secrete hormones directly into the bloodstream: mainly insulin and glucagon. Pancreatic hormones are discussed in Chapter 10. The exocrine function consists of the secretions that empty directly into the digestive tract (and thus are not secreted into the bloodstream) — this is the function of the pancreas that we consider in this section on the gastrointestinal tract. The pancreas is composed of exocrine cells, acini (plural; singular = acinus; adjective = acinar) and networks of ducts that secrete enzymes and alkaline fluids with important digestive functions. The acinar cells are organised into spherical lobules around small secretory ducts (see Fig. 26.24). Secretions drain into a system of ducts that leads to ampulla of Vater (also known as the hepatopancreatic ampulla) where the pancreatic duct and bile duct meet to empty into the duodenum through the hepatopancreatic sphincter. The aqueous secretions of the exocrine pancreas contain potassium, sodium, bicarbonate and chloride. The highly alkaline (bicarbonate-rich) pancreatic juice neutralises the acidic chyme that enters the duodenum from the stomach and provides the alkaline medium needed for the actions of digestive enzymes and intestinal absorption of fat. Because eating stimulates the flow of pancreatic juice, the juice is most alkaline when it needs to be: during digestion. The pancreas is a major source of enzymes for the gastrointestinal tract, as enzymes involved in the chemical digestion of the three main nutrients (proteins, fats and carbohydrates) arise from the pancreas. There are a few enzymes that digest protein, such as trypsin — this is produced in an inactive form, to protect the pancreas from the digestive effects of its own enzymes. Pancreatic lipase digests lipids (fats), while pancreatic amylase digests carbohydrates (remember, salivary amylase is also involved in carbohydrate digestion) (see Table 26.1). Secretions from the pancreas are controlled by hormonal and vagal stimuli. As chyme enters the duodenum, its acidity (pH of 4.5 or less) stimulates the S cells (secretin-producing cells) of the duodenum to release secretin, which is absorbed by the intestine and delivered to the pancreas in the bloodstream. In the pancreas, secretin stimulates the acinar and duct cells to secrete the bicarbonate-rich alkaline fluid that neutralises chyme and prepares it for enzymatic digestion. Secretin also inhibits the actions
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Neck of gallbladder Body of gallbladder
Right and left hepatic ducts
Cystic duct
Fundus of gallbladder
Common hepatic duct Common bile duct Duodenum
Accessory Minor pancreatic duct duodenal Body of pancreas papilla
Ampulla of Vater
Tail of pancreas
Pancreatic duct
Hepatopancreatic sphincter (sphincter of Oddi)
Jejunum Head of pancreas
Alpha cells (secrete glucagon)
Beta cells (secrete insulin)
Pancreatic islet
Duct cells secrete bicarbonate Vein
Acinar cells secrete enzymes
Pancreatic duct (to duodenum)
Centroacinar cells secrete electrolytes and water FIGURE 26.24
Associated structures of the gallbladder, pancreas and pancreatic acinar cells and duct. Bile from the liver and gallbladder travels through the common bile duct towards the hepatopancreatic sphincter. Pancreatic juice travels through the pancreatic duct and accessory pancreatic duct towards the hepatopancreatic sphincter. When the hepatopancreatic sphincter opens, bile and pancreatic juice enters the duodenum.
of gastrin, thereby decreasing gastric acid secretion and motility. The overall effect is to neutralise the contents of the duodenum. Enzymatic secretion follows, stimulated by cholecystokinin and acetylcholine. Cholecystokinin is
released in the duodenum in response to the essential amino acids and fatty acids already present in chyme. Acetylcholine is released from pancreatic branches of the vagus nerve during the cephalic phase of digestion. Cholecystokinin and acetylcholine both act on the
CHAPTER 26 The structure and function of the digestive system
acinar cells, causing enzyme release. Once in the small intestine, activated pancreatic enzymes inhibit the release of more cholecystokinin and acetylcholine. This feedback mechanism inhibits the secretion of more pancreatic enzymes. Pancreatic polypeptide is released after eating and inhibits postprandial (after a meal) pancreatic exocrine secretion.
FO CUS O N L E A R N IN G
1 Explain the blood supply into and out of the liver. 2 Describe the internal structure of the liver. 3 Explain how the liver produces bile and the metabolism of bilirubin. 4 Discuss the role of the liver in the metabolism and storage of nutrients. 5 Outline the importance of the liver in metabolic detoxification and immunosurveillance. 6 Discuss the structure and function of the gallbladder. 7 Explain the different secretions of the pancreas, including the enzymes.
Inferior vena cava
Portal vein
Superior mesenteric artery Hepatic (right colic) flexure
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The large intestine Anatomy and physiology of the large intestine
The large intestine (or large bowel) has a relatively large diameter of 7 cm, is approximately 1.5 m long and consists of the caecum, appendix, colon (ascending, transverse, descending and sigmoid), rectum and anal canal (see Fig. 26.25). The caecum is a pouch that receives chyme from the ileum. Attached to it is the vermiform appendix, an appendage having only little function in immunity. From the caecum, chyme enters the colon, which loops upwards, traverses the abdominal cavity and descends to the anal canal. The four parts of the colon are the ascending colon, transverse colon, descending colon and sigmoid colon. Two sphincters control the flow of intestinal contents through the caecum and colon: the ileocaecal valve, which admits chyme from the ileum to the caecum, and the O’Beirne sphincter, which controls the movement of wastes from the sigmoid colon into the rectum. A thick (2.5–3 cm) portion of smooth muscle surrounds the anal canal, forming the internal anal sphincter. Overlapping it distally is the striated muscle of the external anal sphincter. In the caecum and colon, the longitudinal muscle layer consists of three longitudinal bands called teniae coli. They
Transverse Aorta Splenic colon vein
Splenic (left colic) flexure
Inferior mesenteric artery and vein
Ascending colon Descending colon Ileocaecal valve
Caecum Appendix
Mesentery Ileum
Rectum External anal sphincter muscle
Sigmoid artery and vein
Superior rectal artery and vein Anus
Sigmoid colon
FIGURE 26.25
Divisions of the large intestine. Digested food passes through the caecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum to reach the anus.
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are shorter than the colon and give it a gathered appearance. The circular muscles of the colon separate the gathers into outpouchings called haustra (plural; singular = haustrum). The haustra become more or less prominent with the contractions and relaxations of the circular muscles. The mucosal surface of the colon has rugae (folds), particularly between the haustra and Lieberkühn crypts (intestinal glands), but no villi. Columnar epithelial cells and mucus-secreting goblet cells form the mucosa throughout the large intestine. The columnar epithelium absorbs fluid and electrolytes and the mucus-secreting cells lubricate the mucosa. The colon has a two-layered mucus system: the inner mucus layer is dense and attached to the epithelium, it is impervious to bacteria; the outer mucus layer is loose and unattached, it serves as the habitat and a partial food source for bacteria.5 Most of the movements within the large intestine involve segmentation. The circular muscles contract and relax at different sites, shuffling the intestinal contents back and forth between the haustra, most commonly during fasting. The movements massage the intestinal contents, called the faecal mass at that point, and facilitate the absorption of water. Insoluble fibre, present in the faecal mass, draws some of the water back into the intestinal contents, increasing volume and weight of the faecal mass that stimulates muscle contractions. Soluble fibre in the faecal mass is metabolised by intestinal bacteria in the colon, and converted into a gel that provides lubrication and easy passage of the faeces. Propulsive movement occurs with the proximal-to-distal contraction of several haustral units. Peristaltic movements also occur and promote the emptying of the colon — these mass movements occur a few times per day. The gastrocolic reflex initiates propulsion in the entire colon, usually during or immediately after eating, when chyme enters from the ileum. This reflex causes the faecal mass to pass rapidly into the sigmoid colon and rectum, stimulating defecation (see section below and Fig. 26.26). Gastrin may participate in stimulating this reflex.
Intestinal bacteria
The number of bacteria increases from the stomach to the distal colon. The stomach is relatively sterile because of the secretion of acid that kills ingested pathogens or inhibits bacterial growth. Bile salt secretion, intestinal motility and antibody production suppress bacterial growth in the duodenum, and in the duodenum and jejunum there is a low concentration of aerobes, primarily streptococci, lactobacilli, staphylococci and enterobacteria. Anaerobes are found distal to the ileocaecal sphincter but not proximal to the ileum. They constitute about 95% of the faecal flora in the colon and contribute one-third of the solid bulk of faeces. Bacteroides, clostridia, anaerobic lactobacilli and coliforms are the most common microorganisms from the ileum to the caecum. The intestinal bacteria survive on the indigestible carbohydrates (fibre) within the large intestine. They ferment these carbohydrates, releasing large amounts of gases (some of which exits the body via the rectum, known as flatulence).
The bacteria perform some functions that are beneficial to the human host, including releasing some vitamins (some of the B group vitamins, as well as vitamin K), which can then be absorbed into the bloodstream and contribute to nutrition. The bacteria also have a role in the metabolism of bile salts, oestrogens, androgens, lipids, various nitrogenous substances and drugs, and protection against infection. The normal flora do not have the virulence factors associated with pathogenic microorganisms, thus permitting immune tolerance.10 The balance between gut microbiota and the host is maintained by several mechanisms including gut secretions (gastric acid, biliary salts, mucus), mucosal barrier, intestinal motility, mucosal and systemic immunity, and interactions between different strains of bacteria. Many factors, such as unhealthy diet, ageing, drugs (e.g. steroids or proton-pump inhibitors), and various (gastrointestinal, neurologic, infectious, vascular) diseases can disrupt this homeostasis.6 Infections of the lower gastrointestinal tract occur by three major mechanisms: proliferation or overgrowth of bacteria, perforation of the intestine and contamination of neighbouring structures.
Defecation reflex
The movement of faeces into the sigmoid colon and rectum stimulates the defecation reflex (rectal reflex). The rectal wall stretches and the constricted internal anal sphincter (smooth muscle with autonomic nervous system control) relaxes, creating the urge to defecate (see Fig. 26.26). The defecation reflex can be overridden voluntarily by contraction of the external anal sphincter and muscles of the pelvic floor. The rectal wall gradually relaxes, reducing tension and the urge to defecate passes. Retrograde contraction of the rectum may displace the faeces out of the rectal vault until a more convenient time for evacuation. Pain or fear of pain associated with defecation (e.g. due to haemorrhoids) can inhibit the defecation reflex. Squatting and sitting facilitate defecation because these positions straighten the angle between the rectum and anal canal and increase the efficiency of straining (increasing intraabdominal pressure). Intraabdominal pressure is increased by initiating the Valsalva manoeuvre — that is, inhaling and forcing the diaphragm and chest muscles against the closed glottis to increase both intrathoracic and intraabdominal pressure, which is transmitted to the rectum. Rectal valves are projections of tissue into the lumen of the rectum — these valves have the important function of helping to hold the faeces, while allowing gases to escape.
Digestion in the large intestine
The majority of nutrient absorption has already occurred in the small intestine, so there is no substantial digestion remaining in the large intestine. Although the bacteria of the large intestine digest the carbohydrates as their own fuel source, this does not provide carbohydrates for the human host.
CHAPTER 26 The structure and function of the digestive system
6
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Motor cortex
Somatosensory cortex
Thalamus Sensory neurons Motor neurons to skeletal muscles (voluntary control) Parasympathetic motor neurons (involuntary control) Sympathetic trunk
Spinal cord
Sympathetic motor neurons (involuntary control) Interneurons Enteric neurons
5
Inferior mesenteric ganglion
8
Lumbar region Pelvic ganglion
2
Involuntary motor (parasympathetic and sympathetic) nerve fibres to the sigmoid colon
3 Sacral region
4
Sigmoid colon
7
Voluntary motor nerve fibres to external sphincter (pudendal nerve)
Involuntary motor (parasympathetic and sympathetic) nerve fibres to the rectum and external anal sphincter
1
Stretch receptors in the wall
Rectum Internal anal sphincter (smooth muscle)
External anal sphincter (skeletal muscle)
FIGURE 26.26
Defecation. 1 Stretching (distension) of the rectum stimulates stretch receptors on the rectum wall to initiate action potentials. 2 Nerve impulses send afferent (sensory) signals to myenteric plexus located within intestinal wall and to the sacral region of the spinal cord. 3 In the spinal cord sensory neurons transmit information to: (a) the parasympathetic motor (efferent) neurons; and (b) the cerebral cortex. 4 Activation of parasympathetic neurons initiate a spinal reflex (involuntary response) in which efferent signals to the sigmoid colon and rectum stimulate muscle contractions which causes enhanced peristalsis of faeces and relaxation of the internal anal sphincter (smooth muscle). 5 Afferent signals to the somatosensory cortex result in awareness of the urge to defecate. 6 Neurons in motor cortex provide voluntary (conscious) control of the defecation by sending impulses to the spinal cord motor neurons innervating external anal sphincter (skeletal muscle). 7 Excitatory signals from voluntary motor neurons induce contraction of external anal sphincter to prevent defecation. Inhibitory signals from voluntary motor neurons allow the external anal sphincter to relax so that faeces may pass. 8 Sympathetic neurons innervating internal anal sphincter provide involuntary control; efferent signals to the sigmoid colon and rectum inhibit muscle contractions which causes inhibition of peristalsis and constriction of the internal anal sphincter when there is no need to defecate.
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Absorption in the large intestine
The large intestine absorbs water and some fatty acids (produced by bacterial fermentation). Absorption occurs in the caecum, ascending colon, transverse colon and descending colon. Vitamins B and K (produced by the bacteria) are also absorbed here. By the time the faecal mass enters the sigmoid colon, the mass consists entirely of wastes and is called faeces (or stools), consisting of food residue, unabsorbed gastrointestinal secretions, shed epithelial cells and bacteria. Absorption of some drugs can occur by rectal administration, whereby the drugs are absorbed quickly into the bloodstream.
Fluid movements in the digestive system
Approximately 8.5 L of fluid enters the digestive system every day (see Fig. 26.27): 2 L is ingested and the remaining 6.5 L consists of secretions (from the saliva, stomach, bile, pancreas and small intestine). Of this volume, 99% is absorbed: 90% (7.6 L) in the small intestine and 9% (0.8 L) in the colon. The remaining 100 mL of water is excreted daily in the faeces. The amount of fluid within the digestive system, especially the lower intestine, is important. Diarrhoea
NORMAL SECRETIONS/ ABSORPTION/EXCRETION Saliva 1.5 L
Food 2.0 L
Stomach 2.0 L Bile 0.5 L Pancreas 1.5 L
causes large water loss and can lead to dehydration, particularly in the young and the elderly. There is a continual interchange of fluids between the gastrointestinal tract, blood circulation and lymph with a free interchange of nutrients and other dissolved substances. Fluid from the abdominal part of the digestive tract (except the lower rectum), spleen, pancreas, and gallbladder returns to the circulation by the venous capillaries and veins of the portal system. The blood in the portal system conveys absorbed substances from the intestinal tract to the liver for storage, alteration, or detoxification. From the liver the blood flows through the hepatic vein to the inferior vena cava. Fluid that has been absorbed into the lymphatic system (known as lymph) is emptied into the systemic venous circulation (at the thoracic duct). Lymph formed in the digestive system (called chyle) appears milky white and is rich in lipids, fat-soluble vitamins, and water-insoluble molecules.
The gastrointestinal tract and immunity
The gastrointestinal tract is an important component of the body’s immune system. The intestine possesses the largest mass of lymphoid tissue in the human body, often referred to as gut-associated lymphoid tissue (GALT). The mucosa of the intestine covers a large surface area and mucosal secretions produce antibodies, particularly IgA, and enzymes that provide defense against microorganisms. Paneth cells, located near the crypts of Leiberkühn, produce defensins and other antibiotic peptides and proteins important to mucosal immunity. Peyer’s patches are lymph nodules containing collections of lymphocytes, plasma cells, and macrophages. They locate in the mucosa of the small intestine and produce immunoglobulins. M or microfold cells are a specific cell type in the intestinal epithelium that endocytose a variety of protein and peptide antigens. Instead of digesting these proteins, M cells transport them into the underlying tissue, where they are taken up by local dendritic cells and macrophages and presented to T cells in the GALT. In addition to the GALT, mesenteric lymph nodes that receive lymph draining from the gut and Kupffer cells (phagocytic cells in the liver) play important roles in protecting the body against pathogens.
Small intestine 1.0 L
FOCU S ON L EA RN IN G Anus
Excreted 0.1 L
1 Describe the anatomy of the large intestine. 2 Discuss the motility of the large intestine. 3 Explain the role of intestinal bacteria.
FIGURE 26.27
Normal intake, absorption, secretion and excretion of water. Approximately 2.0 litres of fluid is ingested into the digestive tract each day, with other sources of fluid entering the digestive tract from secretions. The excretion of water via the digestive tract is only approximately 0.1 litres, as the majority of fluid excretion from the body occurs in the urine.
4 Describe the defecation reflex. 5 Explain the digestion and absorption of nutrients in the large intestine. 6 Discuss fluid balance in the digestive system (the amount of fluid ingested, absorbed and secreted).
CHAPTER 26 The structure and function of the digestive system
An overview of nutrition The main nutrients that the body needs are proteins, carbohydrates and fats. In addition, water needs to be consumed in relatively large amounts. Water is discussed fully in Chapters 28 and 29. In this section, we briefly examine human nutrition. Protein is found in highest amounts in animal products; sources of protein in the diet include meat, fish, poultry, eggs, dairy and cereals. Protein is digested and broken down into amino acids, which are then processed by the liver to produce new proteins that have a wide variety of uses in the human body (see Table 26.4). Dietary carbohydrates are mainly of plant origin. Starch (a complex carbohydrate or polysaccharide) is found in cereals, grains, fruits and vegetables. Fibre (or non-starch polysaccharide) is a type of carbohydrate that we are unable to break down and absorb, and it has an important role in maintaining the health of the large intestine (see Chapter 27). Sources of dietary fibre include wholemeal and wholegrain breads and cereals, oats, fruits and vegetables. The sugars, or simple carbohydrates, are not often found in natural foods, other than fructose in honey; they are used in the production of processed foods, such as soft drinks, ice-cream, cakes and biscuits. Carbohydrates are digested and broken down into simple sugars (monosaccharides), namely glucose, galactose and fructose. These are used as an energy source in the form of glucose (see Table 26.4). Fats (or lipids) in the diet are mainly in the form of triglycerides, although we also consume other types such as cholesterol and phospholipids. Different chemical structures of fats include saturated fats (from animal sources, such as butter, cream and fat in meat), monounsaturated fats (usually from plant sources, such as olive oil) and polyunsaturated fats (further subdivided into types including omega-3 (from fish) and omega-6 (from sesame, linseed and peanut oils)). Trans fatty acids are most prominent in our diet in margarines. Further details of some types of dietary fats are given in Box 26.2. Fats are broken down to triglycerides, and small lipid molecules are processed by the liver for a number of functions in the body (see Table 26.4). Energy intake that is beyond the needs of the body is stored for potential usage later. In Australia and New Zealand, 63% of adults were overweight or obese in 2014–2015. Just over 1 in 4 (26%) children aged 5–14 and nearly 4 in 10 (37%) young people aged 15–24 were overweight or obese.11 This is a serious health concern, due to imbalance in energy intake and output. A detailed discussion of this issue can be found in Chapter 35. Although vitamins (organic) and minerals (inorganic) are necessary in only very small amounts, they are
BOX 26.2
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Dietary fat
Saturated fatty acids (palmitic acid) • Solid at room temperature; include animal fats and tropical oils (coconut and palm oil) • Increase low-density lipoprotein (LDL) cholesterol (‘bad’ cholesterol) blood levels • Increase the risk of coronary artery disease Unsaturated fatty acids • Soft or liquid at room temperature; omega-6 fatty acids found in plants and vegetables (olive, canola and peanut oils); omega-3 fatty acids found in fish and shellfish Monounsaturated fatty acids (oleic acid) • Found in both plants and animals • May be beneficial in reducing blood cholesterol, glucose levels and systolic blood pressure • Do not lower high-density lipoprotein (HDL) cholesterol (‘good’ cholesterol) levels • Low HDL levels have been associated with coronary heart disease Polyunsaturated fatty acids (linoleic acid) • Found in plants and fish oils • Omega-6 fatty acids lower total and LDL cholesterol blood levels • High levels of polyunsaturated fatty acids may lower LDL; omega-3 fatty acids lower blood triglyceride levels, reduce platelet aggregation and reduce blood-clotting tendency • Necessary for growth and development and may prevent coronary artery disease, hypertension, inflammatory and immune disorders
nevertheless important for adequate health. They are absorbed into the blood without being digested to smaller components. A full discussion of all vitamins and minerals is beyond the scope of this text, but Table 26.6 lists those for which we have dietary guidelines in Australia and New Zealand. In recent years, studies of chronic disease have indicated that modifying our intake of particular nutrients can help to promote health. For example, eating sufficient amounts of fruits and vegetables can prevent ischaemic heart disease and cancers. Accordingly, dietary guidelines are also available for modifying food intake to decrease the risk of developing chronic diseases (see Table 26.7).12
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TABLE 26.6 Nutrients for which dietary guidelines are available in Australia and New Zealand MAIN NUTRIENTS
VITAMINS
MINERALS
Protein
Vitamin A
Calcium
Fats (including omega-3 and omega-6)
Thiamin
Phosphorus
Riboflavin
Zinc
Niacin
Iron
Vitamin B6
Magnesium
Vitamin B12
Iodine
Folate
Selenium
Pantothenic acid
Molybdenum
Biotin
Copper
Vitamin C
Chromium
Vitamin D
Manganese
Vitamin E
Fluoride
Vitamin K
Sodium
Choline
Potassium
Carbohydrates (including fibre) Water
TABLE 26.7 Adapting nutrient intake to reduce the risk of chronic disease TO REDUCE THE RISK OF CHRONIC DISEASE INCREASE INTAKE OF: DECREASE INTAKE OF:
Vitamin A
Sodium
Vitamin C
Fat (overall amount)
Vitamin E
Carbohydrates (high glycaemic index)
Selenium Folate Potassium Dietary fibre Omega-3 and omega-6 fats
The digestive system is not fully functional at birth; the ability to digest food and move it along the gastrointestinal tract will mature gradually during the infant year. Amylase, the enzyme essential for digestion of complex carbohydrates, is inadequately produced by salivary glands until the third month and by the pancreas for the first 4–6 months of life. Enzymes necessary for the digestion and absorption of saturated fat, such as pancreatic lipase and bile salts, are also deficient during the first year; their secretion enhances with increasing age towards weaning and the introduction of solid foods, due to functional maturation of liver and pancreas.13 The immature neonatal liver is inefficient in the formation of carbohydrates, proteins and vitamins for storage and in ability to detoxify substances. Sucking and swallowing are automatic reflexes at birth, gradually coming under voluntary control as the nerves and muscles develop by 6 weeks of age. In the infant, the larger tongue relatively to the oral cavity and extra fat pads on the sides of the tongue help with sucking. The lower oesophageal sphincter is underdeveloped and opens easily. This allows a small amount of food to reflux from the stomach back into the oesophagus and mouth. Infants with reflux usually stop spitting up between 12 and 24 months; infants who fail to gain weight or vomit frequently could have gastro-oesophageal reflux disease, a more serious form of reflux. Infants require frequent feedings due to the small stomach, with a capacity of about
6 mL/kg. Because they need to receive a large amount of kilojoules in a relatively small volume of food, feeding with high-fat breast milk containing over twice as many kilojoules as proteins or carbohydrates is the most efficient way to meet infant’s kilojoule needs. The gastric pH is less than 4.0 for the first 7–10 days of life. Hydrochloric acid concentration is low until school age. Water and electrolyte absorption is functional but immature in infants. The intestines are proportionally longer than in adults, allowing extra surface area for absorption. However, the longer intestines make infants susceptible to dehydration. Intestinal muscles are poorly developed, and nervous system control is inadequate in infants. Meconium is the first stool excreted, usually within the first 24 hours of life. It consists of materials ingested during embryonic development such as amniotic fluid, skin cells, mucus, bile, epithelial and other cells; it is a greenish-black colour with a viscous, tar-like and sticky consistency. After 24 hours, the stool changes to mustard-like colour and consistency as it mixes with milk. Peristalsis is faster in infants. The normal, breastfed newborn passes at least three stools daily. Infants sometimes suffer from colic — daily periods of distress caused by rapid violent peristaltic waves and increased gas pressure in the rectum. Colic disappears as digestive enzymes become more complex and when normal bacterial flora accumulate.
PAEDIATRICS
Paediatrics and the digestive system
CHAPTER 26 The structure and function of the digestive system
At birth the intestines are sterile. Exposure to the extrauterine environment and consumption of food/ fluids leads to the entry of bacteria to the intestinal tract. Breast milk provides antibodies protecting the gastrointestinal tract until digestive mucosal lining matures and increases the ability to produce the infant’s own antibodies around the age of 6 months. Normal
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intestinal microflora established during the first 2 years can greatly influence a child’s long-term immunity.14 By 2–3 years of age children are able to control bowel functioning. The digestive system attains adult functional maturity during the school years. School-age children often delay defecation in order to continue with preferred activities which might lead to constipation.
Ageing and the digestive system
FOCUS O N L E A R N IN G
1 Discuss the major sources and uses of the main nutrient groups. 2 Define the terms vitamins and minerals. 3 List the effects of ageing on the digestive system.
neurons leads to decline in intestinal motility and blood flow, which results in nutritive substances being absorbed more slowly and in smaller amounts.16 The overall size and weight of the liver decreases. Both the blood flow and the enzyme activity of the liver decrease, so the ability to detoxify substances such as drugs decreases.17 Age-linked altered lipid handling leads to increased fat deposition in the liver and subsequent development of non-alcoholic fatty liver disease which ranges from steatosis (excessive amounts of triglycerides and other fats inside liver cells) to an inflammatory fibrosing disorder called steatohepatitis, which is associated with high risk of developing cirrhosis (replacement of healthy cells with scar tissue), often occurring in the seventh to ninth decades of life. In the pancreas, fibrosis, fatty acid deposits and atrophy occurs.18 There is a corresponding decrease in pancreatic secretion of digestive enzymes, particularly those that digest proteins. The ability of the liver and pancreas to adapt to injury reduces. Although there are no obvious changes in the gallbladder and bile ducts, there is a reduction in production, secretion and flow of bile salts and an age-related decline in hepatic metabolism of cholesterol, leading to increased serum cholesterol levels and an increased frequency of gallstone formation and cholecystitis (see Chapter 27). The rectal muscle mass decreases and the anal sphincter weakens.19 Constipation is common and is related to lowered intestinal motility, immobility, a low-fibre diet and changes in enteric nervous system functions.20
AGEING
With increasing age, the gastrointestinal system experiences a progressive decline in normal function.15–20 These changes can lead to a decline in the quantity and variety of food that is ingested, digested and absorbed, leading to poorer nutrition for the individual. Teeth are lost as a result of periodontal disease and brittle roots that break easily. Taste buds decline in number and eventually become less sensitive; the sense of smell may also diminish (although not always). Salivary secretion decreases, resulting in a dry mouth. Dysphagia (difficulty swallowing, discussed in Chapter 27) becomes more common, particularly in those who have suffered from stroke. As a result of these changes, eating is less pleasurable, appetite is reduced and food is not chewed or lubricated enough, so swallowing is difficult. Alterations in stress hormones and inflammatory mediators can lead to excess catabolism, cachexia (severe tissue wasting), and reduced appetite. In addition, mood disorders, such as anxiety and depression, are powerful inhibitors of appetite. Loss of appetite, otherwise known as anorexia, occurs in up to 30% of elderly individuals.15 Gastric motility, blood flow, and the volume and acid content of gastric juice may be reduced, particularly with gastric atrophy (shrinkage of stomach tissue). The decreased gastric secretion can impair absorption of vitamin B12, calcium, iron and folate. The protective mucosal barrier decreases, so there is increased susceptibility to damage. There are decreases in intestinal absorption due to degeneration of villi; loss of enteric
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chapter SUMMARY An overview of the digestive system • The gastrointestinal tract is a hollow tube that extends from the mouth to the anus and is divided into several organs: the mouth, pharynx, oesophagus, stomach, small intestine and large intestine. The salivary glands, liver, gallbladder and pancreas are the main accessory organs of this system. • The major functions of the gastrointestinal tract are the mechanical and chemical breakdown of food and the absorption of digested nutrients into the bloodstream. • The walls of the gastrointestinal tract have four layers: mucosa, submucosa, muscularis (circular muscle and longitudinal muscle) and serosa. • The main nervous system control of the digestive system is by the enteric nervous system, which is located within the gut wall. In addition, the parasympathetic nervous system (via the vagus nerve) stimulates gastrointestinal motility and sphincter relaxation; and the sympathetic nervous system decreases gastrointestinal activity. • Food is propelled through the gastrointestinal tract by peristalsis: waves of sequential relaxations and contractions of the tunica muscularis. • Splanchnic blood flow provides blood to the oesophagus, stomach, small and large intestine, gallbladder, pancreas and spleen.
• The hormones gastrin and motilin stimulate gastric emptying; the hormones secretin and cholecystokinin delay gastric emptying. • Mucus is secreted throughout the stomach and protects the stomach wall from acid and digestive enzymes. • Gastric glands in the fundus and body of the stomach secrete intrinsic factor (needed for vitamin B12 absorption) and hydrochloric acid, which dissolves food fibres, kills microorganisms and activates the enzyme pepsin. • Chief cells in the stomach secrete pepsinogen, which is converted to pepsin in the acid environment created by hydrochloric acid. • Acid secretion is stimulated by the vagus nerve and gastrin, and is inhibited by sympathetic stimulation and cholecystokinin. • The three phases of acid secretion by the stomach are the cephalic phase (anticipation and swallowing), the gastric phase (food in the stomach) and the intestinal phase (chyme in the intestine). • Mechanical digestion in the stomach breaks food into smaller particles, while chemical digestion breaks proteins into smaller substances. While the stomach is not a main organ of absorption, both alcohol and aspirin are absorbed into the bloodstream here.
The mouth, pharynx and oesophagus
The small intestine
• Digestion begins in the mouth with chewing and salivation. Salivary amylase initiates carbohydrate digestion. • The oesophagus is a muscular tube that transports food from the mouth to the stomach. The tunica muscularis in the upper part of the oesophagus is striated muscle and that in the lower part is smooth muscle. • Swallowing is controlled by the swallowing control centre in the brainstem. The two phases of swallowing are the oropharyngeal phase (voluntary) and the oesophageal phase (involuntary). • The lower oesophageal sphincter opens to admit swallowed food into the stomach and then closes to prevent regurgitation of food back into the oesophagus.
The stomach • The stomach secretes digestive juices, mixes and stores food, and propels partially digested food (chyme) into the duodenum.
• The small intestine is about 5 m long and has three segments: the duodenum, jejunum and ileum. • The peritoneum is a double layer of membranous tissue: the visceral layer covers the abdominal organs and the parietal layer extends along the abdominal wall. • Villi are small finger-like projections that extend from the small intestinal mucosa and increase its absorptive surface area. • Digested substances are absorbed across the intestinal wall and then transported to the liver, where they are metabolised further. The majority of all absorption occurs in the small intestine. • Small molecules of carbohydrates, proteins and lipids are absorbed primarily by the duodenum and jejunum; bile salts and vitamin B12 are absorbed by the ileum. Vitamin B12 absorption requires the presence of intrinsic factor. • Some small lipid molecules are absorbed directly into the lacteals and therefore do not travel in the blood to the liver.
CHAPTER 26 The structure and function of the digestive system
• Minerals and water-soluble vitamins are absorbed throughout the small intestine. • The ileocaecal valve connects the small and large intestines and prevents reflux into the small intestine.
Accessory organs of digestion • The liver is the second largest organ in the body. It has digestive and metabolic functions. • Liver lobules consist of plates of hepatocytes, which are the functional cells of the liver. • There are two blood vessels into the liver: the hepatic portal vein and the hepatic artery. All blood exiting the liver travels through the hepatic vein. • The hepatocytes produce 700–1200 mL of bile per day and secrete it into the bile canaliculi, which are small channels between the hepatocytes. The bile canaliculi drain bile into the common bile duct and then into the duodenum through an opening called the sphincter of Oddi. • Sinusoids are capillaries located between the plates of hepatocytes. Blood from the portal vein and hepatic artery flows through the sinusoids to a central vein in each lobule and then to the hepatic vein and inferior vena cava. • The Dissé space locates between hepatocytes and the endothelial lining of the sinusoid; it drains interstitial fluid into the hepatic lymph system. • Kupffer cells, which are part of the mononuclear phagocyte system, line the sinusoids and destroy microorganisms in sinusoidal blood. • Hepatic stellate cells are vitamin A-storing cells located in the Dissé space; they provide a double lining for sinusoids and regulate the contractility of sinusoids. • The healthy adult liver contains a diverse range of resident immune cells that play essential roles in immune regulation, tissue repair and liver regeneration. The liver protects the rest of the body from excessive immune activation by providing detoxification of blood from the gut as well as immunosurveillance for pathogenic infections and malignant cells. • The bile salts are produced from cholesterol by the hepatocytes. • Bile is produced by the liver and is necessary for fat digestion and absorption. Bile’s alkalinity helps to neutralise chyme, thereby creating a pH that enables the pancreatic enzymes to digest proteins, carbohydrates and sugars. • Bile salts enable fats to be emulsified to reach the brush border of the intestinal mucosa. The fat content of the micelles diffuses through the epithelium into lacteals (lymphatic ducts) in the villi. From there, fats flow into the lymphatics and into the systemic circulation. • Most bile salts are recycled. The absorption of bile salts from the terminal ileum and their return to the liver is known as the enterohepatic circulation of bile. • The liver has an important role in the metabolism of the main nutrients, such that they can be used in the production of new molecules and excesses may be stored until needed.
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• Bilirubin is a pigment released from the lysis of aged red blood cells. The liver metabolises the bilirubin and it is then secreted with the bile as bile pigments. This metabolised bilirubin is excreted from the body in the faeces. • The gallbladder is a sac-like organ located in the inferior surface of the liver. The gallbladder stores bile between meals and ejects it when chyme enters the duodenum. • Stimulated by cholecystokinin, the gallbladder contracts and forces bile through the cystic duct and into the common bile duct. The sphincter of Oddi relaxes, enabling bile to flow through the major duodenal papilla into the duodenum. • The pancreas is an organ located behind the stomach. The pancreatic secretions for digestion include an alkaline solution and enzymes that digest proteins, carbohydrates and fats. • Secretin stimulates pancreatic secretion of alkaline fluid, and cholecystokinin and acetylcholine stimulate secretion of enzymes. Pancreatic secretions originate in acini and ducts of the pancreas and empty into the duodenum through the common bile duct or an accessory duct that opens directly into the duodenum.
The large intestine • The large intestine consists of the caecum, appendix, colon (ascending, transverse, descending and sigmoid), rectum and anal canal. • Haustra are pouches of colon formed with alternating contraction and relaxation of the circular muscles. • The mucosa of the large intestine contains mucussecreting cells and mucosal folds, but no villi. • Distension of the ileum with chyme causes the gastrocolic reflex, or the mass propulsion of faeces to the rectum. • Defecation is stimulated when the rectum is distended with faeces. The contracted internal anal sphincter relaxes and if the voluntarily regulated external sphincter relaxes, defecation occurs. • The largest number of intestinal bacteria are in the colon. They are anaerobes consisting of Bacteroides, clostridia, coliforms and lactobacilli. Intestinal bacteria digest carbohydrates and produce vitamins that can then be absorbed through the intestinal wall and into the bloodstream. • Infections of the lower gastrointestinal tract occur by excessive proliferation of bacteria, perforation of the intestine or contamination from neighbouring structures. • The large intestine absorbs water and electrolytes.
An overview of nutrition • Rich sources of protein are found in animal products. Proteins are digested to amino acids and then used by the body for a wide variety of structural and functional purposes. • Carbohydrates are mainly found in plants. Starch is digested to simple sugars, which are mainly used by the body as an energy source in the form of glucose. Fibre is a non-digestible carbohydrate, which assists with
Continued
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progressing intestinal contents through at an appropriate rate. • Lipids may be saturated (from animal sources) or monounsaturated (from plant sources). Fats are digested to triglycerides, which are used in the body as structure and protection, as well as for storage of excess energy. • Vitamins and minerals are needed in small amounts in our diet.
Paediatrics and the digestive system • The digestive system of the newborn undertakes significant development in the first year, particularly relating to the release of enzymes.
• Sucking and swallowing reflexes are present at birth. Reflux often occurs within the first 12 months after birth.
Ageing and the digestive system • The pleasure from eating decreases with ageing, due to factors such as loss of taste, decreased salivation and dysphagia (difficulty swallowing). • Gastric secretions and intestinal absorption decrease with ageing, so nutrient deficiencies become more common. Constipation becomes more common. • The liver becomes less efficient in metabolism and pancreatic enzyme secretions decrease. Increased fat deposition in the liver occurs.
CASE STUDY
A DU LT Emily is a 34-year-old librarian. She has just had her lunch break, during which she ate a chicken and salad burger with hot chips at a nearby café and sat quietly reading a book while eating. After that, she ate a large slice of chocolate cake, which she had difficulty finishing. Although Emily enjoyed her lunch, on returning to work she feels tired and wishes she could have a nap. 1 Emily’s meal contained components of the main nutrient groups. Briefly describe how each of these nutrients is digested in different regions of the gastrointestinal tract. 2 Discuss how secretions from the liver, gallbladder and pancreas contribute to the digestion of each main nutrient group.
3
Discuss some reasons which may explain Emily’s feeling of tiredness. (Hint: think about the autonomic nervous system function.) 4 After digestion, small molecules need to reach the body cells to supply them with necessary nutrients. Draw a flow diagram to list all the structures (including vessels and organs) that nutrients must pass through before they reach the body cells. 5 Some time after returning to work, Emily senses that it is time to pass faeces. Discuss how she can consciously control this reflex until it is an appropriate time to defecate.
CASE STUDY
A GEING Bill is an 88-year-old who was admitted to the Sunshine Hospital with the symptoms of abdominal pain. He is 175 cm tall; his body weight is 52 kg. Bill was widowed 5 years ago and lives alone in his suburban home. 1 Discuss probable reasons for abdominal pain experienced by Bill. 2 Plan laboratory and diagnostic tests for Bill.
3
Describe possible changes in Bill’s gastric and intestinal functions. 4 Blood tests revealed abnormal levels of liver and pancreatic enzymes. Describe potential results of these tests and their implications. 5 Describe possible reasons and physiological changes underlying Bill’s low body weight.
CHAPTER 26 The structure and function of the digestive system
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REVIEW QUESTIONS 1 Explain whether digestive system activity is generally increased by the sympathetic or parasympathetic branch of the autonomic nervous system. 2 Outline the functions of the upper and lower oesophageal sphincters. 3 Explain why there are 3 layers of stomach muscle. 4 Name the hormones involved in gastric motility. 5 Explain where blood in the hepatic portal vein comes from.
6 Trace the route of bile salts, from formation in the liver to recycling. 7 Describe where pancreatic digestive secretions empty into. 8 Explain what haustra are. 9 For each of the main nutrients, discuss how they are digested and absorbed in the organs of the digestive system. 10 Name the phase of gastric secretion that is stimulated when you think about a favourite food.
Key terms
CHAPTER
27
Alterations of digestive function across the life span Kulmira Nurgali and Carolyn Wildbore
Chapter outline Introduction, 799 Disorders of the gastrointestinal tract, 799 Cancers of the gastrointestinal tract, 799 Inflammatory disorders of the gastrointestinal tract, 807 Nutritional disorders, 818 Disorders of motility, 823 Structural abnormalities of the gastrointestinal tract, 826
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Clinical manifestations of gastrointestinal tract alterations, 829 Disorders of the hepatobiliary system and pancreas, 835 Hepatic disorders, 835 Biliary disorders, 847 Pancreatic disorders, 850
abdominal hernia, 828 acute liver failure, 840 alcoholic cirrhosis, 837 alcoholic hepatitis (steatohepatitis), 837 aphthous ulcers, 817 appendicitis, 813 ascites, 844 cachexia, 821 cholangiocellular carcinoma, 841 cholecystitis, 848 cholelithiasis, 847 chronic active hepatitis, 840 chyme, 829 cirrhosis, 837 coeliac disease, 819 colonoscopy, 803 colorectal cancer, 799 colorectal polyps, 801 Crohn’s disease, 808 Cushing’s ulcer, 817 distension, 829 diverticula, 812 diverticulitis, 812 duodenal ulcers, 817 failure to thrive, 822 fatty liver (steatosis), 836 gallstones, 847 gastric ulcers, 815 gastritis, 813 gastro-oesophageal reflux, 823 hepatic encephalopathy, 846 hepatocellular carcinoma, 841 hiatal hernia, 826 Hirschsprung’s disease, 828 intestinal obstruction, 826 intussusception, 826 irritable bowel syndrome, 810 ischaemic ulcer, 817 jaundice, 846 lactose intolerance, 818 long-term starvation, 821 malnutrition, 821 necrotising enterocolitis, 818 neoplastic polyps, 801 pancreatitis, 850 para-oesophageal hiatal hernia, 826 peptic ulcer, 815 portal hypertension, 842 pyloric stenosis, 825 reflux oesophagitis, 823 short-term starvation, 821 sliding hiatal hernia, 826 splenomegaly, 842 starvation, 821 steatohepatitis, 837 stress ulcer, 817 ulcerative colitis, 807 varices, 842 viral hepatitis, 837 volvulus, 827 vomiting (emesis), 829
CHAPTER 27 Alterations of digestive function across the life span
Introduction The primary function of the digestive system is to digest and absorb nutrients into the blood, to ultimately provide valuable substances for the functioning of all body cells. Impairment of the digestive system can lead to systemic abnormalities and may become life threatening. Structural and neural abnormalities can slow, obstruct or accelerate the movement of chyme at any part of the gastrointestinal tract. Fast movement through the digestive system causes diarrhoea and malabsorption of foods, while slowed or obstructed movement causes constipation. Cancers are a main affliction for this system, with the chief cancer of the gastrointestinal tract being colorectal cancer — a leading cause of death in Australia and New Zealand. It is likely that the modern lifestyle, particularly the choice of foods, adopted by many people in the community increases the risk of developing this cancer. Changes in the cells lining the colon and rectum, often seen in the form of polyps, can be precancerous for a long period, so regular screening may allow for these changes to be detected and treated prior to them progressing to cancer. Cancers of the accessory organs are also seen, with pancreatic cancer having a high mortality rate. Inflammatory and ulcerative conditions of the gastrointestinal wall disrupt secretion, motility and absorption. Inflammation or obstruction of the liver, pancreas or gallbladder can alter metabolism and result in local and systemic symptoms. Many clinical manifestations of gastrointestinal tract disorders are nonspecific and can be caused by a variety of impairments. Nutritional disorders such as lactose intolerance and coeliac disease are the focus of increasing awareness within the community. Those with lactose intolerance have options such as lactose-free dairy foods, and although coeliacs can avoid gluten to manage their condition, many coeliacs unfortunately remain undiagnosed. The liver is a vital organ that has a wide variety of essential functions not only for digestive system function, but also for homeostasis of other body systems. Impairment of the liver by conditions such as alcoholic liver disease or hepatitis can lead to serious complications including insufficient production of blood-clotting factors (which can result in bleeding), inadequate metabolism of toxic substances such as alcohol and other drugs and encephalopathy (altered brain structure). Therefore, the liver should be considered as far more than an accessory organ of digestion: it assists in homeostasis of other systems, such that liver disease can be fatal.
Disorders of the gastrointestinal tract Cancers of the gastrointestinal tract
Cancers of the gastrointestinal tract are often associated with nutritional factors, as these factors can directly impact
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on the epithelial cells lining the tract. For example, colorectal cancer, the most prevalent cancer of the digestive system, is associated with a diet high in fats and red meat and low in vegetables. Cancers of the upper parts of the digestive system are associated with alcohol intake (as well as smoking). Stomach cancer is also associated with bacterial infection. Other cancers of the gastrointestinal tract are quite rare: the incidence of cancers of the lip, tongue, mouth, pharynx, larynx, small intestine and anus each are less than 1% of the total incidence of cancers in the Australian population.1 Gastrointestinal cancers with the highest mortality in Australia are shown in Table 27.1. General principles of cancers are discussed in Chapter 37; here we consider the impact on the digestive system.
Colorectal cancer
The most serious disorder of the digestive system in Australia and New Zealand is colorectal cancer: it is the most prevalent cancer of this system and has a high mortality rate when detected at an advanced stage. Colorectal cancer (or bowel cancer) is the term used to encompass cancers of the caecum, colon and through to the rectum. It is estimated that there are approximately 17 000 new cases of colorectal cancer diagnosed in Australia each year, which accounts for 8.5% of all deaths. Approximately 93% of Australians diagnosed will be over 50 years of age. Approximately two-thirds of those diagnosed with colorectal cancer will have cancers in the colon and one-third will have cancers in the rectum.1 Colorectal cancer has the second-highest incidence rate out of all reportable cancers for both males and females, being second only to prostate cancer for males and breast cancer for females. (Skin cancers have a very high rate but these are not all reportable, therefore not all skin cancers are included in cancer incidence statistics.) In fact, 13.4% of all cancers in Australia and 14.6% in New Zealand are colorectal cancers1,2 — these rates are among the highest in the world.3 Australia ranks as the eighth highest incidence of colorectal cancer in the world, with New Zealand on the ninth position.3 The rate is actually lower in Indigenous populations than in the non-Indigenous populations in both countries.4,5 It is also the second or third most common cause of death from cancer in Australia and New Zealand for both males and females.5 Cancer of the colon tends to occur mainly in individuals older than 50 years of age, so early screening is aimed at those aged 50 and over.5,6 It is estimated that the risk of a person developing bowel cancer by their 85th birthday will be 1 in 12, with females at a lower rate of 1 in 15, compared to males of 1 in 10.6 Clearly age cannot be modified; however, a substantial number of modifiable risk factors that can lower the risk of developing colorectal cancer have been identified (see Box 27.1). For example, increasing physical activity is preventative in a dose-dependent manner, such that more exercise will further reduce the risk;7 avoiding obesity decreases the risk;8 and a diet rich in vegetables, grains, fruit, folate and calcium and low in fat can also decrease the risk.9 These modifiable dietary and lifestyle factors account for most of the risk factors for developing
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TABLE 27.1 Cancer of the gut, liver and pancreas ORGAN
Colorectal
TRENDS BETWEEN 1982 AND 2014 OF CANCER MORTALITY RATE
Declined from 31.5% to 15.6% per 100 000 persons In both males and females, 2nd or 3rd leading cause of cancer deaths
Oesophageal
Increased from 4.4 % to 4.9 % per 100 000 persons 9th or 10th leading cause of cancer deaths in males
Gastric
Declined from 12.3 % to 4.0% per 100 000 persons
RISKS
CELL TYPE
COMMON MANIFESTATIONS
Polyps
Adenocarcinoma (left colon grows in ring; right colon grows as mass)
Pain
Ulcerative colitis Diverticulitis High-refined carbohydrates, low-fibre, high-fat diets
Mass Anaemia Bloody stool Obstruction Distension
Malnutrition
Squamous cell
Chest pain
Alcohol
Adenocarcinoma
Dysphagia
Salty food
Adenocarcinoma
Anorexia
Nitrates — nitrosamines
Squamous cell
Malaise
Tobacco Chronic reflux
Weight loss Upper abdominal pain Vomiting Occult blood Hepatic
Increased from 2.3% to 6.0% per 100 000 persons The 7th leading cause of cancer deaths in males
Hepatitis B, C or D viruses
Hepatomas
Pain
Cirrhosis
Cholangiomas
Anorexia
Intestinal parasite
Bloating
Aflatoxin from mouldy peanuts
Weight loss Portal hypertension Ascites Jaundice
Pancreatic
No change at 5.7% per 100 00 persons In both males and females the 3rd, 4th or 5th leading cause of cancer deaths
Chronic pancreatitis Cigarette smoking Alcohol Diabetic women
Adenocarcinoma (exocrine part of gland, ductal epithelium)
Weight loss Weakness Nausea Vomiting Abdominal pain Depression, jaundice May have insulin-secreting tumours with symptoms of hypoglycaemia
colorectal cancers.10 Regular consumption of aspirin is also preventative against colorectal cancer,11 and aspirin is now recommended for patients with previous colorectal cancer to prevent further disease.3 Lifestyle factors help prevent colorectal cancer in the following ways:12,13 • Physical activity and dietary fibre increase the rate of faecal passage through the intestines, thereby
moving potential carcinogens (substances that promote the formation of cancer) through the intestines quickly. • Dietary fibre helps increase the volume of the stools, which will dilute any carcinogenic substances in the intestines.14 • Dietary fibre assists cells of the colon to undergo normal processes during cell division.
CHAPTER 27 Alterations of digestive function across the life span
A
Modifiable risk factors for prevention of colorectal cancer
BOX 27.1
• Avoid tobacco smoking • Limit alcohol intake — avoid alcohol, or no more than 2 standard drinks for men, and 1 standard drink for women, per day • Increase intake of cereal fibre • Moderate intake of lean red meat (up to 100 g per day), — avoiding charring when cooking, and limiting the intake of processed meats • Garlic and milk are probably protective against colorectal cancer • Foods which may increase the risk of colorectal cancer include those that contain iron, cheese, animal fats, sugars • Foods which may decrease the risk of colorectal cancer include non-starchy vegetables and fruits • Maintain a healthy body mass index — less than 25 (calculations for body mass index are in Chapter 35), and avoiding abdominal fatness • Undertake physical activity — moderate physical activity, 30–60 minutes per day, avoiding sedentary behaviour
• Fish contains omega-3 fatty acids, which can slow down the rate of division of potentially cancerous cells. • Vegetables contain antioxidants, which can limit the formation of carcinogens. • Vegetables promote the liver to excrete carcinogens. • High amounts of red meat may be detrimental, as it can promote bacteria in the large intestine to generate potential carcinogens. • High amounts of fats in the diet are detrimental, as fat can increase the concentration of bile salts in the large intestine, thus promoting carcinogenesis. Clearly, lifestyle factors have a substantial influence on a range of processes involved in the early stages of cancer. It is important as healthcare professionals that we and, in particular, the individuals we encounter are educated about these lifestyle risk factors. The development of colorectal cancer appears to be a result of both these environmental factors and genetic or inherited susceptibility (which is typical of most cancers; see Chapter 37). Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) are genetic conditions (autosomal-dominant inheritance traits) that account for about 3% to 6% of colorectal cancers.15 Both genetic syndromes appear to have a substantial link to cancers that occur earlier in life (approximately age 35–40). Clustering in families is common, with genes for both inherited syndromes having been identified.16
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B
FIGURE 27.1
Neoplastic polyps. A Tubular adenomas (A) are rounded lesions 0.5–2 cm in size that are generally red and sit on a stalk (S) of normal mucosa that has been dragged up by traction of the polyp in the bowel lumen. B Villous adenomas are velvety lesions about 0.6 cm thick that occupy a broad area of mucosa generally 1–5 cm in diameter.
PATHOPHYSIOLOGY
Colorectal polyps are closely associated with the development of cancer. A polyp is a finger-like projection arising from the mucosal epithelium. Most polyps are benign; however, because it can be difficult to distinguish between benign and malignant types, there is currently a strong preference to remove all polyps.3 Neoplastic polyps are benign, premalignant lesions and are classified as tubular (the most prevalent), villous or tubulovillous adenomas (see Fig. 27.1). Those with the villous shape are more likely to become cancerous, although flat adenomas may be more aggressive.17 The larger the polyp, the greater the risk of colorectal cancer — those larger than 1.5 cm are more likely to be malignant than those smaller than 1 cm. Most colorectal cancers arise from these adenomatous polyps. Small adenomas may grow slowly, even appearing unchanged for years.17 These tumours have a long pre-invasive phase and, even when they invade, their growth is still often slow. Adenomas can be detected early, before the submucosa has been penetrated. Colorectal cancer starts in the glands of the mucosal lining, forming an adenocarcinoma. Many cancers are most serious when they undergo metastasis, which is the spread of the original carcinoma to other body tissues. Because the lymphatic channels are located under the muscularis mucosae (the thin layer of muscle within the mucosal layer), colorectal cancer must traverse this layer before metastasis can occur. Once the malignant cells cross the muscularis
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mucosae, the tumour becomes invasive and highly malignant. The liver and lungs are the most common sites of metastasis (see Fig. 27.2). Cancer of the colon is also associated with genetic events. Deletion of genes is linked to the transformation of normal colon epithelial cells to benign and malignant adenocarcinomas. Mutations of oncogenes, tumoursuppressor genes and repair genes are all associated with colon cancer.17 Dietary factors, including a diet high in fat, low in fibre and low in calcium, may promote genetic mutations. CLINICAL MANIFESTATIONS
CONCEPT MAP
Symptoms of colorectal cancer depend on the location, size and shape of the lesion (see Fig. 27.3). Tumours of the right (ascending) colon and left (descending) colon form into two distinct tumour types:18 • Right side lesions are polyp-shaped and extend along one wall of the caecum and ascending colon (see Fig. 27.4). These tumours may be silent, evolving to pain, palpable mass in the lower right quadrant, anaemia, fatigue and dark-red or mahogany-coloured blood mixed with the stools. These tumours can become large and bulky with necrosis (cell damage) and ulceration, contributing to
Genetics
Environment
contributes to
contributes to
Colorectal polyp (benign)
persistent blood loss and anaemia. Obstruction is unusual because the growth does not readily encircle the colon. • Left side tumours start as small, elevated, button-like masses. They grow circumferentially, encircling the entire bowel wall and eventually ulcerating in the middle as the tumour penetrates the blood supply — this creates a typical ‘apple-core’ lesion seen on imaging. Obstruction is common but occurs slowly, and stools become narrow and pencil-shaped. Manifestations include progressive abdominal distension, pain, vomiting, constipation, need for laxatives, cramps and bright red blood on the surface of the stool. Transverse colon (15%) Semisolid faeces Pain, obstruction, change in bowel habits, anaemia
Ascending colon (25%) Liquid faeces Pain, mass, change in bowel habits, anaemia Rectum (45%) Solid faeces Blood in stool, change in bowel habits, rectal discomfort
Descending colon (15%) Solid faeces Pain, change in bowel habits, bright red blood in stool, obstruction
FIGURE 27.3
slow growth
Signs and symptoms of colorectal cancer by location of primary lesion. Clinical manifestations are listed in order of frequency for each region (lymphatics of colon also shown).
progresses to Becomes malignant progresses to colorectal cancer sign of
symptom of
Invasion of Bleeding may Pain, Metastasis gut wall develop early palpable mass to liver or late and lungs symptoms of Anaemia, fatigue
FIGURE 27.2
The development of colorectal cancer. A combination of genetic and lifestyle factors may contribute to changes that can become malignant and lead to effects throughout the body.
FIGURE 27.4
Colorectal cancer. A polyp within the large intestine, viewed using colonoscopy.
CHAPTER 27 Alterations of digestive function across the life span
Rectal carcinomas (occurring up to 15 cm from the anal opening) can spread through the rectal wall to nearby structures: the prostate in men and the vagina in women. Metastasis occurs readily from the lower third of the rectum because it has no serosal covering (outer serous membrane covering). Systemic metastasis occurs through the blood supply known as the haemorrhoidal plexus, which drains into the vena cava. Metastasis commonly occurs in the liver and lungs. Some other conditions commonly confused with colorectal cancer are listed in Table 27.2. EVALUATION AND TREATMENT
Screening for colorectal cancer can be performed by several different methods: 1 Faecal occult blood test. Colorectal cancers are often highly vascular and therefore checking the faeces for blood can be diagnostic. Very small amounts of blood may be detected by ‘occult’ testing methods, where the bleeding is not sufficient to cause visible redness in the faeces. The benefits of this test include: it can detect very small amounts of blood; it is non-invasive; and
2
3
TABLE 27.2 Conditions commonly confused with colorectal cancer CONDITION
SIGNIFICANT CHARACTERISTICS
Diverticulitis
Left-sided pain similar to that of appendicitis; tender lower left quadrant; associated findings: nausea, vomiting, fever, obstruction, anorexia and leucocytosis; mucosa is intact, and perforation, peritonitis and abscesses occur more often than in cancer; sigmoidoscopy (examination of the lower colon using a scope) or barium enema used to distinguish from cancer
Ulcerative colitis
Younger people with chronic attacks of bloody diarrhoea, crampy abdominal pain, fever, malnutrition and dehydration; usually involves the left colon and rectum; endoscopy, barium enema and biopsy performed for definitive diagnosis
Crohn’s disease
Generally involves the right colon and the ileum; chronic diarrhoea with abdominal cramps, fever, weight loss and often a palpable abdominal mass; endoscopic examination and barium enema used to distinguish from cancer
Appendicitis
Vague abdominal symptoms, often with a tender or non-tender mass in the lower right quadrant; associated symptoms: mild fever and leucocytosis; barium enema used to distinguish from cancer
Thrombosed haemorrhoids
Examination shows a tender, swollen, bluish painful mass in the anus; patient will have a history of haemorrhoids
4
5
6
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it can be performed outside of healthcare institutions. Depending on which type of test is being performed, dietary restrictions may be necessary. A positive test result is followed up with colonoscopy. Flexible sigmoidoscopy. A flexible endoscope is inserted into the rectum enabling visualisation up to the sigmoid colon. The procedure does not require sedation or ingestion of bowel preparation fluids, but an enema is used beforehand to clean out the lower intestine. The flexible sigmoidoscope can reach 50–60% of colorectal cancers. During sigmoidoscopy, polyps can be removed or a biopsy taken. Colonoscopy. An endoscope with a camera is inserted into the rectum up as far as the terminal ileum, so that the full length of the large intestine can be examined. Although this procedure requires patients to ingest bowel preparation fluids (prior to the appointment) and undergo sedation, patients are able to return home on the same day. This procedure is particularly efficient as it allows investigation, biopsy and removal of polyps. It is the most accurate method of evaluating the colon and rectum, as it can detect 95% of colorectal cancers.3 Patients who return a positive result from a faecal occult blood test undergo colonoscopy to enable visualisation and removal of polyps. Patients who already have symptoms require an evaluation using colonoscopy, with polyps being removed where possible. Barium enemas. This procedure may be performed if colonoscopy cannot be performed in a particular patient. It involves filling the intestine with barium fluid (via the anus), which allows visualisation using x-ray imagery. A double-contrast barium enema is not as accurate as colonoscopy and, although it can identify colorectal cancer, an additional procedure is then required for removal and biopsy of polyps. CT colonography (virtual colonography). This newer diagnostic testing option produces computerised images using x-ray imaging. This avoids the need to insert an endoscope into the rectum (although a very short tube is inserted to fill the intestine with air); however, colonoscopy is still required for removal and biopsy of polyps.3 Magnetic resonance imaging (MRI). This non-invasive technique is recommended for initial staging and preoperative planning in rectal cancer, because it can accurately define tumour localisation, with regard to the relationship of the tumour to the peritoneum and the anal sphincter.19
Early detection screening recommendations for Australians are summarised in Box 27.2. Regular screening using the faecal occult blood test can decrease the mortality rate from colorectal cancer by approximately 33%.6 The Australian Government is phasing in the introduction of a national bowel cancer screening program using the faecal occult blood test; it is currently available to people of specific ages. The first phase of the program commenced in 2006. The second phase of the program commenced in 2008 and
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BOX 27.2
Screening for colorectal cancer
From the age of 50 years, men and women of the Australian population should be screened using: • faecal occult blood test, once every 2 years • flexible sigmoidoscopy, once every 5 years From the age of 50 years, people who have a moderately increased risk due to their family history of colorectal cancer should be screened using: • colonoscopy (or commence this from 10 years younger than the age at which the family member was diagnosed, if this is less than 50 years) From the age of 25 years, people who have a potentially high risk due to a more extensive family history of colorectal cancer should be screened using: • colonoscopy, every 2 years (or commence this 5 years younger than the age at which the family member was diagnosed, if this is less than 25 years) • genetic screening In a symptomatic patient over 40 years, it is recommended that a full colonoscopy be performed
offered screening to individuals based on age (those turning 50 between January 2008 and December 2010, and turning 55 or 65 between July 2008 and December 2010). The program has expanded in subsequent years to include additional age groups. When fully implemented (by 2019), all Australians aged between 50 and 74 years will be offered free screening every 2 years, consistent with the recommendations of the National Health and Medical Research Council.1,6 The immunochemical faecal occult blood test is being used, which does not require restrictions on diet or medications.6 In 2016 New Zealand commenced a national bowel screening program in certain district health boards.5 The program offers bowel screening for people aged 60–74 years, every 2 years.5 In addition to screening, physical examination of the abdomen detects liver enlargement and ascites; and appropriate lymph nodes are palpated. Evaluation of the liver and lungs for metastasis includes using x-ray, CT scans, MRI and ultrasound. The TNM system is widely used in clinic for classification of malignant tumours. This system defines the size and the depth of the primary tumour (T) invasion, the number of lymph nodes (N) affected and the presence of metastasis (M) in other organs. While the TNM system is used for specific staging clinically, simplified stages for colorectal cancer are shown in Table 27.3. Treatment for cancer of the colon is almost always surgical, with or without chemotherapy or radiotherapy.19 Resection (cancer removal) and anastomosis (intestine rejoining) can be performed for cancer of the ascending, transverse, descending or sigmoid colon and upper rectum. Surgery is performed through abdominal incisions and natural defecation is preserved. Growths in the lower portion of the rectum require removal of the entire rectum with
TABLE 27.3 Staging of colorectal cancer STAGES
DESCRIPTION
Stage 0 (Carcinoma in situ)
Abnormal cells are found in the mucosa (the innermost lining) of the colon or rectum wall, they may become cancer (divide without control and can invade nearby tissues) and spread
Stage I
Cancer has grown from the mucosa to the muscle layer of the colon wall
Stage II
Cancer has grown through the muscle layer to the serosa of the colon wall, but has not spread to nearby organs
Stage III
Cancer has spread through the mucosa to the submucosa and muscle layer of the colon wall, and to nearby lymph nodes or tissues near the lymph nodes
Stage IV
Cancer has spread through the blood and lymph nodes to other parts of the body, such as the lung, liver, abdominal wall or ovary
Recurrence
This is cancer that has been treated and has returned after a period of time when the cancer could not be detected. The disease may return in the colon or rectum, or in another part of the body
the formation of a permanent colostomy (faeces exit the body via an alternative opening made in the abdominal wall). Prognosis after surgery depends on the stage and location of the tumour. Resection of liver metastases can prolong survival.19 As the diagnosis and treatment of colorectal cancer has improved in recent decades, we have seen an overall increase in the 5-year survival rate from 49% in 1982–1986 to 66% in 2006–2010.1 However, side effects of current therapies can be a major hurdle for effective anti-cancer treatment; see ‘Research in Focus: Search for new targets to prevent gastrointestinal side effects of chemotherapy’.
FOCU S ON L EA RN IN G
1 Discuss the lifestyle (modifiable) and genetic (nonmodifiable) risk factors in the development of colorectal cancer. 2 Describe the progression from benign polyps through to metastasis of adenocarcinoma. 3 List the clinical manifestations of colorectal cancer, including the different symptoms depending on the location of the tumour. 4 Compare and contrast different methods of evaluating colorectal cancer. 5 Discuss the benefits of a national bowel cancer screening program. 6 Discuss the treatment options for colorectal cancer.
CHAPTER 27 Alterations of digestive function across the life span
RESEARCH IN F CUS Search for new targets to alleviate gastrointestinal side effects of chemotherapy Diarrhoea, constipation, oral mucositis, nausea and vomiting are common gastrointestinal side effects of chemotherapeutic medications experienced by 80–90% of patients. As a result of these side effects, patients commonly develop malnutrition and dehydration. Early death rates of up to 5% associated with chemotherapy are primarily due to gastrointestinal toxicity. The gastrointestinal side effects often limit the dose of chemotherapy reducing the efficacy of anti-cancer treatment. Chronic post-treatment diarrhoea can persist for over 10 years in cancer survivors. Most drugs used clinically to alleviate gastrointestinal side effects of chemotherapy have adverse effects themselves and often have limited efficacy, thus a search for novel therapies is crucial. Mucositis presenting as inflammation and ulceration of the intestinal epithelium, resulting in alterations of intestinal microflora and gastrointestinal secretion is a significant contributing factor in the pathophysiology of chemotherapyinduced diarrhoea. Intestinal microbiota is known to play an integral role in intestinal homeostasis and is now believed to play a key role in the development of mucositis. Recent studies have revealed that chemotherapy has effects on intestinal microbial composition and their metabolites. The selective inhibition of bacterial enzyme β-glucuronidase has recently been shown to alleviate chemotherapy-induced gastrointestinal toxicity in both animal models and clinical trials. However, while mucosal damage is undoubtedly significant for the acute symptoms associated with chemotherapy, persistence of symptoms long after treatment suggests that there is long-term damage to gastrointestinal innervation. Recent studies have demonstrated that damage to the enteric nervous system residing within the gut wall (enteric neuropathy) contributes significantly to gastrointestinal dysfunction associated with chemotherapy. Further studies to elucidate mechanisms underlying chemotherapy-induced enteric neuropathy and develop novel treatments to alleviate this damage without compromising anti-cancer efficacy of chemotherapy are warranted.
PATHOPHYSIOLOGY
There are two common types of carcinoma of the oesophagus, squamous cell carcinoma (cancer that begins in flat cells lining the oesophagus) or adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Squamous cells changes are mainly from irritants such as smoking and alcohol.20 Adenocarcinomas are often secondary to infiltration by a gastric carcinoma or to the presence of Barrett’s oesophagus or gastro-oesophageal reflux disease (GORD) often referred to as long-term acid reflux. In GORD, the cells of the lower oesophagus change to the cells similar to the cells of the stomach. In Barrett’s oesophagus the cells become similar to the glandular tissue that lines the intestine; these cells can change to high grade dysplasia which is a precancerous form of Barrett’s oesophgus.20 Carcinomas can occur at any level of the oesophageal tract but are most common at the gastro-oesophageal junction. Oesophageal cancer is one of the most rapidly spreading malignancies. The oesophagus itself has several unique properties that facilitate early metastatic spread of cancer in most patients. In contrast to the rest of the gastrointestinal tract, the oesophagus has an extensive network of lymphatics and no serosa; together, this allows for early spread and invasion of cancer cells into surrounding tissue. The pathogenesis of oesophageal carcinoma is facilitated by: (1) alterations of oesophageal structure and function that permit food and drink to remain in the oesophagus for prolonged periods; (2) ulceration and metaplasia caused by oesophageal reflux; (3) chronic exposure to irritants, such as alcohol and tobacco, which cause neoplastic transformation; and (4) obesity (see Chapter 35).21 Chronic inadequate nutrition can impair oesophageal structure and function (see Box 27.3). CLINICAL MANIFESTATIONS
The most common symptom that a patient presents with to a doctor is dysphagia (difficulty swallowing). Less common symptoms are reflux, chest pain, bleeding and weight loss.20 Dysphagia is usually pressure-like and may radiate posteriorly between the scapulae (triangular bones forming the back part of the shoulder). Dysphagia usually progresses rapidly and is mostly painless during the early stages of oesophageal carcinoma.
BOX 27.3
Oesophageal cancer
Carcinoma of the oesophagus is a rare type of cancer, with approximately 1400 new cases each year; males are almost three times more likely to be diagnosed than females.1 Mortality rate is high, 1-year survival is approximately 45%, with only 18% expected to be alive in 5 years.1 Over the last few decades the survival rate has improved; however, patients often present later, with a more advanced and aggressive tumour with the most common presentation being dysphagia (difficulty in swallowing).20
805
• • • • • • • •
Risk factors for oesophageal cancer
Smoking Age over 50 years Male Obesity Alcohol Gastro-oesophageal reflux disease Reflux oesophagitis with dysplasia (Barrett’s oesophagus) Frequent consumption of very hot drinks
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Stage 0 (carcinoma in situ or high grade dysplasia)
Severely abnormal cells in the inner lining of the oesophagus. If left untreated some of these cells may change into an invasive cancer. People with Barrett’s oesophagus are at risk of developing these abnormal cells
Stage I
Cancer is found within the oesophageal wall. It has not spread to nearby tissues, lymph nodes or other organs
Stage II
Cancer has invaded the muscle layer or outer layer of the oesophagus, but has not spread to nearby lymph nodes, or cancer has grown no further than the muscle layer, but is in 1 or 2 lymph nodes. The cancer has not spread to any other organs
Stage III
Stage IV
Cancer has grown into the membrane covering the oesophagus, spread to nearby lymph nodes and into the tissue covering the lungs (pleura), the outer covering of the heart (pericardium) or the diaphragm, but has not spread to another part of the body Cancer has spread to other parts of the body, such as the liver, lungs or bones
Typical location of carcinomas
Pylorus
Le
ure
DESCRIPTION
at
STAGES
Gastric adenocarcinoma usually begins in the glands of the distal stomach mucosa. Approximately 50% of cases develop in the pre-pyloric antrum (see Fig. 27.5). Helicobacter pylori infection induces an inflammatory process in the gastric mucosa that usually lasts for many years and may lead to gland loss (atrophy). Subsequently, the gastric epithelium is replaced by cells with intestinal-type columnar cells (intestinal metaplasia) which is strongly linked to the development of gastric cancer.23 Insufficient acid secretion by the atrophic mucosa creates a relatively alkaline
rv
TABLE 27.4 Staging of oesophageal cancer
PATHOPHYSIOLOGY
r v a t ure
Gastric (stomach) cancer is a relatively common cancer with males more likely to be diagnosed than females. It accounts for approximately 1500 new diagnoses each year in Australia.1 Gastric cancer is within the top 10 cancer incidence and mortality for males in New Zealand.1 One-year survival is approximately 51%, with five-year survival reduced to approximately 26%.1 Gastric cancer traditionally has been prevalent in countries where the diet is high in salted and preserved foods (see Table 27.1), such as in some Asian countries. A combination of international dietary influences and immigration may be contributing to the rate of gastric cancer in Australia.
cu
Gastric cancer
The most important environmental causative factors of gastric cancer are: (1) infection with Helicobacter pylori; (2) intake of heavily salted and preserved foods (namely nitrates in pickled or salted foods such as bacon); (3) low intake of fruits and vegetables; and (4) use of tobacco and alcohol.23 Dietary salt enhances the conversion of nitrates to carcinogenic nitrosamines (cancer-causing chemical compounds) in the stomach, so the combination of both the nitrates and the sodium in the food will increase this conversion to harmful nitrosamines. Salt is also caustic to the stomach and can cause chronic atrophic gastritis. Nitrates are thought to cause stomach cancer once atrophic gastritis has occurred. Helicobacter pylori-associated gastritis increases the risk for gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma. Finally, the presence of salt delays gastric emptying — this increases the time during which carcinogenic nitrosamines can exert their effects on the stomach mucosa. Other non-environmental risk factors are a family history of gastric adenocarcinoma and pernicious anaemia (see Chapter 17), which results from atrophy of the gastric mucosa in the same locations where gastric tumours arise.
er
EVALUATION AND TREATMENT
Individuals with dysphagia undergo endoscopy with biopsy, and the tissue is examined for neoplastic change. Endoscopic ultrasound is also used to determine stage of the cancer, and general stages of oesophageal cancer are shown in Table 27.4. Prevention of gastro-oesophageal reflux is essential to the management of Barrett’s oesophagus. Oesophageal cancer metastasises rapidly and therefore has a poor prognosis — this explains why, despite moderately low incidence, it ranks high on the cancer causes of death. If the malignancy has not spread beyond the local lymph nodes, surgical removal of the tumour usually has excellent prognosis. If metastasis has occurred, incomplete resection is of little benefit for survival. Treatment is combined radiation and chemotherapy.22
ss
806
cu
Grea
ter
FIGURE 27.5
Typical sites of gastric cancer. Gastric cancer is mainly found in the pre-pyloric region.
CHAPTER 27 Alterations of digestive function across the life span
environment that permits bacteria to multiply, whereby they can metabolise the nitrates to nitrosamines. The resulting increase in nitrosamines further damages the DNA of mucosal cells, promoting metaplasia and neoplasia (replacement of cells with different cell types or tumorous cells, respectively). Duodenal reflux may also contribute to intestinal metaplasia. The reflux contains caustic bile salts that destroy the mucosal barrier, which normally protects the stomach. CLINICAL MANIFESTATIONS
The early stages of gastric cancer are generally asymptomatic or produce vague symptoms such as loss of appetite (especially for meat), malaise (tiredness) and indigestion. Later manifestations include unexplained weight loss, upper abdominal pain, vomiting, change in bowel habits and anaemia caused by persistent occult (unseen) bleeding. The prognosis is poor because symptoms do not occur until the tumour has penetrated the muscle layers of the stomach, spread to surrounding tissues and entered the draining lymph nodes and veins, causing distant metastases, particularly to the liver and peritoneal structures. Generally the first manifestations of carcinoma are caused by distant metastases when the disease is already in an advanced stage. EVALUATION AND TREATMENT
Most symptoms suggest a problem in the upper gastrointestinal tract and a barium x-ray film shows the lesion. Direct endoscopic visualisations using a scope down the oesophagus and biopsy usually establish the diagnosis. Another definitive technique is microscopic examination of exfoliated cells obtained by lavage during endoscopy. The broad stages of gastric cancer are shown in Table 27.5. Surgery is the only curative treatment if cancer is detected at the early stages. For locally advanced disease, chemotherapy is usually implemented in combination with surgery.24 Radiation therapy is generally unsuccessful and immunotherapy is still experimental. Chemotherapy combined with radiation reduces the tumour. In metastatic disease, outcomes are poor, with survival being approximately 1 year.24 Individuals who respond well to chemotherapy generally live longer than those who do not.
F O CUS O N L E A R N IN G
1 List the processes that facilitate the development of oesophageal cancer. 2 Briefly describe the two main symptoms of oesophageal cancer. 3 Relate the metastasis of oesophageal cancer to the expected prognosis. 4 Describe how environmental causes can contribute to the development of gastric cancer.
807
TABLE 27.5 Staging of gastric cancer STAGES
DESCRIPTION
Stage 0 (Carcinoma in situ)
Cancer cells in the stomach lining completely contained within the innermost layer of the lining, so there is very little risk of cancer spread
Stage I
Cancer has grown into the stomach lining or the muscle, with no or little spread to nearby lymph nodes
Stage II
Cancer is still within the lining of the stomach, has grown into the muscle or outer layers and might have invaded nearby lymph nodes
Stage III
Cancer has grown into the stomach muscle and outer layers and spread to nearby lymph nodes or through the stomach wall into nearby tissues and organs, such as the liver, colon, or spleen
Stage IV
Cancer has spread to body organs further away from the stomach, such as the lungs, brain or bones
Inflammatory disorders of the gastrointestinal tract
Ulcerative colitis and Crohn’s disease together are known as the inflammatory bowel diseases (IBD). There are more than 75 000 people in Australia and 15 000 people in New Zealand living with IBD.25,26 The number is expected to be more than 100 000 by 2022. Although the diseases have some unique differences, factors such as genetics, immune dysregulation, epithelial barrier dysfunction and microbial flora have some role for pathogenesis of both diseases. In some patients, distinguishing between ulcerative colitis and Crohn’s disease may be difficult (see Table 27.6).
Ulcerative colitis
Ulcerative colitis is a chronic inflammatory disease that causes ulceration of the colonic mucosa, usually in the rectum and sigmoid colon. The lesions appear in susceptible individuals between 20 and 40 years old; however, ulcerative colitis is commonly diagnosed at an advanced age. Risk factors include a family history of the disease. It is estimated that it affects 33 000 people in Australia and 6700 in New Zealand, with numbers in both countries increasing.25,26 Although the cause of ulcerative colitis is unknown, infectious, genetic and immunological factors have all been suggested.27 Immune system causes include humoral immunological factors and activated macrophages. Anti-colon antibodies have been identified in the sera (lining of the bowel) of individuals with ulcerative colitis. T lymphocytes in individuals with ulcerative colitis may have cytotoxic effects on the epithelial cells of the colon. Furthermore, autoimmune disorders such as systemic lupus erythematosus, psoriasis and rheumatoid arthritis may accompany ulcerative colitis.28
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TABLE 27.6 Features of ulcerative colitis and Crohn’s disease FEATURE
ULCERATIVE COLITIS
CROHN’S DISEASE
Incidence Age at onset
20–40 years most common
15–40 years most common
Family history
Less common
More common
Cancer risk
Increased
Increased
Large intestine
Large and small intestine, ‘skip’ lesions common
Pathophysiology Location of lesions
Left side more common
Right side more common
Inflammation and ulceration
Mucosal layer involved
Entire intestinal wall involved
Granulomas
Rare
Common
Friable mucosa
Common
Less common
Anal and perianal fistulae
Rare
Common; abscesses
Narrowed lumen and possible obstruction
Rare
Common; obstruction
Clinical manifestations Abdominal pain
Mild to severe
Moderate to severe
Diarrhoea
Common; 4 times/ day
Common; 4 times/ day
Bloody stools
Common
Less common
Abdominal mass
Rare
Common
Small intestinal malabsorption
Rare
Common
Steatorrhoea
Rare
Common
Clinical course
Remissions and exacerbations
Remissions and exacerbations
PATHOPHYSIOLOGY
The primary lesion of ulcerative colitis begins with inflammation at the base of the crypt of Lieberkühn in the large intestine. The disease is most severe in the rectum and sigmoid colon (see Fig. 27.6). The mucosa is hyperaemic (contains excess blood) and may appear dark red and velvety. Small erosions form and develop into ulcers. Abscess formation causes areas of inflammation and pus, while necrosis indicates death of cells. Ragged ulceration of the mucosa ensues. Oedema and thickening of the muscularis mucosae may narrow the lumen of the involved colon. Mucosal destruction causes bleeding, cramping pain and an urge to defecate. Frequent diarrhoea, with passage of small amounts of blood and purulent mucus (containing pus), is common. Loss of the absorptive mucosal surface
and rapid colonic transit time cause large volumes of watery diarrhoea. CLINICAL MANIFESTATIONS
The course of ulcerative colitis consists of intermittent periods of remission and exacerbation. Mild ulcerative colitis involves less mucosa, so that frequency of bowel movements, bleeding and pain are minimal. Severe forms may involve the entire colon and are characterised by fever, elevated pulse rate, frequent diarrhoea (10–20 stools per day), urgency, obviously bloody stools and continuous crampy pain. Dehydration, weight loss, anaemia and fever result from fluid loss, bleeding and inflammation. Complications include anal fissures, haemorrhoids (dilated anal veins, often referred to as piles) and perirectal abscess. Severe haemorrhage is rare. Oedema, strictures (narrowing) or fibrosis (increased fibrous tissue) can obstruct the colon. Perforation is an unusual but possible complication. The risk of colon cancer increases significantly after 10 years of ulcerative colitis and therefore regular colonoscopies are recommended.29 The systemic manifestations include polyarthritis (arthritis at two or more joints), episcleritis (inflammation of the sclera of the eyes), disorders of the liver and alterations in coagulation.
Crohn’s disease
Crohn’s disease (also known as granulomatous colitis or regional enteritis) is an inflammatory disorder that can affect any part of the digestive tract, is incurable and normally results in repeated surgical resection and intensive medical therapy.25 Risk factors and theories of causation are the same as those for ulcerative colitis, including genetic predisposition and an altered immune response to normal bowel flora.27 In some cases, Crohn’s disease is difficult to differentiate from ulcerative colitis (see Table 27.6). The prevalence of Crohn’s disease may be lower than ulcerative colitis in Australia (affecting 28 000 people), but higher in New Zealand (affecting more than 7000 people). Crohn’s disease is usually diagnosed between the ages of 15 and 40. Of affected individuals, 10–20% have a positive family history. Increased suppressor T cell activity, alterations in immunoglobulin A (IgA) production, macrophage activation, bacterial flora, antigens and susceptibility genes are factors associated with Crohn’s disease.30 Psychological stresses also appear to be causative of both Crohn’s disease and ulcerative colitis. Smoking increases the risk of developing severe disease. PATHOPHYSIOLOGY
The inflammation process of Crohn’s disease begins in the intestinal submucosa and spreads inwards and outwards to involve all layers of the intestinal wall (transmural inflammation). Reduced levels or absence of mucin secretion occur in Crohn’s disease causing changes in the mucosal layer, increased intestinal permeability and greatly enhanced susceptibility to luminal inflammation-inducing toxins. Activated neutrophils and macrophages promote
CHAPTER 27 Alterations of digestive function across the life span
809
B Ulcerative colitis
A
20% 30%
50%
FIGURE 27.6
Ulcerative colitis. A Approximately 50% of cases of ulcerative colitis occur in the rectosigmoid area with 30% of cases extending to hepatic flexure. In 20% of cases ulcerative colitis is diffuse. B The mucosa has been ulcerated away in a severe case of ulcerative colitis.
A
B
Caecal/right colon disease • Combined with ileal (50%) • Alone (20%) Adhesions Terminal ileitis
Fistula Peritonitis Perianal abscesses and fistula
FIGURE 27.7
Crohn’s disease. A The disease is localised to the terminal ileum and ascending colon and the transverse colon in most cases. B A segment of colon that has a thickened wall and in which the mucosa has lost the regular folds, indicative of Crohn’s disease.
inflammation and cause tissue injury. The terminal ileum, ascending colon and the transverse colon are the most common sites of the disease. The inflammation can affect some segments of the intestine but not others, creating ‘skip lesions’ (see Fig. 27.7). Also one side of the intestinal wall may be affected and not the other. The ulcerations of Crohn’s disease produce fissures (tears) that extend inflammation into lymphoid tissue. The typical lesion is a granuloma (small nodule of inflammation) with a cobblestone appearance from projections of inflamed tissue surrounded by ulceration. Fistulae (tube-like connections) may form in the perianal area between loops of intestine or extend into the bladder, such that one part of the intestine is able to connect directly into another area. Strictures may develop, promoting
obstruction. Damage to the enteric nervous system underlies bowel dysfunction in these patients; see ‘Research in Focus: Enteric nervous system in inflammatory bowel disease’. CLINICAL MANIFESTATIONS
Individuals with Crohn’s disease may have no specific symptoms other than an ‘irritable bowel’ for several years. Diarrhoea is the most common sign and, occasionally, colonic bleeding. Weight loss, vomiting, fever and lower abdominal pain accompany Crohn’s disease. If the ileum is involved, the individual may be anaemic as a result of malabsorption of vitamin B12. There may also be deficiencies in folic acid and vitamin D absorption. In addition, proteins may be lost, leading to hypoalbuminaemia (low blood
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albumin). Complications are similar to those occurring in ulcerative colitis, including increased risks of colorectal cancer, lymphoma and osteoporosis.25 When experiencing a flare, patients require near-continuous care to address their clinical needs and surgical treatment is often required to control disease or manage the associated complications.31
RESEARCH IN F CUS Enteric nervous system in inflammatory bowel disease Studies in patients with inflammatory bowel disease (IBD) and in animal models of intestinal inflammation have demonstrated that disordered functions of the gastrointestinal tract are closely associated with malfunctioning of the enteric nervous system (ENS). It has been found that inflammation kills 1 in 5 neurons and permanently alters functions of many remaining neurons in the ENS. Changes in ion channels on the membrane of enteric neurons lead to neuronal hyperexcitability which persists long after the initial inflammatory insult. Alterations in neuropeptide expression, changes in neurotransmitter release and synaptic transmission in enteric neural circuits occur. Invasion of the immune cells into the myenteric and submucosal plexuses (plexitis) are predictive of Crohn’s disease recurrence. The damage to and death of enteric neurons, changes in their electrophysiological properties and changes in synaptic transmission underlie persistent alterations in motility, secretion and gastrointestinal sensation caused by intestinal inflammation. Studies of functional properties of enteric neurons in the inflamed intestine are of great significance for understanding mechanisms underlying intestinal dysfunctions and identification of new targets for effective therapies.
EVALUATION AND TREATMENT OF INFLAMMATORY BOWEL DISEASE
Diagnosis and treatment of ulcerative colitis and Crohn’s disease are similar. The diagnosis is based on the medical history and clinical manifestations. Sigmoidoscopy, barium enema and x-ray films are used in addition to laboratory data. Infectious causes are ruled out by stool culture. Treatment is individualised and depends on the severity of symptoms and the extent of mucosal involvement. First-line standard treatment for IBD includes antibiotics and steroids. A wide range of antibiotics is used to induce and maintain remission, however, the use of antibiotics can lead to dysbiosis in the gastrointestinal tract.32 Steroids suppress the inflammatory response and help to alleviate the cramping pain. Cyclosporine (immunosuppressant) is used for acute severe presentations that have an inadequate response to corticosteroid therapy.33 Infliximab is a monoclonal antibody which binds to tumour necrosis factor alpha (TNFα), and is given as an infusion to reduce the amount of this protein in the body.34 Intravenous
administration of iron may be required, as the inflammatory tissue may prevent absorption of oral iron. Severe, unremitting disease can require hospitalisation and administration of intravenous fluids and support nutrition, such as parenteral nutrition. Surgical resection of the colon may be performed if other forms of therapy are unsuccessful or if there are acute serious complications (sepsis, haemorrhage, perforation, fistula, abscess or obstruction). Proctocolectomy and ileal pouch anal anastomosis have become the standard surgery for IBD; however with pharmacological treatment becoming much more successful, this will hopefully reduce the need for surgery.35 Routine endoscopy for cancer screening should be performed for long-standing disease. Currently, there is no cure for IBD; standard therapies can only reduce the inflammatory process and symptoms of IBD and aim to induce long-term remission. Many of the drugs used to treat IBD, particularly immunosuppressive agents, have a number of well-recognised adverse effects and are often ineffective. Since their use can result in significant adverse events that increase morbidity, patients must be aware of the risks associated with treatment and must be strictly monitored. Although treatment with biologic drugs is not successful in all patients and many of them lose clinical response, new therapies are currently under evaluation.34 There are great advances through clinical trials worldwide looking at new pharmacological treatments for ulcerative colitis and Crohn’s disease. The use of stem cells that have strong immunomodulating potential is an emerging treatment option; see ‘Research in Focus: Stem cell therapy for inflammatory bowel disease’.
Irritable bowel syndrome
Irritable bowel syndrome is a functional gastrointestinal disorder with no specific structural alterations as a cause of disease. It is broadly characterised by abdominal pain and discomfort associated with altered bowel habits. About 10% of the Australian population is estimated to have the disorder36 and it is more common in women, with a greater prevalence during youth and middle age. Individuals with this syndrome are also more likely to have anxiety and depression. Symptoms of irritable bowel syndrome can negatively affect quality of life and activity and present a significant economic burden. PATHOPHYSIOLOGY
The pathophysiology of irritable bowel syndrome is difficult to define, as structural changes do not occur. Some alternative theories for explaining the symptoms are listed here. • Visceral hypersensitivity or hyperalgesia (refer to Chapter 7), particularly with distension of the rectum but also other areas of the gut. The mechanism may be related to a dysregulation of the ‘brain–gut axis’ (the central nervous system’s innervation of the digestive system), the role of serotonin (5-hydroxytryptamine) in the enteric nervous system, changes in the properties (hyperexcitability) of intrinsic sensory neurons in the enteric nervous system
CHAPTER 27 Alterations of digestive function across the life span
RESEARCH IN F CUS Stem cell therapy for inflammatory bowel disease Current treatments for inflammatory bowel disease (IBD) have limited efficacy and induce side effects; large number of patients become refractory (non-responsive) to treatments. In recent years, mesenchymal stem (stromal) cells (MSCs) have gained significant attention due to their therapeutic potential. MSCs are multipotent stem cells that can be derived from many adult tissues including blood, bone marrow and adipose tissue. MSCs are currently being used in clinical trials to treat many disorders including arthritis, multiple sclerosis and IBD. MSCs have many unique biological characteristics that allow them to escape immune rejection and induce endogenous repair mechanisms. MSCs have been shown to induce wound healing and regeneration of damaged tissues following inflammation, injury and destruction. MSCs act in a paracrine manner and secrete large amounts of bioactive factors (cytokines, antioxidants, antiapoptotic, trophic, growth factors) which can reduce inflammation, support cell survival and create an environment favourable for regeneration by endogenous cells. These properties make MSCs a viable therapeutic option in managing IBD. MSCs have shown promising effects in both animal models of IBD and human trials. Clinical trials using MSCs for the treatment of complex perianal fistulas associated with Crohn’s disease and luminal inflammation have demonstrated that MSC therapy in IBD is both efficacious and feasible. MSC therapy is a promising therapeutic option for severe refractory cases especially when surgery is not feasible. However, many unsolved questions concerning the optimal origin and source of MSCs, dosage and modalities of administration need to be further studied. Moreover, MSCs still need to prove their effectiveness compared with conventional treatments in clinical trials.
•
•
•
•
•
811
delayed transit times. Acute intestinal inflammation can cause structural and functional changes to the intestinal innervation which might persist long after healing of the damaged tissues. These changes in intestinal innervation play a fundamental role in the abnormal motility and secretion associated with irritable bowel syndrome.38 Intestinal infection (bacterial enteritis). Intestinal infection with irritable bowel syndrome is common where symptoms of irritable bowel syndrome appear. It appears to be related to ongoing low-grade inflammation and an abnormal immune response in gut tissues.39 Overgrowth or altered composition of intestinal flora (normal gut bacteria). This may precipitate symptoms and it is proposed that methane gas may slow intestinal transit time, resulting in constipation and bloating.40 Altered gut microbiota compositions could lead to dysregulation of the intestinal barrier, increased intestinal permeability leading to increased translocation of pathogenic bacteria and endotoxins into systemic circulation.41 Bile salt malabsorption. Bile salts are actively reabsorbed in the terminal ileum by the bile salt transporter. Bile salt malabsorption is a common but frequently under-recognised cause of chronic diarrhoea.42 Food allergy or food intolerance. Food antigens may activate the mucosal immune system mediating hypersensitivity reactions and symptoms of irritable bowel syndrome. Food elimination approaches are helpful in some cases.39 Psychosocial factors, including emotional stress, influence brain–gut interactions.39
CLINICAL MANIFESTATIONS
Irritable bowel syndrome is characterised by lower abdominal pain or discomfort; predominant diarrhoea, predominant constipation or alternating diarrhoea and constipation; gas and bloating; and nausea. Symptoms are usually relieved with defecation and do not interfere with sleep. EVALUATION AND TREATMENT
F O CUS O N L E A R N IN G
1 Relate the pathophysiology of ulcerative colitis to the clinical manifestations. 2 Relate the pathophysiology of Crohn’s disease to the clinical manifestations. 3 Compare and contrast features of ulcerative colitis and Crohn’s disease. 4 List the treatment options for ulcerative colitis and Crohn’s disease.
or alterations in autonomic or central nervous system processing of information.37 • Abnormal gastrointestinal motility and secretion. Individuals with diarrhoea have more rapid colonic transit times, whereas those with bloating and constipation have
The diagnosis of irritable bowel syndrome is based on signs and symptoms, as there are no specific tests to confirm this syndrome. The diagnostic criteria include abdominal pain being relieved by defecation, and changes in the frequency and appearance of the faeces.43 Diagnostic procedures to rule out other causes of symptoms may include endoscopic evaluations, scans or abdominal ultrasound, blood tests, and tests for lactose intolerance or coeliac disease (discussed in ‘Nutritional disorders’ below). The patient may be evaluated for food allergies, parasites or bacterial growth. There is no cure for irritable bowel syndrome and treatment is individualised to symptoms. Options may include laxatives and fibre, antidiarrhoeals, antispasmodics, low-dose antidepressants and visceral analgesics. Drugs that interact at the serotonin (5-hydroxytryptamine) receptors are used for more severe symptoms; for example, 5-hydroxytryptamine 4 receptor agonists may be used for severe constipation, and 5-hydroxytryptamine 3 receptor
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antagonists may be used for severe diarrhoea. Alternative therapies include probiotics. Research continues to advance the management of this complex syndrome.
Diverticular disease
Large intestine (colon)
Diverticula are abnormal sac-like outpouchings of mucosa through the muscle layers, usually in the wall of the sigmoid colon. This condition is known as diverticulosis, and occurs when small defects in the muscle of the wall of the large intestine or colon allow small pockets or pouches (diverticula) to form. Diverticulitis is infection or inflammation of these abnormal pouches. Diverticular disease is most common in the elderly, but the incidence is increasing in younger individuals, particularly when much of the diet consists of refined foods.
Diverticula
PATHOPHYSIOLOGY
Although diverticula can occur anywhere in the gastrointestinal tract, the most common site is the sigmoid colon. They arise from increases in intraluminal pressure, particularly at weak points in the colon wall, usually where arteries penetrate the tunica muscularis to nourish the mucosal layer (see Fig. 27.8). A common associated finding is thickening of the circular and longitudinal muscles surrounding the diverticula. Hypertrophy and contraction of these muscles increase intraluminal pressure and degree of herniation. Regular consumption of a low-fibre diet reduces faecal bulk, thus reducing the diameter of the colon. The resulting pressure within the narrow lumen can increase enough to rupture the diverticula (see Fig. 27.9). CLINICAL MANIFESTATIONS
EVALUATION AND TREATMENT
Diverticula are often discovered during diagnostic procedures performed for other problems. Sigmoidoscopy permits direct observation of the lesions. Ultrasound and barium enema reveal the muscle hypertrophy, but barium may become trapped in the diverticula and form hard masses. Abdominal CT scanning is used for complicated cases. An increase of dietary fibre intake often relieves symptoms. Importantly, fluid intake must also be increased for fibre to be effective. Surgical resection may be required for diverticulitis or if there are severe complications.
FIGURE 27.8
Diverticula. Abnormal outpouchings of the colon are called diverticula. When they become inflamed, the condition is called diverticulitis.
Gut wall muscle hypertrophy
Low fibre diet causes
causes
Narrowing of intestinal diameter leads to
Increased pressure leads to
Diverticula
FIGURE 27.9
Factors contributing to the formation of diverticula. Diverticuli are commonly caused by a low-fibre diet, and excess growth of the muscle of the gut wall.
CONCEPT MAP
Symptoms of diverticular disease may be vague or absent. Diverticulosis is common and frequently causes no symptoms. Diverticulitis may be painful and disabling and is often a medical emergency. Cramping pain of the lower abdomen can accompany constriction of the hypertrophied colonic muscles. Diarrhoea, constipation, distension or flatulence (accumulation of gas) may occur. If the diverticula become inflamed or abscesses formed, the individual develops fever, leucocytosis (increased white blood cell count) and tenderness of the lower left quadrant. Severe complications, such as haemorrhage, peritonitis, bowel obstruction and fistula formation, are rare.
CHAPTER 27 Alterations of digestive function across the life span
813
F O CUS O N L E A R N IN G
1 Briefly discuss the symptoms of irritable bowel syndrome. 2 List the factors contributing to pathophysiology of irritable bowel syndrome. 3 Relate the treatment options of irritable bowel syndrome to the clinical manifestations. 4 Discuss the formation of diverticula. 5 List the clinical manifestations of diverticular disease.
Appendicitis
Appendicitis is an inflammation of the appendix and is the most common surgical emergency of the abdomen as it affects 7–12% of the population. It generally occurs between 20 and 30 years of age, although it may develop at any age.44 FIGURE 27.10
PATHOPHYSIOLOGY
The exact mechanism of the cause of appendicitis is controversial. Obstruction of the lumen with stool, tumours or foreign bodies with consequent bacterial infection is the most common theory. The obstructed lumen does not allow drainage of the appendix and, as mucosal secretion continues, intraluminal pressure increases. The increased pressure decreases mucosal blood flow and the appendix becomes hypoxic. The mucosa ulcerates, promoting bacterial or other microbial invasion with further inflammation and oedema. Inflammation may involve the distal or entire appendix. Gangrene (tissue necrosis) develops (see Fig. 27.10) from thrombosis of the luminal blood vessels, followed by perforation of the appendix. CLINICAL MANIFESTATIONS
Gastric or peri-umbilical (around the umbilical region) pain is the typical symptom of an inflamed appendix (see Fig. 27.11). The pain may be vague at first, increasing in intensity over 3–4 hours. It may subside and then recur in the right lower quadrant, indicating extension of the inflammation to the surrounding tissues. Nausea, vomiting and anorexia follow the onset of pain and a low-grade fever is common. Diarrhoea occurs in some individuals, particularly children; others have a sensation of constipation. Perforation, peritonitis and abscess formation are the most serious complications of appendicitis. EVALUATION AND TREATMENT
In addition to clinical manifestations, the clinician can usually locate the painful site with one finger. Rebound tenderness (pain evident upon sudden release of pressure from the abdomen, usually indicative of inflammation in the peritoneum) is usually in the right lower quadrant. There may be an increased white blood cell count, indicative
Acute appendicitis. Note the arrow showing inflamed tissue surrounding the base of a gangrenous appendix (which appears black).
of inflammation (see Chapter 13). Ultrasonography and CT scans can assist in differentiating appendicitis from perforated ulcer or cholecystitis (gallbladder inflammation). Laparoscopy (insertion of a scope into the abdominal cavity) may be necessary. Appendectomy is the treatment for simple or perforated appendicitis. This surgery provides quick recovery for simple appendicitis.
Gastritis
Gastritis is an inflammatory disorder of the gastric mucosa. It can be acute or chronic and affect the fundus or antrum, or both. Acute gastritis erodes the surface epithelium and usually results only in superficial damage. The stomach’s protective mucosal barrier is damaged by some drugs, with aspirin well known for being harsh on the stomach lining. Aspirin and some other anti-inflammatory drugs may cause gastritis by inhibiting prostaglandins that normally stimulate the secretion of mucus. Hence, there is less protective mucus in the stomach. Digoxin, a drug used to increase the force of contraction of the heart, can also contribute to the development of gastritis. Acute gastritis occurs most commonly due to alcohol consumption. The clinical manifestations of acute gastritis can include vague abdominal discomfort, epigastric tenderness (in the upper middle portion of the abdomen) and bleeding. Healing usually occurs spontaneously within a few days. Discontinuing injurious drugs, using antacids (agents neutralising stomach acidity) or decreasing acid secretion facilitates healing.
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1. General periumbilical pain increasing in severity as inflamed appendix is distended
3. RUPTURE; PAIN DECREASES temporarily when appendix ruptures and spills contents into peritoneal cavity
2. Localised: severe LRQ pain, deep localised tenderness on palpation as parietal peritoneum over appendix becomes inflamed
4. Peritonitis causes severe steady abdominal pain as infection spreads
FIGURE 27.11
Typical progression of pain in acute appendicitis. Pain in appendicitis commences as generalised abdominal pain, becoming more localised, and becoming more severe and widespread as the inflammation and infection spreads. LRQ = lower right quadrant.
Chronic gastritis tends to occur in the elderly and causes thinning and degeneration of the stomach wall. Chronic atrophic gastritis, also called fundal gastritis, is the most severe type. The gastric mucosa degenerates extensively in the body and fundus of the stomach, leading to gastric atrophy. Loss of chief cells and parietal cells diminishes acid secretion. Pernicious anaemia develops because less intrinsic factor is secreted to facilitate vitamin B12 absorption in the ileum. The pathogenesis may result from an autoimmune disorder, as indicated by the presence of antibodies to the parietal cells, intrinsic factor and gastric cells. Helicobacter pylori infection can also promote mucosal atrophy and tissue injury. Chronic atrophic gastritis is a risk factor for gastric carcinoma, particularly in individuals who develop pernicious anaemia. Chronic gastritis in the antrum only occurs approximately four times more often than atrophic gastritis. It is not associated with decreased hydrochloric acid secretion,
pernicious anaemia or the presence of parietal cell antibodies. Helicobacter pylori is also a major causative factor and mucosal atrophy is rare. In approximately 10% of cases, antibodies to gastrin-secreting cells are found in the serum. Chronic reflux of bile and pancreatic enzymes may contribute to the gastritis by persistently disrupting the mucosal barrier. Gastroscopy (direct visualisation of the stomach with a camera called an endoscope) and biopsy may show a long-standing inflammatory process and gastric atrophy in an individual with no history of abdominal distress. Gastric secretions can be evaluated for hydrochloric acid and intrinsic factor secretion. Individuals may report vague symptoms, including anorexia, fullness, nausea, vomiting and epigastric pain. Gastric bleeding may be the only clinical manifestation of gastritis. Symptoms can usually be managed with smaller meals; a soft, bland diet; and avoidance of alcohol and aspirin.
CHAPTER 27 Alterations of digestive function across the life span
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Helicobacter pylori infection is treated with antibiotics, and vitamin B12 is administered to correct pernicious anaemia.
factors for peptic ulcer disease are summarised in Box 27.4 ‘Risk factors for peptic ulcer’.
Peptic ulcer disease
GASTRIC ULCERS
A peptic ulcer is a break or ulceration in the protective mucosal lining of the stomach or duodenum. Such breaks expose submucosal areas to gastric secretions and autodigestion (digestion of gut mucosa by the body’s secretions). Peptic ulcers can be acute or chronic, superficial or deep. Superficial ulcerations are called erosions because they erode the mucosa but do not penetrate the muscularis mucosae. True ulcers extend through the muscularis mucosae and damage blood vessels, causing haemorrhage, or perforate the gastrointestinal wall (see Fig. 27.12). Risk
A
Gastro-oesophageal sphincter
Oesophagus Oesophageal ulcer
Fundus
Gastric carcinoma Pyloric sphincter Greater curvature
Duodenal ulcers Duodenum
Antrum
Gastric ulcer Inflammation
B Mucus
PATHOPHYSIOLOGY
Use of non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori infection are major causes of gastric ulcer. Generally, gastric ulcers develop in the antral region, adjacent to the acid-secreting mucosa of the body of the stomach. The mucosal barrier becomes altered, such that acid (hydrogen ions) can penetrate to deeper tissue layers more easily. Gastric secretion may be normal or less than normal. Reflux of bile from the duodenum into the stomach disrupts the gastric mucosa and can permit acid (hydrogen ions) to diffuse into the mucosa, where they damage cellular structure (see Fig. 27.13). A vicious cycle can be established as the damaged mucosa liberates histamine, which further stimulates the increase of acid production (see Fig. 27.14). Destruction of small vessels causes bleeding. Chronic gastritis is often associated with development of gastric ulcers and may precipitate ulcer formation by limiting the mucosa’s ability to secrete a protective layer of mucus. CLINICAL MANIFESTATIONS
Mucosa Submucosa Muscularis layer Serosa (visceral peritoneum)
Gastric ulcers are ulcers of the stomach; they occur about equally in males and females, usually between the ages of 55 and 65 years. They are about one-quarter as common as duodenal ulcers (see Table 27.7).
Blood vessel (potential haemorrhage)
The main clinical manifestation of gastric ulcers is intermittent pain in the epigastric region. Pain is relieved by ingestion of food, which creates a typical pain–food–relief pattern. However, the pain of gastric ulcers also may occur immediately after eating. Gastric ulcers tend to be chronic rather than alternating between periods of remission and
Stomach contents
C
Perforated ulcer
Chyme flows from inside stomach through wall into peritoneal cavity Peritoneal cavity FIGURE 27.12
Peptic ulcers. A Common locations. B Peptic ulcer. C Perforated ulcer.
BOX 27.4
Risk factors for peptic ulcer
• Smoking • Advanced age • Habitual use of non-steroidal anti-inflammatory drugs (NSAIDs) • Alcohol • Chronic diseases, such as emphysema, rheumatoid arthritis, cirrhosis and diabetes • Psychological stress • Infection of the gastric and duodenal mucosa with Helicobacter pylori
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TABLE 27.7 Characteristics of gastric and duodenal ulcers CHARACTERISTICS
GASTRIC ULCER
DUODENAL ULCER
Age at onset
50–70 years
20–50 years
Family history
Usually negative
Positive
Sex (prevalence)
Equal in women and men
Greater in men
Stress factors
Increased
Average
Ulcer producing drugs
Normal use
Increased use
Cancer risk
Increased
Not increased
Abnormal mucus
May be present
May be present
Parietal cell mass
Normal or decreased
Increased
Acid production
Normal or decreased
Increased
Serum gastrin
Increased
Normal
Incidence
Pathophysiology
Associated gastritis More common
Usually not present
Helicobacter pylori
Usually present (95–100%)
Often present (60–80%)
FIGURE 27.13
Gastric ulcer. Folds in the stomach mucosa surround the ulcer (arrow), seen as a break in the mucosa and filled with blood.
Non-steroidal anti-inflammatory drugs or Helicobacter pylori infection
Clinical manifestations Located in upper abdomen Intermittent
Located in upper abdomen Intermittent
Pain–antacid or Pain–antacid–relief food–relief pattern pattern Pain when Food–pain pattern stomach empty (when food in stomach) Nocturnal pain common Clinical course
Chronic ulcer without pattern of remission and exacerbation
Pattern of remissions and exacerbation for years
Heals more slowly
Heals more quickly
results in Acid able to penetrate gastric mucus allows Acid damages cells of mucosa contributes to
Pain
as part of the inflammatory response Cells release histamine stimulates Acid production causing Formation of ulcer
FIGURE 27.14
The cause and progression of ulcers. A combination of acid penetrating the mucosa and increased acid production contribute to the formation of ulcers.
CONCEPT MAP
Stimulates reduced Stimulates acid acid secretion, hypersecretion gastric atrophy and risk of gastric cancer
CHAPTER 27 Alterations of digestive function across the life span
exacerbation. Gastric ulcers cause anorexia (loss of appetite), vomiting and weight loss. Complications include perforation of ulcer, resulting in acute bleeding, a common cause of mortality. DUODENAL ULCERS
Duodenal ulcers occur with greater frequency than other types of peptic ulcers and tend to develop in younger persons. PATHOPHYSIOLOGY
Infection with Helicobacter pylori and use of NSAIDs are the major cause of duodenal ulcer. Hypersecretion of acid and pepsin is the primary cause and inadequate secretion of bicarbonate by the duodenal mucosa may also be involved.45 Factors that contribute to ulcer formation include the following:46 • a greater than usual number of parietal (acid-secreting) cells in the gastric mucosa leading to increased basal and stimulated acid secretion and increased acid load in the duodenum • high serum gastrin levels that remain high longer than normal after eating and continue to stimulate secretion of acid and pepsin (may be caused by Helicobacter pylori) • Helicobacter pylori infection. All these factors, singly or in combination, cause acid and pepsin concentrations in the duodenum to penetrate the mucosal barrier and cause ulceration. CLINICAL MANIFESTATIONS
Clinical manifestations of duodenal ulcers are similar to gastric ulcers, with the main symptom of chronic intermittent pain in the epigastric area. Some individuals may have no symptoms; the first manifestation may be haemorrhage or perforation, particularly with a history of aspirin or anticoagulant use. Complications include bleeding, perforation and obstruction of the duodenum or outlet of the stomach. Bleeding is the most common cause of mortality, particularly among the elderly. Perforation occurs with destruction of all layers of the duodenal wall and causes sudden severe epigastric pain. Obstruction may be the result of oedema from inflammation or scarring from chronic injury. Duodenal ulcers often heal spontaneously but recur within months without treatment. Relief of pain accompanies healing. Bleeding from duodenal ulcers causes haematemesis (vomiting blood) or melaena (digested blood appearing in the faeces). STRESS ULCERS
A stress ulcer is an acute form of peptic ulcer that tends to accompany severe illness, systemic trauma or neural injury. Emotional stress may be causative.47 Usually multiple sites of ulceration are distributed within the stomach or duodenum.
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Decreased mucosal blood flow, mucosal ischaemia and reperfusion injury are important contributing events in stress ulcer formation. Stress ulcers may be classified as follows: • Ischaemic ulcer: develops within hours of events such as haemorrhage, multisystem trauma, severe burns, heart failure or sepsis that causes ischaemia of the stomach and duodenal mucosa. • Cushing’s ulcer: stress ulcer associated with severe head trauma or brain surgery that results from decreased mucosal blood flow and hypersecretion of acid caused by overstimulation of the vagus nerve.48 • Aphthous ulcers (also called canker sores) are recurring shallow, red or white round or oval sores or ulcers inside the mouth with no known cause. They can occur on the gums, inside of the lips and cheeks or underneath the tongue.49 The primary clinical manifestation of stress ulcers is bleeding. Acid suppression with antacids and proton pump inhibitors may provide the best prophylactic treatment. Stress ulcers seldom become chronic. EVALUATION AND TREATMENT OF PEPTIC ULCER DISEASE
The evaluation and treatment of gastric and duodenal ulcers are similar. X-ray examinations using barium may show an anatomical deformity created by the ulcer crater. Flexible endoscopic evaluations may also be performed. Testing gastrin levels can identify ulcers associated with gastric carcinomas (see Table 27.7). Helicobacter pylori can be detected by endoscopic evaluation and biopsy, serology or non-invasively with a urea breath test or stool antigen test.50 Management of duodenal and gastric ulcers is aimed at: (1) relieving the causes and effects of hyperacidity; (2) administering antacids and drugs that reduce acid secretion (such as proton pump inhibitors) and antibiotics, and, if Helicobacter pylori is present to be treated with antibiotics. Lifestyle modifications can assist in the treatment of ulcers, such as lowering stress levels, reducing the amount of drug therapy that acts as an irritant to the stomach or duodenum, and irritants such as alcohol and smoking. Smoking cessation has been shown to assist ulcer healing. The risk of ulcer may be reduced with a diet high in vitamin A and fibre.45 Endoscopic heater probes (which diathermy the ulcer) are effective to stop bleeding. Complications are treated with either endoscopic/radiologically or surgical approaches. In most cases, aphthous ulcers are harmless and resolve by themselves without medical treatment. If aphthous ulcers are severe and recurrent, topical or systemic therapy is applied. Traditionally, glucocorticoid, antimicrobial and anti-inflammatory therapies are administered topically or systemically to reduce pain, suppress inflammation and eliminate ulcers. Patients should be encouraged to maintain good oral hygiene, avoid foods that may trigger or prolong the eruption of new aphthae (e.g. nuts, acidic foods or drinks).49
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Necrotising enterocolitis is an ischaemic, inflammatory condition of the bowel that causes necrosis (cell damage), perforation and death if untreated. Necrotising enterocolitis occurs primarily in premature infants; affected infants have a mean gestational age of 31 weeks and weigh less than 1500 g (this is less than half the average full-term birth weight). As premature birth is associated with increased maternal age older than 35 years, the incidence of this disorder may increase as women in Australia and New Zealand have their babies at older ages. Current global estimates of as many as 15 million babies born preterm every year, accounting for 11% of live births worldwide.51,52 The risk of necrotising enterocolitis decreases as the gastrointestinal tract matures. PATHOPHYSIOLOGY
The exact pathophysiological mechanisms responsible for necrotising enterocolitis have yet to be identified. It is likely that the condition is multifactorial with several mechanisms proposed. Factors contributing to the development of necrotising enterocolitis include prematurity, very low birth weight, exaggerated inflammatory response to bacteria colonising the gastrointestinal tract, leading to mucosal destruction, infections, immunological injury, perinatal stress, congenital defects and the effects of medications and enteral feeding practices.52,53 Accumulation of gas in the mucosa and submucosa leads to reduced mucosal blood flow, ischaemia and necrosis of intestinal segments. The injury leads to release of inflammatory mediators, bacterial invasion or perforation of the bowel wall, or both.52
CLINICAL MANIFESTATIONS
Manifestations of necrotising enterocolitis usually appear within 2 weeks of birth. They range from mild abdominal distension to bowel perforation, sepsis and death. Abdominal pain, unstable temperature, bradycardia (low heart rate) and apnoea (not spontaneously breathing) are nonspecific signs. Affected infants have occult or grossly bloody stools, gastric retention, abdominal distension and septicaemia (infection within the blood), with elevated white blood cell and falling platelet counts. Premature infants often have more severe disease and other disorders such as respiratory distress syndrome (see Chapter 25). EVALUATION AND TREATMENT
Diagnosis is based on clinical manifestations, laboratory results and plain films of the abdomen that show gas accumulation in the intestine. Prevention of necrotising enterocolitis includes prenatal glucocorticoids and standardised feeding schedules.54 Treatments include cessation of feeding, gastric suction to decompress the intestines, fluid and electrolyte maintenance and administration of antibiotics to control sepsis. Surgical resection and peritoneal drainage are the treatment of choice for perforation;54 however, for very ill infants weighing less than 1000 g, peritoneal drainage without laparotomy may improve survival. Overall survival has not changed in the past decades; the average mortality is 20–30%.52 Human breast milk and probiotics have been shown to protect against necrotising enterocolitis and reduce disease severity and overall mortality in premature infants.53
F OCU S O N L E ARN IN G
Nutritional disorders
1
Lactose intolerance
Describe the progression of appendicitis.
2 List the clinical symptoms, diagnosis and treatment of appendicitis. 3 Compare and contrast acute and chronic gastritis. 4 Describe the formation and progression of peptic ulcers. 5 Discuss the role of Helicobacter pylori infection in pathophysiology of gastritis and ulcers. 6 Relate ulcer progression to the clinical manifestation of bleeding. 7 Discuss the diagnosis of ulcers and Helicobacter pylori infection. 8 Discuss how the treatment options for peptic ulcer disease relate to gastric and duodenal ulcers.
Lactose intolerance occurs in people who are deficient in the enzyme necessary for digesting lactose, a sugar (disaccharide) found in milk. As you may recall from Chapter 26, the names of most digestive enzymes end in the letters ‘-ase’; this is also true for the enzyme lactase, responsible for the breakdown of lactose (milk sugar). Normally, lactase breaks down lactose into the smaller components, glucose and galactose; however, when the lactose cannot be digested, it is not absorbed across the intestinal wall. PATHOPHYSIOLOGY
The deficiency of the enzyme lactase allows undigested lactose to remain in the intestines, where bacterial
PAEDIATRICS
Paediatrics and necrotising enterocolitis
CHAPTER 27 Alterations of digestive function across the life span
fermentation causes large quantities of gases to form. Undigested lactose also increases the osmotic gradient in the intestines, causing fluids to remain in the intestines and leading to irritation and osmotic diarrhoea. CLINICAL MANIFESTATIONS
Clinical manifestations of lactase deficiency are bloating, crampy abdominal pain, diarrhoea and flatulence. Because of the fluid volume that remains in the intestines (rather than being absorbed), dehydration may also occur. Lactase deficiency usually does not develop until adulthood. Secondary (acquired) lactase deficiency can be caused by several diseases of the intestine, including coeliac disease, gastroenteritis and bacterial overgrowth. EVALUATION AND TREATMENT
The disorder is diagnosed by a lactose-tolerance test, whereby blood glucose levels are monitored following ingestion of lactose; in the lactose-intolerant person, the blood glucose level will not rise normally, as the lactose is not digested to glucose and absorbed into the blood. Avoiding milk and adhering to a lactose-free diet relieves symptoms. Hydrogen lactose breath testing, a biopsy of the jejunum and a laboratory test for enzyme activity may also assist with diagnosis.55 Treatment consists of reducing milk consumption; other dairy products such as cheese may need to be increased in the diet to ensure adequate calcium intake. Alternatively, oral lactase supplementation may be used to replace the deficient enzyme. Some people can tolerate lactose in fermented forms, such as cheese and yoghurt, or by adding soy food.55
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PATHOPHYSIOLOGY
The major pathophysiological characteristics of coeliac disease are atrophy and flattening of villi in the duodenum and jejunum of the small intestine, which results in malabsorption of most nutrients (see Fig. 27.15). Gluten leads to destruction of mucosal cells, which causes inflammation, and water and electrolytes are secreted, leading to watery diarrhoea. Potassium loss leads to muscle weakness. Magnesium and calcium malabsorption can cause seizures or tetany (involuntary contraction of skeletal muscles, often causing pain). Unabsorbed fatty acids combine with calcium within the intestinal lumen, and phosphorus excretion leads to bone reabsorption. The secretion of intestinal hormones, such as secretin and cholecystokinin, may be diminished, so secretion of pancreatic enzymes and expulsion of bile from the gallbladder decrease, contributing to malabsorption. Fat malabsorption in the jejunum is the major cause of steatorrhoea (fatty stools). Deficiencies of fat-soluble
A
Coeliac disease
Coeliac disease (or gluten-sensitive enteropathy) is the loss of mature intestinal villous epithelium caused by hypersensitivity to gluten, the protein component of cereal grains. The gluten in wheat, rye, oats and barley causes a T cell–mediated (see Chapter 12) autoimmune injury to the intestinal epithelial cells of genetically susceptible individuals.56 There is currently discrepancy in the literature regarding whether oats are detrimental or not, as some individuals with coeliac disease are able to tolerate oats much better than others. Pathogenesis appears to be complex, involving dietary, genetic and immunological factors. Coeliac disease is associated with other immune disorders, including diabetes mellitus and thyroid disease. The number of patients diagnosed with coeliac disease is on the rise, with approximately 1% of the population affected.57 Coeliac disease was previously considered a disorder of early childhood; however, it is now apparent that only 20% of cases are diagnosed before the age of 20, with many people being diagnosed between the ages of 30 and 40 and some people being diagnosed in their 60s.56 There is also evidence that many people are undiagnosed and may be asymptomatic.58
B
FIGURE 27.15
Coeliac disease. A Normal small intestinal mucosa with villi appearing as finger-like projections. B In coeliac disease, there are flat intestinal mucosa, with total villus atrophy.
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constipation is occasionally seen despite steatorrhoea (fatty stools). Abdominal pain is more prominent in older children.59 In children, manifestations of malabsorption, such as rickets, tetany, frank bleeding or anaemia, may be obvious. The tongue is smooth and red and the child may bruise and bleed easily. Hypomagnesaemia and hypocalcaemia (low blood levels of magnesium and calcium) cause irritability, tremor, convulsions, tetany, bone pain, osteomalacia and dental abnormalities. If vitamin D deficiency is prolonged, rickets (see Chapter 21) and clubbing of the terminal phalanges are likely. Eighty-six per cent of older children have fingerprint changes (ridge atrophy). In older children, delayed puberty and infertility may be manifestations of otherwise subtle coeliac disease. In adults, symptoms are similar, with diarrhoea being the main symptom, as well as bloating, abdominal pain and constipation. Other symptoms such as tiredness and anaemia result from malabsorption of nutrients.57 While previously there was a tendency for the development of osteoporosis (as the damaged small intestine could not absorb sufficient calcium), it is now common practice to
vitamins are common in those with coeliac disease. Vitamin K malabsorption leads to hypoprothrombinaemia (deficiency of prothrombin, integral for blood clotting; see Chapter 16). In one-third of cases, iron and folic acid malabsorption is manifested as cheilosis (chapped lips and mouth), anaemia and a smooth red tongue. Vitamin B12 absorption is impaired in those with extensive ileal disease, and folate and iron deficiencies are common (see Fig. 27.16). As autoimmune antibodies circulate in the blood with this disease, other systemic symptoms include skin, liver and joint conditions. CLINICAL MANIFESTATIONS
CONCEPT MAP
The onset of clinical manifestations of coeliac disease in children depends on the infant’s age when gluten-containing cereals are added to the diet. In 50% of affected children, onset occurs by 18 months of age, with latent intervals varying from months to years. The classic symptoms in children diagnosed under the age of 2 years are diarrhoea, irritability and weight loss,59 with diarrhoea being a usual early sign. The stools are pale, bulky, greasy and foul smelling. As early as 3 or 4 months of age, growth failure, anorexia and constipation can begin. In older children,
GLUTEN INTOLERANCE causes Injury to villi of small intestine
results in
T cell, antibody and complement activator
Mucosal damage leading to to small intestine
results in
causing
leading to
results in
Decreased surface area
Decreased intestinal hormones and
can lead to Inflammatory enteritis
Decreased carbohydrate absorption
results in
Decreased protein absorption
which results in Lactose intolerance
Decreased pancreatic function
Decreased fat absorption
leads to
Diarrhoea
Loss of lactase enzyme in mucosa
leads to which worsens
resulting in
Decreased electrolytes Decreased proteins
ends with
ends with
which worsens
MALNUTRITION
FIGURE 27.16
Pathophysiology of coeliac disease. The pathophysiology of coeliac disease commences with exposure to gluten, leading to damage to the small intestinal villi, inflammatory and immune responses, and alterations in hormonal function. Diarrhoea and malnutrition are common consequences.
CHAPTER 27 Alterations of digestive function across the life span
regularly screen all diagnosed coeliacs using bone scans (dual-energy x-ray absorptiometry) to allow early identification of those at particular risk. Other extraintestinal manifestations are also common including dermatitis, short stature, arthritis, fatigue, headache, psychiatric disorders and neurologic problems.60 EVALUATION AND TREATMENT
Blood tests for autoantibodies (IgA, IgG, antigliaden from gluten and anti-tissue transglutaminase) are useful and intestinal biopsy is mandatory to detect the classic mucosal changes caused by coeliac disease, particularly the loss of villi. The initial biopsy is generally followed by a second intestinal biopsy to demonstrate regeneration of intestinal villi after treatment with a gluten-free diet. A wide variety of screening tests for malabsorption may also be useful. Treatment consists of the immediate and permanent institution of a diet free of cereal grains (wheat, rye, barley and oats). As products and flours from these cereals can be found in a wide variety of foods, patient education is critical for adherence to a gluten-free diet. Lactose intolerance may accompany coeliac disease, due to the destruction of villi in the small intestine where the enzyme lactase is located. Infants and adults may need vitamin D, iron and folic acid supplements to treat deficiencies. There is an increased incidence of malignant disease, particularly lymphoma, in individuals who fail to respond to gluten-free diets.61
Malnutrition
Malnutrition is lack of nourishment from inadequate amounts of kilojoules (calories), protein, vitamins or minerals, and is caused by improper diet, alterations in digestion or absorption, or a combination of these factors. It is perhaps surprising to learn that malnutrition is a relatively common complaint for groups of our population — approximately 34–43% of hospitalised patients are malnourished,62 with 73% of residents of aged-care facilities having malnutrition in Australia.63 Furthermore, almost two-thirds of patients undergoing rehabilitation for conditions such as stroke either have malnutrition or are at risk of it developing.64 The importance of this issue cannot be underestimated, as malnutrition limits the body’s ability to recover from illness, as well as decreasing the overall health status of the elderly population.
Starvation
Starvation is a state of extreme malnutrition and hunger from lack of nutrients. Short-term starvation (1–14 days of fasting) and long-term starvation (14–60 days of fasting) have different effects.63 Therapeutic short-term starvation is part of some weight reduction programs because it causes an initial rapid weight loss that reinforces the individual’s motivation to diet. Therapeutic long-term starvation is
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used in medically controlled environments to facilitate rapid weight loss in morbidly obese individuals. Pathological long-term starvation can be caused by poverty, chronic diseases of the cardiovascular, pulmonary, hepatic, renal and digestive systems; malabsorption syndromes; and cancer. Cachexia is physical wasting with loss of weight and muscle atrophy, fatigue and weakness. Inflammatory mediators (i.e. TNF-α, interferon gamma or interleukin 6) associated with advanced cancer, AIDS, tuberculosis and other major chronic progressive diseases contribute to cachexia. Anorexia (loss of appetite) and cachexia (severe tissue wasting) often occur together. Cachexia is not the same as starvation. A healthy person’s body can adjust to starvation by slowing metabolism, but in cachexia the body does not make this adjustment. Short-term starvation, or extended fasting, consists of several days of total dietary abstinence or deprivation. Once all available energy has been absorbed from the intestine, glycogen (stores of glucose) in the liver is released to the blood as glucose (through glycogenolysis) after 4–8 hours. Following this, other molecules (such as lactate and amino acids) are used by the liver to produce glucose (by gluconeogenesis). Both of these processes deplete stored nutrients and thus cannot meet the body’s energy needs indefinitely. Fatigue decreases physical activity and energy expenditure. Interestingly, some hospitalised patients may have short-term starvation. Patients who are kept nil by mouth for days, due to a range of reasons, may experience a decrease in dietary energy intake, because the intravenous fluids provide very little nutritional value. Long-term starvation begins after a longer period of dietary abstinence and eventually causes death. The major characteristic of long-term starvation is an increased use of ketone bodies (products of lipid and pyruvate metabolism) as a cellular energy source. Depressed insulin and glucagon levels result in lipid stores being released as fatty acids (through lipolysis), which supply energy to cardiac and skeletal muscle cells. Although this meets most energy needs of the cells, glucose is still an essential fuel for neurons. Once the supply of adipose tissue is depleted, proteolysis begins (breakdown of proteins). The breakdown of muscle protein is the last process to supply energy for life. Organ failure of the renal and respiratory systems follows and death results from cardiac failure due to severe alterations in electrolyte balance. Adequate ingestion of appropriate nutrients is the obvious treatment for starvation — see the box ‘Research in Focus: Re-feeding syndrome’. In medically induced starvation, the body is maintained in a ketotic state until the desired amount of adipose tissue has been lysed. Starvation imposed by chronic disease, long-term illness or malabsorption is treated with enteral or parenteral nutrition.
Obesity
Excessive intake of food or energy can lead to obesity — this is an epidemic in countries such as Australia and New Zealand and is discussed in detail in Chapter 35.
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RESEARCH IN F CUS Re-feeding syndrome Re-feeding syndrome is defined as the clinical complications that occur as a result of fluid and electrolyte shifts during nutritional rehabilitation of malnourished patients. Patients who weigh less than 70% of ideal body weight or lose weight rapidly are at greatest risk for the syndrome. These include patients with anorexia nervosa (characterised by an abnormally low body weight, intense fear of gaining weight, distorted perception of body weight and shape, and amenorrhoea), oncology patients undergoing chemotherapy, malnourished elderly patients, certain postoperative patients, patients with chronic alcoholism, and morbid obesity with massive weight loss and prolonged fasting. In these patients loss of body minerals causes the movement of phosphate, magnesium, calcium and potassium out of the cells and into the plasma. When parenteral or enteral nutritional re-feeding therapy is initiated, the body goes from a catabolic to an anabolic state, in which an increase in insulin levels stimulates the intracellular movement of glucose and these ions. Subsequently, the plasma concentrations can decrease to dangerously low levels causing hypophosphataemia,
hypomagnesaemia, hypocalcaemia and hypokalaemia (low phosphate, magnesium, calcium and potassium in the blood). Rapid expansion of the extracellular fluid volume can also occur with carbohydrate re-feeding and may cause fluid overload. Liver inflammation and postprandial (after meal) hypoglycaemia (low level of sugar in the blood) can complicate the body’s conversion from a catabolic to an anabolic state. Hypophosphataemia contributes to alterations in red blood cell shape and function, leading to tissue hypoxia and increased respiratory drive. The consequences of these alterations include life-threatening arrhythmias, congestive heart failure, muscle weakness (including the respiratory muscles), delirium, coma and death. Atrophy of the intestinal mucosa and pancreatic impairment may cause severe diarrhoea during early re-feeding. Re-feeding syndrome is prevented by slowly reinstituting feeding and monitoring plasma ions and glucose level. While most complications are reversible with recovery, some, such as bone loss, may never recover completely even once weight is restored. Early diagnosis and treatment of malnutrition are paramount to prevent initial weight loss and subsequent loss of bone.
Failure to thrive is the inadequate physical development of an infant or a child. It is manifested as a deceleration in weight gain, a low weight/height ratio or a low weight/ height/head circumference ratio. It is a nutritional disorder that may be due to underlying pathophysiology or psychosocial causes. PATHOPHYSIOLOGY
Pathophysiological causes of failure to thrive include gastro-oesophageal reflux, pyloric stenosis (narrowing of the pylorus), gastroenteritis, infection by intestinal parasites or congenital anomalies, or chronic diseases of major body systems. All these disorders reduce the availability of nutrients for maintenance and growth. This can also create developmental problems, psychosocial problems and emotional problems for the child. Failure to thrive may also result from environmental causes and can be complicated by families having inadequate economic resources and parental lack of knowledge. Parental stressors may include: • lack of nurturing in the parent’s own childhood • unwanted pregnancy • inability to bond with the infant because of health or other problems • postpartum (postnatal) depression • family crisis, such as marital problems or a death in the family • stress caused by single parenthood or social isolation • mental, emotional or physical illness.
CLINICAL MANIFESTATIONS
Clinical manifestations are retarded growth accompanied by manifestations of the underlying disease. For the psychosocial causes, failure to thrive involves retarded growth plus reduced energy level, reduced responsiveness and interaction with the environment, social isolation, spasticity and rigidity when held or touched, inability to make eye contact or smile and rejection of food. Weight loss and decelerated growth are accompanied by overall retardation of development. EVALUATION AND TREATMENT
Failure to thrive is suggested if a child exhibits particularly slow growth (falls below the third percentile on the growth curve or is falling off a previously established growth curve). If no genetic, endocrine or other systemic disorders are identified and if the physical and laboratory examinations show no abnormalities other than delayed growth, an environmental cause is indicated. Hospital admission is recommended if the diagnosis is unclear or the child is in nutritional or emotional jeopardy. Eating patterns, food preferences, kilojoule intake and family interactions can be assessed during the hospital stay. If the cause is environmental, the hospitalised child usually begins to gain weight. If a pathophysiological problem has been identified, management of failure to thrive consists of treating the cause. Management involves the immediate total care of the child and measures to address both the psychosocial and the emotional problems of the caregivers and the parent–child interactions.
PAEDIATRICS
Paediatrics: failure to thrive
CHAPTER 27 Alterations of digestive function across the life span
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Fig. 27.17). In individuals who develop reflux oesophagitis, the muscle tone tends to be lower than normal, such that the sphincter is contracted less. Vomiting, coughing, lifting or bending that increases abdominal pressure can contribute to the development of reflux oesophagitis. The severity of the oesophagitis depends on the composition of the gastric contents and the length of time they are in contact with the oesophageal mucosa. As the lining of the oesophagus is not protected from acid (in the same way as the stomach mucosa), the oesophagus is quite susceptible to damage from the acidic chyme (see Fig. 27.18). If the chyme is highly acidic or contains bile salts and pancreatic enzymes, reflux oesophagitis can be severe, as is usually seen in those
F O CUS O N L E A R N IN G
1 Discuss why lactose-intolerant people cannot consume large quantities of regular milk. 2 Describe how lactose intolerance is managed. 3 Discuss the effects of gluten on the small intestine of the patient with coeliac disease. 4 Describe how coeliac disease is diagnosed and treated. 5 Discuss the relevance of malnutrition in our society. 6 Describe changes in the body during starvation. 7 Discuss the necessity to re-feed slowly to avoid re-feeding syndrome.
Disorders of motility Gastro-oesophageal reflux and GORD
Gastro-oesophageal reflux is the reflux of chyme (partially digested food mixed with gastric secretions) from the stomach to the oesophagus. The lower oesophageal sphincter may relax inappropriately 1–2 hours after eating, permitting gastric contents to regurgitate into the oesophagus. The acid is usually cleared from the oesophagus by peristaltic action within 1–3 minutes and the sphincter then closes again. In some individuals, however, a combination of factors causes an inflammatory response to reflux called reflux oesophagitis. This is a relatively common condition, with over 61 000 Australians requiring hospitalisations for gastro-oesophageal reflux disease each year.44 If the reflux occurs more frequently, it is diagnosed as gastro-oesophageal reflux disease (GORD), in which the reflux occurs more than twice per week forming a chronic condition, leading to persistent oesophagitis.
FIGURE 27.18
Gastro-oesophageal reflux disease. Endoscopic view of oesophageal inflammation (oesophagitis) caused by ‘splashing back’ of acids from the stomach in a patient with gastro-oesophageal reflux disease. The arrows indicate the extent of the acid damage.
PATHOPHYSIOLOGY
Most of the time, the lower oesophageal sphincter remains closed, thereby preventing gastro-oesophageal reflux (see Oesophagus
Diaphragm
Spicy food Alcohol
Oesophageal mucosal barrier integrity • Oesophagitis • Barrett’s oesophagus
Hiatal hernia
Lower oesophageal sphincter closed
Lower oesophageal sphincter • Abnormal tone • Abnormal relaxation
Diaphragm Intraabdominal pressure
Pylorus Liquid Stomach
Reflux
Gastric contents chemistry
FIGURE 27.17
The causes of gastro-oesophageal reflux. Main causes of gastro-oesophageal reflux are increased intraabdominal pressure, such as due to obesity or pregnancy, and decreased function of the lower oesophageal sphincter. Spicy food and alcohol can worsen the reflux.
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with GORD. In individuals with weak oesophageal peristalsis, refluxed chyme remains in the oesophagus longer than usual. Delayed gastric emptying contributes to reflux oesophagitis by both lengthening the period during which reflux is possible and increasing the acid content of chyme. Disorders that delay emptying include gastric or duodenal ulcers, which can cause pyloric oedema (swelling due to fluid), and hiatal hernia, which can weaken the lower oesophageal sphincter. CLINICAL MANIFESTATIONS
The clinical manifestations of reflux oesophagitis are heartburn (pain in the chest, which actually doesn’t involve the heart), acid regurgitation, dysphagia (difficulty swallowing), chronic cough, asthma and upper abdominal pain within 1 hour of eating. The symptoms worsen if the individual lies down or if intraabdominal pressure increases (e.g. as a result of coughing, vomiting or straining at defecation). Oedema, strictures, oesophageal spasm or decreased oesophageal motility may result in dysphagia with weight loss. Alcohol or acid-containing foods, such as citrus fruits, can cause discomfort during swallowing. EVALUATION AND TREATMENT
Diagnosis of reflux oesophagitis is based on clinical manifestations, oesophageal endoscopy that shows oedema and erosion, and ambulatory pH monitoring of the oesophagus. Endoscopy also allows evaluation for metaplastic changes (termed Barrett’s oesophagus) and the development of oesophageal carcinoma.65 A barium swallow is used to identify associated conditions, such as hiatal hernia, gastric ulcers and abnormal contours of the oesophageal lumen. Antacids relieve symptoms by neutralising gastric contents. Weight reduction and cessation of smoking also help to alleviate symptoms. Proton pump inhibitors (such as omeprazole, dexlansoprazole) are the agents of choice for controlling symptoms and healing oesophagitis.66 Sucralfate, a sucrose sulfate-aluminium complex, provides a barrier to prevent degradation of mucus by acid and coat ulcerated tissue. Smooth muscle stimulants (such as cisapride) can increase lower oesophageal sphincter motility and rate of gastric emptying, however, their use is limited due to cardiovascular side effects (arrhythmias).67 If other
treatments fail or if reflux oesophagitis does not heal, the lumen of the lower oesophageal sphincter may be narrowed with laparoscopic surgery.
Faecal incontinence
Faecal incontinence may be due to an inability to have a voluntary bowel movement (linked to constipation) or an inability to control bowel movements (linked to diarrhoea). Although it affects those who were born with an anorectal malformation, it is being seen increasingly in the elderly, those with previous bowel surgery and older women who have had previous obstetric complications.68 Those with irritable bowel syndrome are at greater risk of faecal incontinence, due to the effects of diarrhoea. Faecal incontinence may also result from diarrhoea induced by laxatives or excessive consumption of some artificial sweeteners. Although approximately 2% of the population are thought to suffer from faecal incontinence, in a rural Australian setting 20% of patients attending gynaecology and colorectal clinics were found to have faecal incontinence,68 indicating that there may be more sufferers than suspected. Many individuals may not report their symptoms to medical staff due to embarrassment, so underreporting may be common. Treatment may include medications to assist in faecal bulk formation (Metamucil) and antidiarrhoeal drugs (loperamide). An individualised bowel management program, where the type of enema, medication and diet are adjusted based on the patient’s symptoms may be particularly useful.69
FOCU S ON L EA RN IN G
1 Describe the factors that contribute to the development of gastro-oesophageal reflux and its symptoms. 2 List the methods for diagnosing and treating gastrooesophageal reflux. 3 Explain the difference between gastro-oesophageal reflux and gastro-oesophageal reflux disease. 4 Discuss faecal incontinence.
Gastro-oesophageal reflux In newborns, gastro-oesophageal reflux is normal because neuromuscular control of the lower oesophageal (gastrooesophageal) sphincter is not fully developed, thereby allowing return of stomach contents into the oesophagus. The frequency of reflux is highest in premature infants and decreases during the first 6–12 months of postnatal life. Normal infants and children have been shown to have some reflux but may be asymptomatic. Gastro-oesophageal
reflux can progress to gastro-oesophageal reflux disease when complications such as bleeding or failure to thrive develop. PATHOPHYSIOLOGY
Delayed maturation of the lower oesophageal sphincter or impaired hormonal response mechanisms are possible causes. Factors that maintain integrity of this sphincter in children include anatomical issues such as the angle
PAEDIATRICS
Paediatrics and disorders of motility
CHAPTER 27 Alterations of digestive function across the life span
at which the oesophagus enters the stomach. Irritation of the mucosa by acidic gastric contents results in inflammation of the oesophageal epithelium and stimulation of the vomiting reflex. CLINICAL MANIFESTATIONS
Of affected infants, 85% vomit excessively during the first week of life and usually have other symptoms by 6 weeks. Aspiration pneumonia develops in one-third of infants with gastro-oesophageal reflux. In cases that persist into childhood, chronic cough, wheezing and recurrent pneumonia are common. Inadequate retention of nutrients can adversely impact growth and weight gain. Oesophagitis resulting from exposure of the oesophageal mucosa to acidic gastric contents is manifested by pain, bleeding and eventually stricture formation and abnormal motility. Approximately 25% have iron deficiency anaemia caused by frank or occult blood loss.70 EVALUATION AND TREATMENT
The clinical manifestations are often adequate to confirm a diagnosis of gastro-oesophageal reflux. A barium swallow and oesophageal pH monitoring with a probe are useful diagnostic procedures in complex cases. Mild gastro-oesophageal reflux resolves without treatment. Small, frequent feedings and frequent burping are also accepted strategies for managing reflux. Medications to increase motility, to increase lower oesophageal sphincter pressure or to decrease gastric acid production and surface barrier agents have been used to treat this condition.70 If no improvement is seen with medical management or the child has life-threatening events with reflux, an anti-reflux surgical procedure, including gastropexy (whereby the stomach is stitched to the abdominal wall) and fundoplication (whereby the fundus of the stomach is wrapped around the oesophageal sphincter and stitched to strengthen the valve such that reflux does not occur), is performed.71 Pyloric stenosis Pyloric stenosis is an obstruction of the pyloric sphincter caused by hypertrophy of the sphincter muscle; the cause is unknown. One of the most common disorders of early infancy, it affects infants between the ages of 2 weeks and 4 months. The incidence of pyloric stenosis is 3 per 1000 live births per year.72 Full-term infants are affected more often than premature infants. PATHOPHYSIOLOGY
Individual muscle fibres thicken, so the whole pyloric sphincter becomes enlarged and inelastic. The mucosal
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lining of the pyloric opening is folded and narrowed by the encroaching muscle. Because of the extra peristaltic effort necessary to force the gastric contents through the narrow pylorus, the muscle layers of the stomach may become hypertrophied (enlargement of the tissue) as well. CLINICAL MANIFESTATIONS
Between 2 and 3 weeks after birth, an infant who has fed well and gained weight begins to vomit without apparent reason. The vomiting gradually becomes more forceful (projectile). Food is often regurgitated through the nose. The vomiting usually occurs immediately after eating and the vomitus (material that has been vomited) consists of the bulk of the feeding plus some food retained from previous feedings, but is almost always free of bile. In severe, untreated cases, increased gastric peristalsis and vomiting lead to severe fluid and electrolyte imbalances, malnutrition and weight loss that can be fatal within 4–6 weeks. Infants with pyloric stenosis are irritable because of hunger and they may have oesophageal discomfort caused by repeated vomiting and oesophagitis. The vomitus may be blood-streaked because of rupture of gastric and oesophageal vessels. EVALUATION AND TREATMENT
Diagnosis is based on the history, clinical manifestations and findings on ultrasound. Occasionally, gastric peristalsis is observable over the abdomen. A firm, small, movable mass, approximately the size of an olive, is felt in the right upper quadrant in 70–90% of infants with pyloric stenosis. Ultrasound clearly shows the hypertrophied pyloric muscles and narrowed pyloric channel. The standard treatment for hypertrophic pyloric stenosis is a pyloromyotomy, in which the muscles of the pylorus are surgically split and separated. Preoperative and postoperative medical management to correct fluid and electrolyte imbalance has been the key to the high success rate and low complication rates with this surgery.73 Some infants may respond to medical and nutritional management, which is based on the theory that the pylorus will open spontaneously by 6–8 months of age if nutrition can be maintained. Antispasmodic drugs are given to relax the pyloric spasm and the infant is re-fed after vomiting. Rehydration of infants following vomiting is particularly important, as infants are susceptible to dehydration. Endoscopic balloon dilation has also shown some success.
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Structural abnormalities of the gastrointestinal tract Hiatal hernia PATHOPHYSIOLOGY
Hiatal hernia is the protrusion (herniation) of the upper part of the stomach through the diaphragm and into the thorax (see Fig. 27.19). The two most common types of hiatal hernia are as follows: • Sliding hiatal hernia. The stomach slides or moves into the thoracic cavity through the oesophageal hiatus; a congenitally short oesophagus, trauma or weakening of the diaphragmatic muscles at the gastro-oesophageal junction is contributory. Coughing, bending, tight clothing, ascites, obesity and pregnancy accentuate the hernia. • Para-oesophageal hiatal hernia. The greater curvature of the stomach herniates through a secondary opening in the diaphragm and lies alongside the oesophagus. Symptoms include congestion of mucosal blood flow leading to gastritis and ulcer formation. Strangulation of the hernia is a major complication (where the herniated part of the stomach becomes occluded, resulting in tissue death). Hiatal hernias of both types tend to occur in conjunction with several other diseases, including reflux oesophagitis, peptic ulcer, cholecystitis (gallbladder inflammation), cholelithiasis (gallstones), and diverticulosis.
A
Oesophagus
Diaphragm Sliding hiatal hernia
B Diaphragm
Stomach Oesophagus
Stomach
Paraoesophageal hiatal hernia
FIGURE 27.19
Types of hiatal hernia. A Sliding hiatal hernia. Part of the stomach protrudes into the thoracic cavity by sliding superiorly. B Para-oesophageal hiatal hernia. Part of the stomach protrudes by sliding alongside the oesophagus.
CLINICAL MANIFESTATIONS
Generally, a wide variety of symptoms develop later in life, although hiatal hernias are often asymptomatic. Manifestations include gastro-oesophageal reflux, dysphagia, heartburn and epigastric pain. Regurgitation and substernal (under the sternum) discomfort after eating are common. EVALUATION AND TREATMENT
Diagnostic procedures include examinations using barium as a contrast medium, endoscopy and chest x-ray. Treatment for sliding hiatal hernia is usually conservative. The individual can diminish reflux by eating small, frequent meals and avoiding the recumbent (lying down) position after eating. Abdominal supports and tight clothing should be avoided and weight control is recommended for obese individuals. Individuals who are uncomfortable at night benefit from sleeping in a semi-upright position. Treatment for hiatal hernias is mainly pharmacological with the use of proton pump inhibitors, H2 receptor blockers and over the counter antacids, staying a healthy weight and avoiding lifting heavy objects can also help. If a combination of lifestyle changes and drug therapy does not relieve reflux symptoms surgical intervention is needed. The operation is called a fundoplication, mainly as laparoscopic surgery. Fundoplication surgery involves wrapping the upper portion of the stomach around the base of the oesophagus to reinforce the strength of the lower oesophageal sphincter.
Intestinal obstruction
Intestinal obstruction can be caused by any condition that prevents the normal flow of chyme through the intestinal lumen (see Table 27.8). Obstructions can occur in either the small or the large intestine. Intestinal obstruction is classified by cause as simple or functional. Simple obstruction is mechanical blockage of the lumen; functional obstruction is a failure of motility (paralytic ileus), often occurring after abdominal surgery. Simple obstruction of the small intestine is the most common type of intestinal obstruction. Acute obstructions usually have mechanical causes, such as adhesions or hernias (see Fig. 27.20A, D). Chronic or partial obstructions are more often associated with tumours or inflammatory disorders, particularly of the large intestine. Intussusception is the telescoping or invagination of one portion of the intestine into another (see Fig. 27.20B). Usually, the ileum invaginates the caecum and part of the ascending colon by collapsing through the ileocaecal sphincter (ileocolic intussusception). In adults, it can occur after previous abdominal surgery and it accounts for 80–90% of intestinal obstructions in infants. As the proximal portion of the intestine collapses into the distal portion, it drags its mesentery into the enveloping lumen. This results in constriction of the mesentery and obstructs venous return. Oedema and compression obstruct the flow of chyme through the intestine. Unless the intussusception is treated, gangrene ensues.
CHAPTER 27 Alterations of digestive function across the life span
TABLE 27.8 Common causes of intestinal obstruction CAUSE
PATHOPHYSIOLOGY
Hernia
Protrusion of the intestine through a weakness in the abdominal muscles or through the inguinal ring
Intussusception
Telescoping of one part of the intestine into another; this usually causes strangulation of the blood supply; more common in infants 10–15 months of age than in adults
Volvulus
Twisting of the intestine on its mesenteric pedicle, with occlusion of the blood supply; often associated with fibrous adhesions; occurs most often in middleaged and elderly men
Diverticulosis
Inflamed saccular herniations (diverticuli) of the mucosa and submucosa through the tunica muscularis of the colon; diverticuli are interspersed between thick, circular, fibrous bands; most common in obese individuals older than 60 years
Fibrous adhesions
Peritoneal irritation from surgery or trauma leads to formation of fibrin and adhesions that attach to intestine, omentum or peritoneum and can cause obstruction; most common in the small intestine
Paralytic ileus
Loss of peristaltic motor activity in the intestine; associated with abdominal surgery, peritonitis, hypokalaemia, ischaemic bowel, spinal trauma or pneumonia
Tumour
Tumour growth into the intestinal lumen; adenocarcinoma of the colon and rectum is the most common tumoral obstruction; most common in individuals older than 60 years
Volvulus occurs when a section of the intestine twists on itself, resulting in an emergency as the intestinal blood supply is restricted (see Fig. 27.20C). In children, it can occur due to anatomical abnormalities. A loop of the intestine forms a ‘U’ shape and the adjacent regions at the top of the U then rotate around each other, forming the twist of volvulus. Dilation of the stomach occurs, which results in vomiting, leading to dehydration and electrolyte imbalances. This condition may be asymptomatic and discovered during unrelated abdominal surgery or it may cause minor abdominal complaints, such as nausea after meals, vomiting or abdominal pain. Surgical treatment is necessary to avoid gangrene.
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A
B
C
D
FIGURE 27.20
Intestinal obstructions. A Constriction adhesions. B Intussusception. C Volvulus. D Hernia.
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An abdominal hernia occurs when the intestine protrudes through an opening of the abdominal wall muscles, often due to muscle weakening (see Fig. 27.20D). The most common type of abdominal hernia is the inguinal hernia, where the intestine protrudes down into the genital area (in males into the scrotal sac). In some mild cases, the patient may actually be experienced in physically manipulating the gut back into place. However, the hernia can become strangulated, when it progresses to obstruction, limiting progression of intestinal contents.
FOCU S ON L EA RN IN G
1 Explain the different types of hiatal hernia. 2 List some options for management of hiatal hernia. 3 Describe the different types of intestinal obstruction.
PAEDIATRICS
Paediatrics and Hirschsprung’s disease Hirschsprung’s disease, also known as congenital aganglionic megacolon, is a functional obstruction of the colon caused by inadequate motility. The term aganglionic means without ganglia (a collection of neuronal cell bodies), because the enteric nervous system of the digestive system is incomplete. It is the most common cause of colon obstruction, accounting for about one-third of all gastrointestinal obstructions in infants. The incidence rate is 1 in 5000, with a preponderance in males. There is an increased incidence in children with Down syndrome.74
Distended sigmoid colon
PATHOPHYSIOLOGY
Hirschsprung’s disease is a congenital malformation characterised by the absence of enteric ganglia in a segment of the colon. It is caused by the failure of enteric neuronal progenitor cells to migrate into the gastrointestinal tract, particularly the distal colon, during embryonic development. In most cases, the aganglionic segment is limited to the rectal end of the sigmoid colon. The abnormally innervated segment of the distal colon obstructs faecal movements, causing the proximal colon to become distended — hence the term megacolon (see Fig. 27.21). CLINICAL MANIFESTATIONS
Mild to severe constipation is the usual manifestation. Diarrhoea may be the first sign because only water can travel around the impacted faeces. The most serious complication in the neonatal period is enterocolitis (inflammation of the intestines) related to faecal impaction (blockage). Bowel dilation stretches and partly occludes the encircling blood and lymphatic vessels, causing oedema, ischaemia, infarction of the mucosa and significant outflow of fluid into the bowel lumen. Copious liquid stools result. Infarction and destruction of the mucosa enable enteric microorganisms to penetrate the bowel wall. Frequently, gram-negative sepsis occurs, accompanied by fever and vomiting. Severe and rapid
Aganglionic portion Rectum
FIGURE 27.21
Hirschsprung’s disease. The enlarged sigmoid colon is characteristic of this disease.
electrolyte changes may take place, causing collapse and death. EVALUATION AND TREATMENT
The definitive diagnosis is made by rectal biopsy showing an absence of ganglion cells in the submucosa of the colon. X-ray films show dilated loops of colon and contrast films show aganglionic areas.75 The affected segment is resected within the first few months of life. Alternatively, enemas are given until the lumen is clear and then stool softeners are prescribed for life. In general, the prognosis of Hirschsprung’s disease is satisfactory for children who undergo surgical treatment. Bowel training may be prolonged, but most children achieve bowel continence before puberty.
CHAPTER 27 Alterations of digestive function across the life span
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Clinical manifestations of gastrointestinal tract alterations In the previous sections, you have learned about the alterations to the digestive system that have the greatest impact in Australia and New Zealand — disorders that are the most prevalent in our community. We now expand on this knowledge with a detailed discussion of the signs and symptoms that are associated with these conditions. For healthcare professionals, a focus on the clinical manifestations is particularly important.
Vomiting
Vomiting (emesis) is the forceful emptying of stomach and intestinal contents (chyme) through the mouth. Stimuli initiating the vomiting reflex include severe pain; distension (stretching) of the stomach or duodenum; and activation of the chemoreceptor trigger zone in the medulla. A wide variety of medical conditions, disorders and medications can induce vomiting, so it is likely that you will encounter patients with vomiting in many areas of clinical practice. PATHOPHYSIOLOGY
Vomiting is a protective response to a number of factors that may potentially be harmful to the body — so important is this response, that there is a vomiting control centre in the medulla of the brainstem, located near the other control centres essential for life (namely, the cardiac and respiratory control centres). The vomiting control centre is responsible for coordinating sensory stimuli and then directing motor output to the muscles involved. Examples of sensory stimuli that may produce this reflex include extreme emotions such as fear, unpleasant sights or odours, severe pain, increased intracranial pressure and motion or balance signals from the equilibrium apparatus of the inner ear. Another important area that sends signals to the vomiting control centre is the chemoreceptor trigger zone: neurons of this zone located in the brainstem (beside the fourth ventricle) receive inputs more specifically associated with the gastrointestinal system, such as contaminated food, toxic substances in the stomach and anti-cancer drugs (chemotherapy). CLINICAL MANIFESTATIONS
Vomiting begins with deep inspiration: the glottis closes, intrathoracic pressure falls and the abdominal muscles contract, creating increased abdominal pressure. The lower oesophageal sphincter relaxes and waves of peristalsis move in reverse, forcing chyme from the stomach and duodenum up into the oesophagus. The contractions of the abdominal muscles are extremely strong, forcing the diaphragm high into the thoracic cavity. The high intrathoracic pressure forces the upper oesophageal sphincter to open and chyme is expelled from the mouth — this material is now referred to as the vomitus (see Figs 27.22 and 27.23). The upper part of the oesophagus contracts, forcing the remaining
FIGURE 27.22
Emesis (vomiting). Summary of components of the vomiting reflex. In particular, the force for vomiting comes from the contraction of the diaphragm down onto the stomach, and the compression of the stomach from the abdominal muscles.
Deep inspiration (diaphragm lowered) Abdominal muscle contraction leads to Increased abdominal pressure also Reverse peristalsis and relocation of lower oesophageal sphincter
progresses to
progresses to Diaphragm raised causes Increased thoracic pressure progresses Retching to Relaxation of upper oesophageal sphincter ends in Vomiting
FIGURE 27.23
The process of vomiting. The increased abdominal pressure which compresses the stomach, and the reverse peristalsis of the duodenum, lead to relaxation of the oesophageal sphincters and vomiting.
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chyme back into the stomach, and the lower oesophageal sphincter then closes. The cycle may be repeated. TREATMENT
Disturbances in hydration, electrolytes and acid–base balance can become severe consequences of vomiting. This is of particular concern for babies and young children, who are more susceptible to changes in fluid balance and thus need careful monitoring. Therefore, the treatment of this condition requires restoring the balance of fluids and electrolytes. Oral rehydration solutions usually contain electrolytes (sodium and potassium), as well as glucose and/or sucrose. During vomiting, intravenous restorations may be necessary, as orally administered substances are likely to be vomited before being absorbed into the bloodstream. Some of the widely used treatments are metoclopramide and prochlorperazine, which are usually given parenterally (although oral doses may be taken as prophylaxis). Chemotherapy medications can cause severe nausea and vomiting, and antiemetic treatments are targeted specifically for this use. Commonly used drugs are blockers (or antagonists) of particular receptors associated with the vomiting response: metoclopramide and prochlorperazine block dopamine receptors associated with the chemoreceptor trigger zone; ondansetron blocks the 5-hydroxytryptamine or serotonin receptors associated with the gastrointestinal tract that send signals to the vomiting centre; netupitant and rolapitant block neurokinin (NK)-1 receptors broadly distributed in the central and peripheral nervous systems.76
Nausea
Nausea and retching usually precede vomiting. Nausea is a subjective experience of feeling likely to vomit; this may or may not progress to retching and vomiting. Retching is similar to vomiting, except that no food or chyme reaches the mouth, as the upper oesophageal sphincter remains closed. As the abdominal muscles relax, the contents of the oesophagus drop back into the stomach. This process may be repeated several times before vomiting occurs or it may not progress to vomiting at all. A response by the ‘fight or flight’ branch of the nervous system (sympathetic nervous system) causes tachycardia (increased heart rate), tachypnoea (increased respiratory rate) and sweating that accompany retching and vomiting. Also, the ‘rest and digest’ branch (parasympathetic nervous system) mediates copious salivation, increased gastric motility and relaxation of the upper and lower oesophageal sphincters. This is an example of a body process that has both the sympathetic and the parasympathetic branches working together for the same function. Spontaneous vomiting not preceded by nausea or retching is called projectile vomiting. It is caused by direct stimulation of the vomiting centre by neurological lesions (such as tumours or aneurysms) involving the brainstem, or it can be a symptom of gastrointestinal obstruction (pyloric stenosis in children). The metabolic consequences of vomiting are fluid, electrolyte and acid–base disturbances (see Chapter 29).
Constipation
Constipation is difficult or infrequent defecation. It is a common complaint caused by personal habits and various disorders and drugs. It usually means a decrease in the number of bowel movements per week, hard stools and difficult evacuation, but the definition must be individually determined. Normal bowel habits range from 1 to 3 evacuations per day to 1 per week. PATHOPHYSIOLOGY
Constipation can be caused by neurogenic disorders of the large intestine in which neural pathways or neurotransmitters are altered and delay transit time. It might also be an early symptom of other neurological disorders — see ‘Research in Focus: Assessment of the enteric nervous system for the early diagnosis of Parkinson’s disease’. A low-fibre diet (the habitual consumption of highly refined foods) decreases the volume and number of stools and causes constipation. Other contributing factors include a sedentary lifestyle, lack of regular exercise and consistent suppression of the urge to empty the bowel. Excessive use of antacids containing calcium carbonate or aluminium hydroxide often results in constipation. Opioid analgesics, particularly codeine, tend to inhibit bowel motility and therefore patients receiving these medications require adequate education about dietary changes to prevent constipation. Ageing may also result in changes in neuromuscular function causing constipation.77 CLINICAL MANIFESTATIONS
Constipation can be a serious medical problem, as the increased abdominal pressure created during straining (in an attempt to pass stools) can affect the heart. During straining (also known as the Valsalva manoeuvre), temporary bradycardia (slowing of the heart rate) occurs as venous return is slowed; however, when straining ceases, the sudden increase in venous return can cause cardiac overload and acute myocardial infarction (see Chapter 23). Changes in bowel evacuation patterns, such as less frequent defecation, smaller stool volume, difficulty in evacuating the rectum or a feeling of bowel fullness and discomfort, require investigation. When faeces are passed, they are often hard and dry. EVALUATION AND TREATMENT
The history and physical examination and stool diaries provide precise information regarding the nature of constipation. Functional constipation — that is, constipation resulting from lifestyle or bowel habits — usually has a long history. Dysfunctional constipation relating to another medical condition is more likely to be sudden; constipation can accompany the development of physical changes and requires careful evaluation. The individual’s description of frequency, stool consistency, associated pain and presence of blood is significant. In assessing frequency, it is important to discover whether bowel evacuation was stimulated by enemas or laxatives. Palpation of the abdomen discloses colonic distension, masses and tenderness. Digital examination
CHAPTER 27 Alterations of digestive function across the life span
RESEARCH IN F CUS Assessment of the enteric nervous system for the early diagnosis of Parkinson’s disease The traditional view of Parkinson’s disease, as a primary disorder of brain motor neurons, has been reconsidered in recent years. Symptoms such as dysphagia, nausea, and distension as a result of impaired gastric emptying, and bowel dysfunction, including both reduced bowel movement frequency and difficulty defecating, are among the most common nonmotor symptoms of Parkinson’s disease. Enteric nervous system (ENS) pathology is considered to be responsible for the gastrointestinal dysfunction that is so often encountered by patients with Parkinson’s disease. A recent autopsy survey has shown that almost all patients display Lewy bodies (α-synuclein aggregates, a hallmark of Parkinson’s disease) within their ENS. Furthermore, it was suggested that these lesions in enteric neurons develop early in the course of disease, prior to the appearance of pathology in substantia nigra neurons. Recent findings suggest that the severity of enteric pathology is indicative of disease progression and severity. Since the ENS is accessible through routine colonic biopsies it can be used for investigating novel histopathologic markers in living patients, increasing our understanding of the pathophysiology of the disease. This approach opens new avenues for the early diagnosis of Parkinson’s disease, and may also hold promise for the investigation of other neurodegenerative disorders.
of the rectum is performed to assess muscle tone of the anal sphincters and detect anal lesions. Stool transit time is evaluated. Sigmoidoscopy is used to visualise the lumen directly. A barium enema may be required if no lesions are directly visualised and symptoms continue after simple treatment. The treatment for dysfunctional constipation is to manage the underlying disorder. Management of functional constipation usually consists of bowel retraining, in which the individual establishes a satisfactory bowel evacuation routine without becoming preoccupied with bowel movements. The individual may also need to engage in moderate exercise, drink more fluids and increase fibre intake. Bulk supplements (such as Metamucil), stool softeners (such as Coloxyl) and laxative agents (e.g. Glycoprep) are useful for some individuals. Enemas are fluids inserted into the anus and can be used to establish bowel routine, but they should not be used habitually.
Diarrhoea
Diarrhoea is an increase in the frequency of defecation and the fluidity and volume of faeces. More than 3 stools per day is considered abnormal. Many factors determine stool volume and consistency, including the water content of the colon and the presence of unabsorbed food and intestinal
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secretions. Stool volume in the normal adult averages less than 200 grams per day; in children it depends on age and size, and an infant may pass up to 100 grams per day. PATHOPHYSIOLOGY
Diarrhoea in which the volume of faeces is increased is called large-volume diarrhoea. It is generally caused by excessive amounts of water or secretions, or both, in the intestines. Small-volume diarrhoea, in which the volume of faeces is not increased, usually results from excessive intestinal motility. There are several major mechanisms of diarrhoea (see Fig. 27.24):
FIGURE 27.24
The pathophysiology of diarrhoea. In all cases, the chyme contains more fluid than usual. A In small volume diarrhoea, increased intestinal motility causes the passage of chyme to pass too quickly for water to be absorbed. B In osmotic diarrhoea, a type of large-volume diarrhoea, the undigested sugars within the intestines draw water out of the mucosal cells into the lumen. C In secretory diarrhoea, a type of large-volume diarrhoea, an excessive amount of mucus is secreted by the gut wall, which means that more mucus passes with the chyme than usual.
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• Osmotic diarrhoea. A non-absorbable substance in the intestine draws excess water into the intestine and increases stool weight and volume, producing large-volume diarrhoea. Causes include lactase and pancreatic enzyme deficiency and excessive ingestion of some synthetic (artificial), non-absorbable sugars. We usually refer to these synthetic products as artificial sweeteners. These are found in many ‘diet’ food products as alternatives to sugar (sucrose). • Secretory diarrhoea. Excessive mucosal secretion of fluid and electrolytes produces large-volume diarrhoea. Causes include bacterial enterotoxins (a toxin produced by bacteria such as Escherichia coli, which is specific to the gastrointestinal tract), neoplasms, or exotoxins released from overgrowth of Clostridium difficile following antibiotic therapy. The elderly and immunocompromised people are particularly at risk of diarrhoea due to Clostridium difficile.78 • Bile salt malabsorption. Bile salts are produced in the liver and play a key role in the absorption of dietary fats from the small intestine (see Chapter 26). Following their involvement in micelle formation in the small intestine, about 95% of bile salts are actively reabsorbed in the ileum and returned to the liver via the hepatic portal vein (a process known as the enterohepatic circulation). If the bile salts are not reabsorbed in the ileum they enter the large intestine where they stimulate fluid secretion, increase mucosal permeability and mucus secretion and stimulate colonic contractions. Symptoms of bile salt malabsorption include watery diarrhoea, bloating, faecal urgency and faecal incontinence. Bile salt diarrhoea may be caused by a number of diseases and conditions such as Crohn’s disease, coeliac disease, irritable bowel syndrome, chronic pancreatitis, removed gallbladder (cholecystectomy) and enteritis induced by radiotherapy. Bile salt diarrhoea in which the cause is unknown is called idiopathic bile salt diarrhoea.79,80 • Changes in intestinal transit. Damage to the enteric nervous system and intestinal muscles caused by inflammation or toxicity can lead to changes in intestinal contractions and transit resulting in smallvolume non-watery diarrhoea. It is associated with inflammatory disorders of the intestine, such as ulcerative colitis and Crohn’s disease, post-inflammatory irritable bowel syndrome and a common side effect of chemotherapy.81 CLINICAL MANIFESTATIONS
Apart from the mechanism, diarrhoea can be classified as acute or chronic, depending on its cause. Symptoms of acute diarrhoea include fatigue and drowsiness, thirst, loss of appetite, nausea, headache and faintness, as well as decreased urinary volume. Systemic effects of prolonged diarrhoea are dehydration and electrolyte imbalance.
Normally, faeces do not contain much sodium, but are high in potassium; however, diarrhoea can cause an extensive loss of both potassium and sodium, which can become serious if untreated. Manifestations of acute bacterial or viral infection include fever, with or without cramping pain. Fever, cramping pain and bloody stools accompany diarrhoea caused by inflammatory bowel disease. Steatorrhoea (fat in the stools) and diarrhoea are common signs of malabsorption syndromes. EVALUATION AND TREATMENT
A thorough history is taken to document the onset and frequency of diarrhoea. Exposure to contaminated food or water is indicated if the individual has travelled in foreign countries or areas where drinking water might be contaminated. Physical examination helps identify underlying systemic disease. Stool culture, examination of stool specimens for blood, abdominal x-ray films and intestinal biopsies provide more specific data. There are some specific tests for bile salt diarrhoea including selenium homocholic acid taurine (75SeHCAT) test measuring the amount of bile salts in the stool and 7a-hydroxy4-cholesten-3-one (C4) test measuring bile salt precursor in the blood, indicative of increased production of bile salt.80 Treatment for diarrhoea includes restoration of fluid and electrolyte balance, management of distressing symptoms and treatment of causal factors. Nutritional deficiencies need to be corrected in cases of chronic diarrhoea or malabsorption. The use of probiotic food products (foods that contain live bacteria, such as yoghurt) may be useful in the prevention of diarrhoea resulting from Clostridium difficile, as may be other infection control techniques (such as adequate handwashing) and avoiding excessive use of broad-spectrum antibiotics.82
RESEARCH IN F CUS Faecal microbiota transplantation Faecal microbiota transplantation (FMT) is a very promising new treatment option for treating a range of bowel conditions such as Clostridium difficile infection, ulcerative colitis and irritable bowel syndrome. Faecal microbiota transplantation involves transplanting normal faecal bacteria from a healthy donor to a person affected by one of these conditions. The premise behind the faecal microbiota transplantation is that transplanting healthy faecal bacteria into a person with unhealthy bacteria will correct the underlying bacterial imbalance, seen in persons with recurrent bowel conditions. Routes of administration include via a nasogastic, nasojejunal tube, gastroscopy, colonoscopy and retention enema.
CHAPTER 27 Alterations of digestive function across the life span
833
Diarrhoea is a common gastrointestinal problem during infancy and early childhood and is the leading cause of death in children younger than 5 years of age.83 Infants have low fluid reserves and relatively rapid gut peristalsis and metabolism. Therefore, the danger of dehydration is great with prolonged diarrhoea. Disturbances can occur by processes that increase fluid secretion into the gastrointestinal lumen (secretory diarrhoea), draw fluid into the lumen by osmosis (osmotic diarrhoea) or prevent fluid absorption in the intestine. Most episodes are selflimiting in that once the original cause in the gastrointestinal tract has been passed (along with the diarrhoea), recovery begins and usually resolves within 72 hours. Acute diarrhoea Acute diarrhoea in children is almost synonymous with acute viral or bacterial gastroenteritis. Rotavirus is the single most significant cause of gastroenteritis in infants and young children. Severe dehydration results from vomiting and diarrhoea. Vaccines for rotavirus are on the childhood immunisation schedules. Viral gastroenteritis tends to be self-limiting. Bacterial gastroenteritis is treated with antibiotics if the causal pathogen can be identified. Other causes of acute diarrhoea in the older child include antibiotic therapy, appendicitis, chemotherapy, inflammatory bowel disease, parasitic
Dysphagia
Dysphagia is difficulty swallowing. Functional dysphagia is caused by neural or muscular disorders that interfere with voluntary swallowing or peristalsis. Disorders that affect the striated muscles of the upper oesophagus interfere with the oropharyngeal (voluntary) phase of swallowing. This is common in patients who have suffered from cerebrovascular accidents (stroke) and therefore is reasonably common in elderly patients. Other neurological impairments such as Parkinson’s disease may also cause dysphagia (see Chapter 9). Dysphagia can also result from mechanical obstruction of the oesophagus or a disorder that impairs oesophageal motility. Intrinsic obstructions originate in the wall of the oesophageal lumen and include tumours, strictures and diverticular herniations (outpouchings). Extrinsic mechanical obstructions originate outside the oesophageal lumen and narrow the oesophagus by pressing inwards on the oesophageal wall. The most common cause of extrinsic mechanical obstruction is tumour. CLINICAL MANIFESTATIONS
Distension and spasm of the oesophageal muscles during eating or drinking may cause a mild or severe stabbing
infestation, parenteral infections and ingestion of toxic substances. Chronic diarrhoea Children with acute gastroenteritis often remain mildly symptomatic for up to 4 weeks; therefore, diarrhoea that persists for longer than 4 weeks is considered to be chronic. Children with chronic diarrhoea can be divided into two groups: (1) otherwise well children whose growth is normal; and (2) ill children whose growth is retarded. Causes of chronic diarrhoea in the first group include abnormal colonic motility, lactose intolerance, encopresis (involuntary defecation), parasitic infestation and antibiotic use. Chronic diarrhoea in the second group is usually caused by a disease that impairs absorption. PATHOPHYSIOLOGY
Common causes of acute diarrhoea in infants include Hirschsprung’s disease, infections and milk protein allergies. Infectious diarrhoea in newborns is usually associated with day-care epidemics involving pathogens such as Escherichia coli, Klebsiella, staphylococci, Salmonella and Shigella. Diarrhoea caused by these agents has a rapid onset and acidosis and shock can occur quickly. Clostridium difficile, often associated with previous antibiotic therapy, can cause acute, profuse, watery diarrhoea and symptoms of colitis.
pain at the level of obstruction. Discomfort occurring 2–4 seconds after swallowing is associated with upper oesophageal obstruction. Discomfort occurring 10–15 seconds after swallowing is more common in obstructions of the lower oesophagus. If obstruction results from a growing tumour, dysphagia begins with difficulty swallowing solids, in particular bread and meat, and advances to difficulty swallowing semisolids and liquids. If motor function is impaired, both solids and liquids are difficult to swallow. Regurgitation of undigested food, unpleasant taste, vomiting, aspiration and weight loss are common manifestations of dysphagia. Aspiration of oesophageal contents can lead to pneumonia. EVALUATION AND TREATMENT
Knowledge of the patient’s history and clinical manifestations contributes significantly to a diagnosis of dysphagia. A barium swallow is used to visualise the contours of the oesophagus and identify structural defects. Manometry uses an instrument to determine the duration and amplitude of abnormal pressure changes associated with obstruction or loss of neural regulation. Oesophageal endoscopy is performed to examine the oesophageal mucosa and obtain biopsy specimens.22
PAEDIATRICS
Paediatrics and diarrhoea
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The individual is taught to manage symptoms by eating slowly, eating small meals, taking fluid with meals and sleeping with the head elevated to prevent regurgitation and aspiration. Anticholinergic drugs block the effects of acetylcholine at the neuromuscular junction and result in muscle relaxation — a well-known example, botox (botulism toxin), may relieve symptoms of dysphagia. For oesophageal dysphagia, choice of management depends on the aetiology; it may include endoscopic dilation or myotomy for structural abnormalities, or topical steroid therapy for eosinophilic oesophagitis.84
from the jejunum, ileum, colon or rectum, can be caused by polyps, inflammatory disease, cancer or haemorrhoids (see Fig. 27.25B). Acute, severe gastrointestinal bleeding is life threatening, depending on the volume and rate of blood loss, associated disease, patient’s age and effectiveness of treatment. The physiological response to gastrointestinal bleeding depends on the amount and rate of the loss. Changes in blood pressure and heart rate are the best indicators of massive blood loss in the gastrointestinal tract. During the early stages of blood volume depletion, the peripheral vascular compartment constricts to shunt blood to vital organs, particularly the brain, heart and lungs. A sign that this is happening is postural hypotension (a drop in blood pressure that occurs with postural change from lying to sitting or standing), light-headedness and loss of vision. If blood loss continues, hypovolaemic (low blood volume) shock progresses (see Fig. 23.50 for further details on hypovolaemic shock). Diminished blood flow to the kidneys causes decreased urine output and may lead to oliguria (low urine output), tubular necrosis and renal failure. Ultimately, insufficient cerebral and coronary blood flow causes irreversible anoxia and death. The accumulation of blood in the gastrointestinal tract is irritating and increases peristalsis, causing diarrhoea. If bleeding is from the lower gastrointestinal tract, the diarrhoea contains large amounts of frank blood. Bleeding from the upper gastrointestinal tract is usually manifest as melaena — black or tarry stools that are sticky and have a characteristic foul odour. It results in partial digestion of the blood components within the length of the gastrointestinal tract. Small amounts of blood in the faeces may go unnoticed — this is occult, or unseen, bleeding. The presence of bright-red blood in the faeces is usually due to bleeding in the rectal or anal area, particularly with a tear or haemorrhoids.
Anorexia
Anorexia is a clinical manifestation that needs clarification. It is simply a lack of desire to eat, despite physiological stimuli that would normally produce hunger. This nonspecific symptom may be associated with a large number of disorders and diseases including nausea, abdominal pain, diarrhoea, cancer, heart disease, renal disease and psychosocial distress. It may be relatively short-lasting and resolve if the underlying cause improves. Anorexia nervosa is a more specific condition of decreased food intake of neurological origin and is discussed in Chapter 39.
Gastrointestinal bleeding
Upper gastrointestinal bleeding, which is defined as bleeding in the oesophagus, stomach or duodenum, is characterised by frank (easily observed), bright-red bleeding or ‘coffee-ground’ material that has been affected by stomach acids. Haematemesis refers to vomiting blood and should be distinguished from haemoptysis, which is coughing up blood-stained sputum from the lungs. Upper gastrointestinal bleeding is commonly caused by bleeding varices (varicose veins) in the oesophagus, peptic ulcers or a Mallory-Weiss tear at the oesophageal–gastric junction from severe retching (see Fig. 27.25A). Lower gastrointestinal bleeding, or bleeding
Oesophageal varices
A
B Mallory-Weiss tears
Colitis (infections, IBD) Polyps
Gastric ulcer Duodenal ulcer
Ischaemic colitis
Angiodysplasia Acute erosive gastritis
Gastric carcinoma
Carcinoma
Diverticula Haemorrhoids
FIGURE 27.25
Gastrointestinal bleeding. Main causes of bleeding in A, the upper gastrointestinal system and B, the lower gastrointestinal system. IBD = inflammatory bowel disease.
CHAPTER 27 Alterations of digestive function across the life span
FO CUS O N L E A R N IN G
1 Describe the vomiting reflex and list some common factors that trigger this reflex. 2 Explain how vomiting is treated. 3 Discuss the factors that contribute to constipation. 4 Describe the treatment options for constipation. 5 Explain the common causes of diarrhoea. 6 Compare and contrast acute and chronic diarrhoea in children. 7 Discuss the development of dysphagia, mentioning those patients who are most likely to develop this condition. 8 Discuss the symptoms and management of dysphagia. 9 Discuss the different types of gastrointestinal bleeding.
Disorders of the hepatobiliary system and pancreas The accessory organs of digestion (liver, gallbladder, pancreas) secrete substances necessary for digestion and, in the case of the liver, carry out additional metabolic functions needed for homeostasis of all body systems. Disorders of these organs are usually caused by inflammatory disease, obstruction of ducts and tumours. It is somewhat unfortunate that the liver, gallbladder and pancreas are known as ‘accessory’ organs, as the word accessory may give the incorrect impression that these organs are of low importance; it simply means that their secretions empty into the gastrointestinal system. The critical importance of these organs is shown by the serious illnesses and mortality that accompanies their dysfunction. The most common pancreatic disorder is diabetes mellitus, which is introduced in Chapter 11 and discussed in detail in Chapter 36.
Hepatic disorders
The main type of injury that occurs in the liver involves damage to the hepatocytes by cirrhosis (inflammation and fibrosis), which is strongly associated with high fat diets and alcohol consumption. Viral hepatitis also severely impairs hepatocyte function and may increase the likelihood of cancer development. Blockages of the blood supply into the hepatocytes, or of the bile drainage away from hepatocytes, can result in a range of clinical manifestations and liver conditions.
Inflammatory processes of the liver NON-ALCOHOLIC LIVER DISEASE
The most prevalent liver disease in Australia is non-alcoholic fatty liver disease (NAFLD) and is the accumulation of fat
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(steatosis) in the liver cells, and may progress to irreversible liver cirrhosis.85 It is estimated that 5.5 million Australians are affected with NAFLD, with an estimated increase to over 7 million affected by 2030.44 Steatosis in NAFLD is directly related to modifiable risks such as excess consumption of fats, obesity (refer to Chapter 35), and insulin resistance (which is a reduction in tissue sensitivity to the actions of insulin; see Chapter 36 for discussion of decreased sensitivity to insulin). NAFLD is often diagnosed through an incidental finding because of abnormal liver tests. A medical and lifestyle history needs to be taken from the patient including any reduced physical activity, weight gain and if that weight is centrally located, in conjunction with liver function blood tests.85 Other causes of abnormal liver function test results need to be excluded. Risk factors associated with NAFLD include the consumption of excess fats, as these are stored in the liver as triglycerides. Furthermore, energy consumption beyond the individual’s requirements in terms of either proteins or carbohydrates (particularly carbohydrates of high glycaemic index; refer to Chapter 36), can also be converted into fats such as triglycerides that are stored in the liver. Indeed, the rise in obesity in recent decades has also seen a rise in the rates of NAFLD. Other risk factors which are similar to risk factors of major preventable diseases in Australia and New Zealand, are also similar for NAFLD; these include insulin resistance, type 2 diabetes, obesity (predominately central abdominal), high cholesterol and cardiovascular disease.86 These pathophysiological stages of NAFLD are described in detail below, as the stages are the same for alcoholic and non-alcoholic liver disease; it is mainly the cause which differs. The management of these inflammatory liver diseases is also discussed together. ALCOHOLIC LIVER DISEASE
Alcohol consumption can cause liver disease, and the mildest form is steatosis or fatty liver, which may progress to irreversible liver cirrhosis. The long-term amount and duration of alcohol consumption are related to the extent of liver damage, so those who have consumed higher volumes of alcohol are at greater risk of developing cirrhosis. Although there is a misconception that some drinks are ‘less harmful’ than others, abuse of any type of alcoholic beverage can cause cirrhosis. A standard drink is defined as having 10 grams of alcohol, and different types of drinks may equate to more than a standard drink in what may appear to be a normal serving size. Alcoholic liver disease is less common in those with low alcohol consumption, such in patients who consume no more than two standard alcohol drinks for men and one standard drink for women a day.86 Those of the Indigenous populations in Australia and New Zealand who do consume alcohol are more likely to drink more than the recommended daily amounts. The rate of alcohol-attributable injury, disease and death are particularly high among Indigenous populations.87,88 These
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data show that alcohol use is a significant concern for our communities. The lifetime risk of mortality from chronic disease due to alcohol consumption rises when more than two standard drinks per day are consumed, for both men and women (see Box 27.5 for guidelines on alcohol consumption). However, as the amount of alcohol consumed increases, the risks become even greater for women than for men. Some reasons why women are more susceptible to higher amounts of alcohol than men include both the smaller liver size and the lower proportion of lean tissue in women compared with men. It must also be remembered that individuals have differences in alcohol metabolism.89 Of course, alcohol consumption may be beneficial for health — for example, lowering the risk of some cardiovascular conditions. However, it needs emphasising that such benefits are achieved when alcohol consumption is relatively low and that an improvement in the risk of these cardiovascular conditions could be achieved by exercise or dietary modifications.88 Moreover, the benefits of drinking alcohol only begin to appear from middle age; drinking prior to this does not provide health benefits.85 Finally, the number of alcohol-related actual deaths still outweighs the number of deaths prevented in both countries. Alcohol is directly toxic to the liver. The alcohol is absorbed into the bloodstream and transported directly to the liver through the hepatic portal vein. The liver can metabolise the alcohol from approximately one standard drink per hour.88 Alcohol is metabolised to acetaldehyde, which is actually a toxic substance — excessive amounts significantly alter hepatocyte function. Because the liver has such an important role in the metabolism of a wide variety of substances (a few thousand!), many body processes are affected by altered hepatocyte function. Normal liver functions such as enzyme and protein production may be decreased, and hormone and ammonia degradation are diminished. Acetaldehyde also inhibits the export of proteins from the liver, alters the metabolism of vitamins and minerals, and induces malnutrition. Cellular damage initiates an inflammatory response that, along with necrosis (cell damage), results in excessive collagen formation. Fibrosis
BOX 27.5
Guidelines for alcohol consumption
The current Australian and New Zealand guidelines for alcohol consumption that reduces the lifetime risk of harm from alcohol-related disease or injury recommend: • two alcohol-free days in a week Australian guidelines recommend: • drinking no more than two standard drinks on any day for men and women New Zealand guidelines recommend: • drinking no more than three standard drinks for men, and two standard drinks for women on any given day
and scarring alter the structure of the liver and obstruct biliary and vascular channels. More details of the long-term effects of alcohol on the liver are discussed below (in ‘Pathophysiology of alcoholic and non-alcoholic liver disease’). In addition to the effects on the liver, long-term alcohol consumption has many other effects on health, as summarised in Box 27.6. It is preferable to consume alcohol with food, as this minimises the effects directly on the stomach, as well as slowing the rate of alcohol absorption into the bloodstream. Malnutrition can add to the risk of cirrhosis in alcohol abusers. Malnutrition may occur because those who drink large amounts of alcohol may skip meals (as they are drinking alcohol instead). Also, the alcohol that is being consumed does not supply any beneficial nutrients to the diet and is described as being ‘empty calories’.90 Malnutrition impairs liver function and can contribute to the development of cirrhosis. PATHOPHYSIOLOGY OF NON-ALCOHOLIC AND ALCOHOLIC LIVER DISEASE
Alcoholic and non-alcoholic liver disease both progress through similar stages, starting with fatty liver (steatosis), through to steatohepatitis, and finally liver cirrhosis. It is the cause of the inflammatory disease which differs, whether it is alcoholic or non-alcoholic, with non-alcoholic due to excess lipid consumption being the main cause of liver disease in Australia and New Zealand. Fatty liver (steatosis) is the mildest form of alcoholic and non-alcoholic liver disease. It can be caused by relatively small amounts of alcohol, may be asymptomatic and is reversible with the cessation of drinking. It can also be caused by relatively ‘moderate’ consumption of excess nutrients, particularly excess fats, although it can also be caused by excesses carbohydrates or proteins that are stored as fat in the liver. The fatty infiltration of hepatocytes (liver
BOX 27.6
Long-term effects of alcohol on health
• Cardiovascular diseases (hypertension, arrhythmias, ischaemic heart disease, increased triglycerides, shortness of breath, some types of cardiac failure, haemorrhagic stroke) • Cancers (mouth, pharynx, larynx, oesophagus, liver, colorectal, breast) • Diabetes (insulin sensitivity, type 2 diabetes mellitus, metabolic syndrome) • Overweight and obesity • Liver diseases (fatty liver, hepatitis B, hepatitis C, alcoholic hepatitis, alcoholic cirrhosis) • Malnutrition (deficiency of vitamin A, folate and thiamine) • Cognitive impairments and mental health conditions (depression, anxiety, dementia)
CHAPTER 27 Alterations of digestive function across the life span
cells) is usually asymptomatic. At this stage, the inflammatory liver disease is fully reversible so, depending on the primary cause, abstaining from alcohol or avoiding excess intake of fats or other nutrients is vital to prevent worsening of the condition. Steatohepatitis is an intermediate stage of inflammatory liver disease. It may be more specifically known as alcoholic hepatitis or non-alcoholic steatohepatitis (common abbreviation NASH), depending on whether alcohol is the main cause. It is characterised by fatty infiltration, inflammation, degeneration and necrosis of hepatocytes and infiltration of white blood cells (polymorphonuclear leucocytes and lymphocytes). The injured hepatocytes begin undergoing the onset of fibrosis. The mechanism of hepatocyte injury is not clearly understood, but immunological factors and inflammatory mediators are involved. Altered liver function may be evident from liver function tests, such as AST and ALT (refer to Chapter 26); however, these may also be at normal levels. An ultrasound also shows an enlarged liver. The inflammation and necrosis caused by steatohepatitis stimulate the irreversible fibrosis characteristic of the cirrhotic stage of disease — this means that as this stage worsens, some changes of the liver cannot be reversed, even if alcohol consumption or excess fat consumption is ceased. Cirrhosis is an irreversible inflammatory disorder that disrupts liver structure and function and is a leading cause of death, and can be caused by either excess fat consumption or excess alcohol intake. While cirrhosis may be due to a number of causes, the main cause of cirrhosis of the liver is excess fat consumption, excess consumption of energy, and alcohol consumption.85 Non-alcoholic cirrhosis and alcoholic cirrhosis are characterised by chronic inflammation and result in fibrosis. Disorganisation of hepatic tissues is caused by diffuse fibrosis and regeneration of tissue between fibrous bands that give the liver a cobbly appearance. In cirrhosis, the liver becomes severely impaired due to significant fat accumulation and altered metabolism,87 and modification of risks at this stage will be too late to reverse the disease, although may be sufficient to slow the rate of liver decline. The liver may be larger or smaller than normal and usually it is firm when palpated. Cirrhosis develops slowly over a period of years. CLINICAL MANIFESTATIONS OF NON-ALCOHOLIC AND ALCOHOLIC LIVER DISEASE
The majority of patients with steatosis are asymptomatic, although some patients may experience fatigue and right upper quadrant discomfort. Fatty infiltration causes no specific symptoms or abnormal liver function test results. The liver is usually enlarged and the individual has a history of regular alcohol or excess nutrient intake during the previous weeks or months. Anorexia, nausea, jaundice and oedema develop with advanced fatty infiltration or steatohepatitis. Fever and jaundice (yellow colour due to build-up of bilirubin) may also occur. The clinical manifestations of advanced liver disease become more severe. Toxic effects of alcohol can also cause
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testicular atrophy, reduced libido and decreased fertility in men. Cirrhosis is a multiple-system disease and causes hepatomegaly (enlarged liver), gastrointestinal haemorrhage, portal hypertension, hepatic encephalopathy and oesophageal varices. These severe complications are described individually in ‘Clinical manifestations of hepatobiliary alterations’ below. Anaemia results from blood loss, poor nutrition and splenomegaly (enlarged spleen). The presence of numerous and severe manifestations increases the risk of death (see Fig. 27.26). EVALUATION AND TREATMENT OF NON-ALCOHOLIC AND ALCOHOLIC LIVER DISEASE
The diagnosis of NAFLD and alcoholic liver disease is based on the individual’s history and clinical manifestations. The results of blood tests may be normal in early states, although these become abnormal as the liver disease progresses through the later stages, with elevated serum enzymes and bilirubin (a waste product metabolised by the liver), decreased serum albumin (a plasma protein produced by the liver) and prolonged prothrombin time (as the liver cannot produce sufficient quantities of clotting factors, the time for blood to clot is extended). Liver biopsy can confirm the diagnosis of cirrhosis, but biopsy is not necessary if clinical manifestations of cirrhosis are evident. Management of NAFLD is primarily through lifestyle changes which include increasing physical activity, losing weight, following a healthy diet and avoidance of alcohol.85 In the early stages, this may lead to reversal of the condition; however, once the disease progresses to the irreversible stages of steatohepatitis and cirrhosis, management of risks slows the progression of liver damage, improves clinical symptoms and prolongs life. As the disease progresses, management of complications, such as ascites, gastrointestinal bleeding and encephalopathy, is essential, along with a nutritious diet. Individuals with severe symptoms are treated with corticosteroids and other drugs, including antioxidants and tumour necrosis factor-alpha (TNF-α) inhibition. In some cases, liver transplantation can be successful for treatment of end-stage liver disease. VIRAL HEPATITIS
Viral hepatitis is a relatively common systemic disease that primarily affects the liver. Five strains of viruses cause different types of hepatitis: hepatitis A, hepatitis B, hepatitis C, hepatitis D and hepatitis E. These five viruses can cause acute hepatitis, and types B and C also cause chronic liver disease, hepatic cancer and liver failure.91,92 The virus can be carried for years, usually without significant liver damage. Characteristics of the different types of viruses that cause hepatitis are presented in Table 27.9. Hepatitis A is on the decline in Australia since an effective vaccine became available in Australia in the 1990s;93 this is recommended for those travelling to countries where hepatitis A is endemic, as well as for Aboriginal Australians and Torres Strait Islanders, who are at higher risk.94 The main route of transmission of this virus is via the faecal–oral route.
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CONCEPT MAP
Alcohol consumption leads to IRREVERSIBLE
REVERSIBLE
Fatty liver: steatosis
if individual chooses
if individual chooses Cessation of alcohol consumption
Sustained alcohol consumption progresses to
returns to
Alcoholic hepatitis: steatohepatitis
Normal liver function
progresses to Alcoholic cirrhosis manifestations include Hepatic encephalopathy
Ascites
Portal hypertension and gastrointestinal haemorrhage
Hepatorenal failure
Life threatening FIGURE 27.26
Alcoholic liver disease progresses from fatty liver (steatosis) to alcoholic cirrhosis. Alcoholic cirrhosis is characterised by irreversible changes that can be life-threatening.
A total of 6502 notifications of people newly diagnosed with hepatitis B were reported in 2015 in Australia with an estimated 232 600 people living with hepatitis B. Of this number 38% were born in Asia-Pacific and 9.3% were Aboriginal and Torres Strait Islander peoples.92,95 The number of notifications of newly diagnosed hepatitis B has declined over the last decade due to the impact of the infant and adolescent vaccination program. In New Zealand it is estimated there are 100 000 people infected with hepatitis B; 200–300 New Zealanders die each year from the disease.96 This virus is transmitted by direct contact with blood and body fluids; because it is present in saliva, it can easily be transmitted by children. An effective vaccine is now on the childhood immunisation registers for Australia and New Zealand (see Tables 14.6 and 14.7 and Box 27.7). Infants of mothers who are chronic hepatitis B surface antigen (HBsAg) carriers, children with haemophilia who receive frequent blood transfusions and children who live in institutions for those with mental disabilities are all at risk for hepatitis B infection.97
The hepatitis C notification rate has been stable between 2012 and 2015, with an estimated 227 306 people living with hepatitis in Australia.92 However notification rates for the Aboriginal and Torres Strait Islander population increased by 43% in the 5 years 2010–2015.95 This rate is four times higher than in the non-Indigenous population. Fifty-five per cent of hepatitis C infections are from injecting drug users which has remained stable for the 5 years 2010–2015, with others infected through methods such as unsterile tattooing or body piercing procedures, needle-stick injuries and other forms of blood-to-blood contact. In New Zealand it is estimated that there are 50 000 people affected with hepatitis C; however, it is estimated that only half have been diagnosed with the disease and are unaware they have hepatitis C. Most children with hepatitis C were born of mothers who have a history of injecting drugs.96 Hepatitis D is mainly transmitted by blood products and intravenous drug use. Hepatitis D is caused by an incomplete virus, which requires simultaneous infection
CHAPTER 27 Alterations of digestive function across the life span
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TABLE 27.9 Characteristics of viral hepatitis CHARACTERISTIC
HEPATITIS A
HEPATITIS B
HEPATITIS C
HEPATITIS D
HEPATITIS E
Viral type
RNA
DNA
RNA
RNA
RNA
Antigens or antibodies
Anti-HAV
HBsAg
Anti-HCV
Anti-HDV
Anti-HEV
HBcAg HbeAg
Route of transmission
Faecal–oral, parenteral, sexual
Parenteral, sexual
Parenteral, sexual
Parenteral, faecal– Faecal–oral oral, sexual
Incubation period
30 days
60–180 days
35–60 days
30–180 days
15–60 days
Onset
Nonspecific
Insidious
Insidious
Insidious
Acute
Acute with fever Carrier state
Negative
Positive
Positive
Positive
Negative
Severity
Mild
Severe; may be prolonged or chronic
Unknown
Severe
Severe in pregnant women
Chronic hepatitis
No
Yes
Yes
Yes
No
Increased risk of liver cancer
Increased risk of liver cancer
Age-group affected
Children and young Any adults
Any
Any
Children and young adults
Prophylaxis
HAV vaccine, hygiene, immune serum globulin
HBV vaccine, hygiene, blood screening
Hygiene, blood screening, interferon alpha
HBV vaccine, hygiene
Hygiene, safe water
Treatment
Symptomatic support
Interferon-alpha
Interferon alpha
Interferon-alpha
Symptomatic support similar to HAV
Peginterferon-alpha Peginterferon-alpha Antivirals
Antivirals
DNA = deoxyribonucleic acid; HBcAg = hepatitis B core antigen; HBeAg = hepatitis B e antigen (a fragment derived from the same propeptide for HBcAg); HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; RNA = ribonucleic acid.
BOX 27.7
Hepatitis vaccines for children
In Australia: • hepatitis A vaccine: for Aboriginal and Torres Strait Islander children aged 12 and 18 months 2 doses • hepatitis B vaccine: for all children from birth to age 6 months, 4 doses. In New Zealand: • hepatitis B vaccine: for all children from age 6 weeks to 5 months, 3 doses. (For full details see Tables 14.6 and 14.7.)
with hepatitis B; therefore, vaccination against hepatitis B will protect against hepatitis B and D. The rate of infection of hepatitis E is rare. Hepatitis E is transmitted via the faecal–oral route from contaminated food and water. It is most common in areas with poor sanitation and sewage management.92
PATHOPHYSIOLOGY
All five types of viral hepatitis can cause acute jaundice. The pathological effects of hepatitis are similar to those caused by other viral infections. Hepatic cell necrosis, scarring (with chronic disease) and inflammatory processes occur with varying severity. The inflammatory process can damage and obstruct bile canaliculi, leading to obstructive jaundice. Damage tends to be most severe in cases of hepatitis B and C. Co-infection of hepatitis B virus with hepatitis C virus, hepatitis D virus or human immunodeficiency virus (HIV) occurs as these viruses share the same route of transmission (direct contact of body fluids such as sharing intravenous needles and sexual transmission). Progression of liver disease is more rapid in these cases.98 CLINICAL MANIFESTATIONS
The spectrum of manifestations ranges from absence of symptoms to acute liver failure, with rapid onset of liver failure and coma. Acute viral hepatitis causes abnormal liver function test results. The serum AST (aspartate
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transaminase) and ALT (alanine transaminase) are elevated but not consistent with the extent of cellular damage. The clinical course of hepatitis usually consists of three phases: 1 Pre-icteric (or prodromal) phase. Begins about 2 weeks after exposure; marked by fatigue, anorexia, malaise, nausea, vomiting, headache, cough and low-grade fever; infection is highly transmissible during this phase. Because there is no jaundice present during this stage, patients suffering from these general symptoms may appear to have influenza. 2 Icteric phase. Begins 1–2 weeks after pre-icteric phase and lasts 2–6 weeks; jaundice begins, dark urine and light-coloured stools are common; liver is enlarged and tender and percussion (tapping the abdomen over the liver) causes pain. 3 Recovery phase. Begins with resolution of jaundice, about 6–8 weeks after exposure; symptoms diminish, but the liver remains enlarged and tender; liver function returns to normal 2–12 weeks after the onset of jaundice. Acute liver failure is a clinical syndrome resulting in severe impairment or necrosis of liver cells and potential liver failure. The disorder rarely occurs with hepatitis A, but is a common complication associated with hepatitis B and C infection. In particular, those with compromised immune systems such as children and those with other illness are more likely to progress to acute liver failure. Toxic reactions to drugs and congenital metabolic disorders can also cause acute liver failure.99 Acute liver failure is characterised by massive hepatic necrosis and causes severe encephalopathy, manifested as altered motor functions, confusion, stupor and coma. It can also include intestinal bleeding, cardiorespiratory insufficiency and renal failure. The death of hepatocytes may be caused by viral or immunological damage. Acute liver failure usually develops within 6–8 weeks after the initial symptoms of viral hepatitis (or metabolic liver disorder). Anorexia, vomiting, abdominal pain and progressive jaundice are initial signs, followed by ascites and gastrointestinal bleeding. Liver function tests show elevations of serum bilirubin, AST and ALT, and blood ammonia (a substance from protein metabolism that is normally removed by the liver). Prothrombin time is prolonged, as the liver is unable to produce adequate levels of blood-clotting factors. Renal failure and pulmonary distress can occur. Chronic active hepatitis is the persistence of clinical manifestations and liver inflammation after acute hepatitis B, hepatitis C or hepatitis D — the patient does not undergo the recovery phase. In chronic hepatitis, liver function tests remain abnormal for longer than 6 months and hepatitis B surface antigen persists. Chronic, active hepatitis B is a predisposition to cirrhosis and primary hepatic cancer. Hepatitis C infection also has a substantial role in liver cancer in Australia and New Zealand.92 Extrahepatic manifestations, including arthralgias (joint pain), fatigue, neurological and renal symptoms, occur in some individuals.100
Hepatitis B and C viruses are the main causes of chronic hepatitis in children. Manifestations of chronic hepatitis include malaise, anorexia, fever, gastrointestinal bleeding, hepatomegaly (enlarged liver), oedema and transient joint pain. Serum ALT and bilirubin levels are elevated. There may be evidence of impairment of the functions of the liver in producing substances, such as prolonged prothrombin time and hypoalbuminaemia. EVALUATION AND TREATMENT
The diagnostic tests for viral hepatitis depend on whether antigens or antibodies are present (see Table 27.9). The most specific diagnostic test for viral hepatitis is a blood test for specific hepatitis virus antigens (HBsAg, hepatitis B surface antigen). Diagnosis of type A, type C and type D hepatitis is based on the presence of antibodies for each viral type. Liver function tests, including liver enzyme levels, are sensitive for liver cell injury and can also indicate other viral liver diseases, drug toxicity or alcoholic hepatitis. There is no specific treatment for acute viral hepatitis. For most individuals the disease is self-limiting with full recovery. Physical activity may be restricted. A low-fat, high-carbohydrate diet is beneficial if bile flow is obstructed, as fats cannot be digested without adequate levels of bile. For chronic hepatitis, treatment is directed at suppressing viral replication before irreversible liver cell damage occurs. Antiviral therapies include interferon-alpha and specific antiviral agents. Cyclic and combination therapy may prevent drug resistance and new agents are being developed.101 See ‘Research in Focus: Hepatitis: antiviral therapies’. After ingestion and gastrointestinal uptake, hepatitis A replicates in the liver and is secreted into the bile. To prevent transmission of hepatitis A, handwashing and the use of gloves for disposing of bedpans and faecal matter are imperative. Hepatitis A may be shed in the faeces for up to 3 months after the onset of symptoms. The administration of immune globulin before exposure or early in the incubation period can prevent hepatitis A and hepatitis B. Vaccines are available to protect against hepatitis A and B infections, with the hepatitis B vaccine protecting against hepatitis D too. Because co-infection of hepatitis is of concern, patients with hepatitis C should be offered vaccines for hepatitis A and B.102 Prophylaxis is recommended for healthcare workers and others who are at risk for contact with infected body fluids, particularly children. Treatment of acute liver failure is supportive. The hepatic necrosis is irreversible and 60–90% of affected children die. Liver transplantation may be lifesaving and should be considered early. Survivors usually do not develop cirrhosis or chronic liver disease. Diagnosis of chronic hepatitis is based on the clinical manifestations and liver biopsy. Chronic infections from hepatitis B and C are the most common indications for liver transplant in Australia.103 Most of the morbidity and mortality associated with chronic hepatitis B infection results from liver cirrhosis and cancer.104
CHAPTER 27 Alterations of digestive function across the life span
The cost of treatment is expensive and drugs are sometimes poorly tolerated. Viral resistance limits drug use but advances are continuing to be made in the development of new drugs and hepatoprotective agents. With progression to end-stage liver disease, transplantation becomes the only option.103 Aggressive vaccination for the prevention of hepatitis is needed.102
841
FOCU S ON L EA RN IN G
1 Discuss the significance of non-alcoholic liver disease in our population. 2 Describe the progression of fatty liver through to cirrhosis. 3 List the clinical manifestations and management options of alcoholic liver disease. 4 List the main routes of transmission for the types of hepatitis most prevalent in Australia and New Zealand.
RESEARCH IN F CUS Hepatitis: antiviral therapies
5 Describe the clinical manifestations of hepatitis.
Chronic hepatitis B virus and C virus infections affect millions of individuals worldwide and diseases can progress to cirrhosis or hepatocellular carcinoma.
7 Discuss the available vaccines, evaluation and treatments for viral hepatitis.
Drug therapy has made major advances in the last few years; for those with chronic infection of hepatitis C, simple oral antiviral therapies now offer high cure rates of up to 95% with minimal side effects. Current available treatments have variable efficacies against different genotypes so at present pretreatment genotyping is still recommended. Sustained virological response at 12 weeks posttreatment instead of 24 weeks post-treatment is now considered standard of care. Zepatier is a fixed-dose combination of grazoprevir 100 mg and elbasvir. Zepatier has been approved by the Therapeutic Goods Administration (TGA) for genotype 1 and 4 in treatment-naïve and experienced patients as a dual oral combination therapy or in combination with ribavirin for genotype 1a and 4 treatment-experienced on-treatment virologic failures. Viekira Pak is a composite pack containing paritaprevir/ ritonavir/ombitasvir and dasabuvir tablets. Viekira Pak combines three direct-acting hepatitis C antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles. Viekira Pak is approved by the TGA for genotype 1-infected patients. Harvoni contains ledipasvir and sofosbuvir fixed-dose combination and is indicated for the treatment of chronic hepatitis C genotype 1 infection in adults. Sovaldi/Daklinza (sofosbuvir/daclatasvir) are both directacting antivirals. This is the TGA-approved drug combination for genotype-3 hepatitis C virus.
6 Describe acute liver failure and chronic hepatitis, usually associated with hepatitis B and C.
BOX 27.8
Risk factors for primary liver cancer
• Exposure to mycotoxins: the most significant mycotoxins are the aflatoxins, particularly those produced by Aspergillus flavus, a mould found on spoiled corn, peanuts and grain • Alcohol abuse • Obesity • Chronic liver disease, especially cirrhosis • Infection with hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV), particularly in conjunction with cirrhosis — these infections act either as carcinogens or as co-carcinogens in chronically infected hepatocytes
The rates of primary liver cancer in Australia are rising. Chronic hepatitis B and C, cirrhosis and dietary exposure to fungal aflatoxin are significant risk factors.104 Between 1991 and 2009 the incidence of cancer of the liver rose from 2.5 to 5.5 per 100 000.1 It was estimated that 1407 Australians would be diagnosed with liver cancer in 2012, with almost as many dying; in fact there were 1440 deaths from this cancer in 2012.1 PATHOPHYSIOLOGY
HEPATIC CANCER
Cancer of the liver usually develops secondary to metastatic spread from a primary site elsewhere in the body — in fact, the liver is one of the most common sites of cancer metastasis. Approximately 80% of cases of primary liver cancer are due to chronic hepatitis B and C infection.103 Primary liver cancer is rare before the age of 40 years and is most common during the sixth decade (see Box 27.8).
Primary carcinomas of the liver are hepatocellular or cholangiocellular. Hepatocellular carcinoma (hepatocarcinoma) develops in the hepatocytes, whereas cholangiocellular carcinoma (cholangiocarcinoma) develops in the bile ducts. Hepatocellular carcinoma can be nodular (multiple, discrete nodules), massive (a large tumour mass) or diffuse (small nodules distributed throughout most of the liver). It is closely associated with cirrhosis from chronic hepatitis. Because carcinoma of the liver invades the hepatic and portal veins, it often spreads to the heart and lungs (which
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are immediately downstream from the liver in terms of blood flow). Other sites of metastases are the brain, kidneys and spleen. Cholangiocellular carcinoma can occur anywhere along the bile duct and extend directly into the liver, usually as a solitary lesion. It is difficult to distinguish an invasion of cholangiocellular carcinoma from a metastatic adenocarcinoma, except by neoplastic changes found in nearby ducts.
Clinical manifestations of hepatobiliary alterations
CLINICAL MANIFESTATIONS
Portal hypertension is abnormally high blood pressure in the hepatic portal venous system (the hepatic portal vein drains the nutrient-rich blood from the gastrointestinal tract to the liver). Pressure in this system is normally 3 mmHg; portal hypertension is an increase to at least 10 mmHg.
The clinical presentation of liver cancer in adults is characterised by vague abdominal symptoms, such as nausea and vomiting, fullness, pressure and dull ache in the right hypochondrium (the right upper quadrant of the abdomen). Manifestations of hepatocellular carcinoma can occur slowly or abruptly. In individuals with cirrhosis, deepening jaundice or abrupt lack of appetite is a sign of hepatocellular carcinoma. Obstruction by the tumour can cause sudden worsening of portal hypertension and development of ascites. As the tumour enlarges, it causes pain. Cholangiocellular carcinoma more commonly presents insidiously as pain, loss of appetite, weight loss and gradual onset of jaundice. Some carcinomas of the liver rupture spontaneously, causing haemorrhage. Others are discovered accidentally during evaluation of a bone fracture or surgical exploration. EVALUATION AND TREATMENT
The diagnosis of liver cancer is based on clinical manifestations, laboratory findings, radiological exam-ination and tissue pathology. In individuals without cirrhosis, liver scans can document filling defects. CT or ultrasonography is used to detect solid tumours, but neither can distinguish benign from malignant tumours. Surgical resection is possible only if the tumour is localised to a removable lobe of the liver. Chemotherapeutic agents are administered systemically or locally, but their effectiveness may be limited because of the presence of advanced cirrhosis. The survival rate for those with symptomatic liver cancer is only 3–4 months. Surgery is hazardous and usually not undertaken if the individual has cirrhosis. Most individuals develop metastases after surgical resection, but long-term survival is possible. Liver transplant offers a cure if the waiting time is short.
F OC US O N L E ARN IN G
1 Relate hepatic cancer to chronic hepatitis. 2 Distinguish between primary liver cancer and liver cancer secondary to metastasis from other organs. 3 List some common symptoms of liver cancer. 4 Discuss the treatment options for this condition.
Of all the accessory organ disorders, acute or chronic liver disease leads to significant systemic, life-threatening complications. These complications include portal hypertension, ascites, hepatic encephalopathy and jaundice; these are linked in a concept map (see Fig. 27.27). PORTAL HYPERTENSION
PATHOPHYSIOLOGY
Portal hypertension is caused by disorders that obstruct or impede blood flow through any component of the portal venous system (into the liver) or vena cava (out of the liver). The poor blood flow through the liver causes a build-up of blood pressure prior to the liver. The most common cause of portal hypertension is obstruction caused by cirrhosis of the liver.105 Intrahepatic causes (from within the liver; see Fig. 27.28) result from an abnormal flow of blood through the liver sinusoids. Conditions such as inflammation or fibrosis of the sinusoids, as occur in cirrhosis of the liver and viral hepatitis, can block blood flow and lead to portal hypertension. Liver fibrosis in children can also lead to portal hypertension. Posthepatic causes occur from hepatic vein thrombosis or cardiac disorders that impair the pumping ability of the right side of the heart. This causes blood to back up through the inferior vena cava and the liver, eventually increasing pressure in the portal system. Long-term portal hypertension results in abnormalities in organs that are prior to the liver in terms of blood flow — the backlog in blood pressure in the hepatic portal vein affects organs anatomically associated with the gastrointestinal system and causes several problems that are difficult to treat and can be fatal: • Varices. These are distended, tortuous, collateral (branching connections) veins. Prolonged elevation of pressure in collateral veins causes their transformation into varices, particularly in the lower oesophagus and stomach, but also in the rectum, leading to haemorrhoidal varices (see Fig. 27.29). Rupture of varices can cause life-threatening haemorrhage • Splenomegaly (enlargement of the spleen) caused by increased pressure in the splenic vein, which branches from the portal vein • Ascites • Hepatic encephalopathy. Ascites and hepatic encephalopathy are discussed in the next sections.
CHAPTER 27 Alterations of digestive function across the life span
843
is characterised by Obstruction of liver sinusoids leads to Insufficient blood flow through liver causes causes
Impaired hepatocyte function causes
↓ Metabolism of ammonia
↓ Metabolism of bilirubin
leads to Hepatic encephalopathy
causes
is evident in
Portal hypertension development of
causes ↓ Production of albumin
Ascites
which contributes to
development of
CONCEPT MAP
Advanced liver disease
development of Bleeding varices
Splenomegaly
Jaundice
FIGURE 27.27
Clinical manifestations of liver disease. Severe liver disease leads to alterations in the circulation through the liver. The severely altered liver function and portal hypertension can lead to hepatic encephalopathy, jaundice, low levels of albumin, ascites, bleeding varices and splenomegaly.
CLINICAL MANIFESTATIONS
Vomiting of blood from bleeding oesophageal varices is the most common clinical manifestation of portal hypertension. Slow, chronic bleeding from varices in the oesophagus and stomach causes anaemia, with digested blood in the stools. Usually the bleeding is from varices that have developed slowly over a period of years. The elevated venous pressure results in rupture of oesophageal varices, causing haemorrhage and voluminous vomiting of dark-coloured blood. The ruptured varices are usually painless. Mortality from ruptured oesophageal varices ranges from 30% to 60%. Recurrent bleeding of oesophageal varices indicates a poor prognosis. Most individuals die within 1 year. EVALUATION AND TREATMENT
Portal hypertension is often diagnosed at the time of variceal bleeding and confirmed by endoscopy and evaluation of portal venous pressure. Distended collateral veins may radiate over the abdomen, giving rise to the description of caput medusae (Medusa head; see Fig. 27.30). The individual usually has a history of jaundice, hepatitis or alcoholism.
Emergency management of bleeding varices includes use of vasopressors (drugs that cause constriction of the affected blood vessels) and compression of the varices with an inflatable Sengstaken-Blakemore tube (a tube inserted into the oesophagus and stomach that provides direct pressure on the varices), sclerotherapy (injection of solution into the veins to stop the bleeding when under endoscopic examination) or variceal ligation (tying off the blood vessels that are bleeding). Surgical shunts may decompress the varices, but this treatment can precipitate encephalopathy or liver failure. Liver transplant is an alternative with end-stage liver disease; however, if the individual is actively bleeding, transplantation surgery is complicated.106 FOCU S ON L EA RN IN G
1 Draw a concept map that relates the liver clinical manifestations. 2 Explain the different causes of portal hypertension. 3 Discuss the physical consequences of portal hypertension. 4 Describe the serious nature of bleeding varices.
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Part 4 Alterations to body maintenance
POSTHEPATIC • Vena cava obstruction • Hepatic vein thrombosis • Veno-occlusive disease • Heart failure
Oesophageal varices
INTRAHEPATIC • Cirrhosis
Short gastrics
Portal vein thrombus Common bile duct
Hepatic portal vein PREHEPATIC • Portal vein thrombosis • Increased splenic flow
Superior mesenteric
Splenic Coronary Inferior mesenteric
FIGURE 27.28
Portal hypertension. The three forms of portal hypertension are posthepatic, intrahepatic and prehepatic.
Haemorrhoidal varices FIGURE 27.29
ASCITES
Ascites is the accumulation of fluid in the peritoneal cavity and is the most common complication of cirrhosis. Ascites traps body fluid in a ‘third space’ from which it cannot escape (third spacing is described in Chapter 29). The effect is to reduce the amount of fluid available for normal physiological functions. Cirrhosis is the most common cause of ascites, but other causes include heart failure, constrictive pericarditis, abdominal malignancies, nephrotic syndrome and malnutrition. Of individuals who develop ascites caused by cirrhosis, 25% die within 1 year. Continued heavy drinking of alcohol is associated with this mortality.
Varices related to portal hypertension. The portal vein, its major tributaries and the most important shunts (collateral veins) between the portal and caval systems.
PATHOPHYSIOLOGY
Several factors contribute to the development of ascites. Impaired excretion of sodium by the kidneys promotes water retention. Portal hypertension and reduced serum albumin levels cause capillary hydrostatic pressure (pressure outwards from the capillary; see Chapter 22) to exceed capillary osmotic pressure (pressure into the capillary). This imbalance pushes water into the peritoneal cavity. As a result peripheral vasodilation and decreased blood flow to the kidneys occur, as fluid is redirected to the peritoneal cavity; this also results in hormonal stimulation that promotes renal sodium and water retention (the main hormones are aldosterone and antidiuretic hormone). This expands plasma volume and can accelerate portal hypertension and ascites formation.
FIGURE 27.30
Portal hypertension. Dilation of the collateral venous circulation (arrows) may become evident on the abdomen of individuals with cirrhosis. Seen here is caput medusa, which consists of dilated veins radiating from the umbilicus.
Ascites can be complicated by bacterial peritonitis, an inflammatory response that increases mesenteric capillary permeability. As plasma seeps out of the permeable mesenteric capillaries, it adds to the volume of ascitic fluid. Fig. 27.31 summarises the mechanisms by which cirrhosis of the liver causes ascites.
CHAPTER 27 Alterations of digestive function across the life span
845
leads to
leads to
Portal hypertension
Hepatocyte failure
resulting in which causes
↑ Capillary filtration pressure means that
↓ Albumin production
More fluid exits the capillary
resulting in
means that contributes to
Less fluid returns to capillary
Bacterial peritonitis
↓ Plasma volume
causes ↑ Capillary permeability
(Loss of fluid from plasma)
ends with which Ascites worsens
↓ Capillary oncotic pressure
↑ Renin, aldosterone and antidiuretic hormone causes ↑ Renal absorption of sodium and water
causes
Decreased renal blood flow
triggers hormonal response
FIGURE 27.31
Mechanisms of ascites caused by cirrhosis. Liver cirrhosis leads to portal hypertension, hepatocyte failure, and activation of the renin-angiotensin-aldosterone system. Together, these contribute to the development of ascites.
CLINICAL MANIFESTATIONS
The accumulation of ascitic fluid causes weight gain, abdominal distension and increased abdominal girth (see Fig. 27.32). Large volumes of fluid (10–20 L) displace the diaphragm and cause dyspnoea by decreasing lung capacity. Ventilatory rate increases and the individual assumes a semi-Fowler position (sitting up in bed at approximately 35–45°) to relieve the dyspnoea. Approximately 10% of individuals with ascites develop bacterial peritonitis, which causes fever, chills, abdominal pain, decreased bowel sounds and cloudy ascitic fluid. EVALUATION AND TREATMENT
Diagnosis is usually based on clinical manifestations and identification of liver disease. Paracentesis is used to aspirate ascitic fluid for bacterial culture, biochemical analysis and microscopic examination. The goal of treatment is to relieve discomfort. If restoration of liver function is possible, the ascites diminishes spontaneously. In the meantime, dietary salt restriction and potassium-sparing diuretics
FIGURE 27.32
Marked ascites and an umbilical hernia. This patient had cirrhosis and portal hypertension. The umbilical hernia had ruptured a few days before the photograph.
CONCEPT MAP
Cirrhosis
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Part 4 Alterations to body maintenance
can reduce ascites. Serum electrolytes are monitored carefully because the individual is at risk for hyponatraemia and hypokalaemia (low blood sodium and potassium, respectively). Palliative measures include paracentesis to remove 1–2 L of ascitic fluid and relieve respiratory distress. However, the removal of too much fluid relieves pressure on blood vessels and carries the risk of hypotension, shock or death. Despite repeated paracentesis, ascitic fluid re-accumulates in individuals with irreversible disease. Paracentesis is also likely to cause peritonitis. Other procedures include shunts to direct fluid into the bloodstream, as well as liver transplant. Individuals with ascites and portal hypertension have a poor prognosis. HEPATIC ENCEPHALOPATHY
Hepatic encephalopathy (altered brain function) is a complex neurological syndrome characterised by impaired cerebral function, flapping tremor (known as asterixis) and EEG changes (electroencephalogram — shows the waves of brain function). The syndrome may develop rapidly during acute hepatitis or slowly during the course of chronic liver disease and the development of portal hypertension. PATHOPHYSIOLOGY
Hepatic encephalopathy results from a combination of biochemical alterations that affect neurotransmission, causing central nervous system disturbances and alterations in consciousness. Liver dysfunction and collateral vessels that shunt blood around the liver to the systemic circulation both permit toxins absorbed from the gastrointestinal tract to circulate freely to the brain, whereas in the healthy person, the liver would normally detoxify those substances. The most hazardous substances are end products of intestinal protein digestion, particularly ammonia. Ammonia that reaches the brain may alter cerebral energy metabolism or interfere with neurotransmitters. Infection, haemorrhage, electrolyte imbalance, zinc deficiency, sedatives and analgesics can worsen the encephalopathy.107 CLINICAL MANIFESTATIONS
Subtle changes in personality, memory loss, irritability, lethargy and sleep disturbances are common initial manifestations of hepatic encephalopathy. Symptoms can then progress to confusion, flapping tremor of the hands, stupor, convulsions and coma. Coma is usually a sign of liver failure and ultimately results in death. EVALUATION AND TREATMENT
Diagnosis of hepatic encephalopathy is based on a history of liver disease and clinical manifestations. EEG and blood chemistry tests provide supportive data. Correction of fluid and electrolyte imbalances and withdrawal of depressant drugs metabolised by the liver are first steps in the treatment of hepatic encephalopathy. Restricting dietary protein intake and eliminating intestinal bacteria help to reduce blood
ammonia levels. Lactulose may be administered to prevent ammonia absorption in the colon. JAUNDICE
Jaundice (icterus) is a yellow or greenish pigmentation of the skin caused by hyperbilirubinaemia (plasma bilirubin concentrations above 40 mmol/L). Hyperbilirubinaemia and jaundice can result from excessive haemolysis of red blood cells or obstructive disorders of the bile ducts or liver cells (see Fig. 27.33). PATHOPHYSIOLOGY
Obstructive jaundice can result from extrahepatic obstruction (obstruction to bile flow out of the liver) or intrahepatic obstruction (obstruction to bile flow or production from within the liver). Extrahepatic obstructive jaundice develops if the common bile duct is occluded (e.g. by a gallstone or tumour). Bilirubin metabolised by the hepatocytes cannot flow into the duodenum. Therefore, it accumulates in the liver and enters the bloodstream, causing hyperbilirubinaemia and jaundice. As bilirubin increases in the blood, it is also excreted via the kidneys and therefore it appears in the urine. Intrahepatic obstructive jaundice involves disturbances in hepatocyte function and obstruction of bile canaliculi.108 This commonly results from alcoholic cirrhosis and viral hepatitis. The metabolism of bilirubin is impaired and elevated levels appear in the blood and urine. Obstruction of bile canaliculi diminishes flow of metabolised bilirubin out of the liver into the common bile duct. In mild cases, some of the bile canaliculi open. Consequently, the amount of bilirubin in the intestinal tract may be only slightly decreased. Excessive haemolysis (breakdown) of red blood cells can cause prehepatic jaundice (or haemolytic jaundice). Bilirubin is formed through breakdown of the haem component of aged red blood cells — when increased, this exceeds the ability of the liver to metabolise bilirubin, causing blood levels to rise. Mild prehepatic jaundice is normal in newborns (see below). Severe haemolytic crisis, such as that which occurs with sickle cell anaemia and haemolytic drugs, can cause jaundice. If hyperbilirubinaemia continues to increase, both haemolytic and liver disorders are indicated. The causes of jaundice are summarised in Table 27.10. CLINICAL MANIFESTATIONS
Hyperbilirubinaemia may cause the urine to darken several days before the onset of jaundice. The complete obstruction of bile flow from the liver to the duodenum causes light-coloured stools. With partial obstruction, the stools are normal in colour and bilirubin is present in the urine. Fever, chills and pain often accompany jaundice resulting from viral or bacterial inflammation of the liver (e.g. viral hepatitis). Manifestations of liver injury from any cause commonly include anorexia, malaise and fatigue. Yellow discolouration may first occur in the sclera of the eye (see
CHAPTER 27 Alterations of digestive function across the life span
Intrahepatic obstructive jaundice
due to Extrahepatic obstructive jaundice caused by
caused by Hepatocellular damage or obstruction of bile canaliculi
Bile duct obstruction (cholestasis)
Bilirubin accumulates in liver and enters bloodstream
Hyperbilirubinaemia
means that
Decreased bile secretion results in
leads to leads to
Excessive lysis of red blood cells
means that
means that Liver unable to metabolise bilirubin
Prehepatic jaundice
CONCEPT MAP
Haemolytic mechanisms
Obstructive mechanisms due to
847
Light-coloured stools
Hepatocytes cannot metabolise bilirubin as rapidly as it is formed, so bilirubin enters the bloodstream
leads to ending in
Bilirubin deposition in tissues (jaundice)
causes
FIGURE 27.33
Mechanisms of jaundice. The main causes of jaundice include liver dysfunction (intrahepatic), impairment to the outflow of bile (extrahepatic), and excess destruction of red blood cells (prehepatic).
Fig. 27.34) and then progress to the skin. Pruritus (itching) often accompanies jaundice because bilirubin accumulates in the skin. EVALUATION AND TREATMENT
Laboratory evaluation of serum bilirubin levels is essential. The history and physical examination identify underlying disorders, such as alcoholism, exposure to hepatitis virus or gallbladder disease. The treatment for jaundice consists of correcting the cause.
FOCU S ON L EA RN IN G
1 Describe the factors that lead to the development of ascites. 2 Discuss how ascites can be treated. 3 Discuss the progression of hepatic encephalitis. 4 Explain how hepatic encephalitis can be diagnosed and treated. 5 Discuss the different causes and progression to jaundice. 6 List the clinical manifestations of jaundice.
Biliary disorders
Obstruction and inflammation are the most common disorders of the gallbladder. Obstruction is caused by gallstones, which are aggregates of substances in the bile. The gallstones may remain in the gallbladder or be ejected with bile into the cystic duct. Gallstones that become lodged in the cystic duct obstruct the flow of bile into and out of the gallbladder and cause inflammation. Gallstone formation
is termed cholelithiasis. Inflammation of the gallbladder or cystic duct is known as cholecystitis.
Cholelithiasis
Cholelithiasis (gallstones) is a prevalent disorder in developed countries, where the incidence rate is 10–20%,
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TABLE 27.10 Common types of jaundice
BOX 27.9
TYPE
MECHANISM
CAUSES
Obstructive (posthepatic) jaundice
Obstruction of passage of bilirubin from liver to intestine
Obstruction of bile duct by gallstones or tumour (extrahepatic obstructive jaundice) Obstruction of bile flow through the liver (intrahepatic obstructive jaundice) Drugs
Prehepatic (haemolytic) jaundice
Destruction of erythrocytes (increased bilirubin production)
Neonatal jaundice Haemolytic disease of the newborn Haemolytic anaemias Transfusion of incompatible blood
Hepatocellular Failure of liver (hepatic) cells (hepatocytes) jaundice to metabolise bilirubin, and of bilirubin to pass from liver to intestine
Alcoholic liver disease or biliary cirrhosis Viral hepatitis
• • • •
Modifiable risk factors for gallstones
Obesity, metabolic syndrome, high energy intake Rapid weight loss Diseases such as cirrhosis, Crohn’s disease Gallbladder stasis (from spinal cord injury or drugs such as somatostatin)
of cholesterol in the bile fluid, the cholesterol cannot all be fully ‘dissolved’, so some of it appears in a solid form known as stones. This process usually occurs within the gallbladder, with other locations also in the biliary ducts (see Figs 27.35 and 27.36). The stones may lie dormant or become lodged in the cystic or common bile duct, causing pain and cholecystitis (inflammation). If the stones block the common bile duct, it can cause pathophysiology of the liver as well, due to insufficient drainage of the bile from the liver. The stones can accumulate and fill the entire gallbladder (see Fig. 27.37). Pigmented stones form from increased levels of bilirubin, which binds with calcium. CLINICAL MANIFESTATIONS
Abdominal pain and jaundice are the cardinal manifestations of cholelithiasis. Vague symptoms include heartburn, flatulence, epigastric discomfort and food intolerances, particularly to fats and cabbage. The pain, known as biliary colic, is caused by the lodging of one or more gallstones in the cystic or common duct. It can be intermittent or steady and usually occurs in the right upper quadrant, radiating to the mid-upper area of the back. Jaundice indicates that the stone is located in the common bile duct. EVALUATION AND TREATMENT
FIGURE 27.34
Jaundice observed in the sclera. Note the yellowed discolouration in the sclera.
although many individuals are asymptomatic. There are two types of gallstones: cholesterol and pigmented. Cholesterol stones are the most common, accounting for approximately 80–85% of cases in developed countries.109 Risk factors include female sex and middle age, as well as a number of potentially modifiable risk factors shown in Box 27.9. PATHOPHYSIOLOGY
Cholesterol gallstones form in bile that has excessive amounts of cholesterol produced by the liver. With a high amount
Diagnosis is based on the history, physical examination and ultrasound, CT scan or magnetic cholangiopancreatography (MRCP) which look at the bile ducts.110 An oral cholecystogram usually outlines the stones. Intravenous cholangiography is used to differentiate cholelithiasis from other causes of extrahepatic biliary obstruction if the cholecystogram is negative. Laparoscopic cholecystectomy is the preferred treatment for uncomplicated gallstones that cause obstruction or inflammation, stones can also be removed with a endoscopic cholangiopancreatography (ERCP).
Cholecystitis
Cholecystitis can be acute or chronic, but both forms are almost always caused by a gallstone lodged in the cystic duct.110 The gallbladder becomes distended and inflamed, with pain similar to that caused by gallstones. Pressure against the distended wall of the gallbladder decreases blood flow and may result in ischaemia, necrosis and perforation. Fever, leucocytosis, rebound tenderness and abdominal muscle guarding are common findings. Serum bilirubin
Stone intermittently obstructing cystic duct, causing intermittent biliary colic (20%)
3
2
Stone impacted in cystic duct, causing acute cholecystitis (10%) 4
Asymptomatic stone (75%) * *
1
*
Stone in the cystic duct compressing or fistulising into the common bile duct, causing Mirizzi’s syndrome (< 0.1%)
* *
7
*
Long-standing cholelithiasis, resulting in gallbladder carcinoma (< 0.1%) 6
*
Stone eroding through gallbladder into duodenum, resulting in cholecystoenteric fistula (prerequisite for gallstone ileus) and leading in some cases to 5 Bouveret’s syndrome (gastric outlet obstruction) Stone impacted in distal common bile duct, causing jaundice, biliary (< 0.1%) colic-type pain and risk of ascending cholangitis or acute biliary pancreatitis (5%) FIGURE 27.35
Schematic depiction of the natural history and complications of gallstones. The percentages indicate the approximate frequencies of complications occurring in untreated patients, as based on natural history data. The most frequent outcome is for the patient with a stone to remain asymptomatic throughout life. Biliary pain, acute cholecystitis, cholangitis and pancreatitis are the most common complications. (The sum of the percentages is > 100% because patients with acute cholecystitis generally have had prior episodes of biliary pain.)
FIGURE 27.37
Resected gallbladder containing mixed gallstones. There are a large number of gallstones in this gallbladder; note that their appearance is very much like stones.
FIGURE 27.36
Multiple gallstones. Any collection of grouped calcifications in the right upper quadrant (arrows) is most likely due to gallstones but does not indicate acute cholecystitis.
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levels may be elevated. The acute abdominal pain of cholecystitis must be differentiated from that caused by pancreatitis, myocardial infarction and acute pyelonephritis of the right kidney. Cholangiography or radioactive scan can confirm the diagnosis. Opioid analgesics may be required to control pain, and antibiotics are often prescribed to manage bacterial infection
in severe cases. Persistent symptoms or development of chronic cholecystitis punctuated by recurrent, acute attacks usually requires gallbladder resection (cholecystectomy). Biliary obstruction may also lead to acute pancreatitis. If pancreatic abscesses/cysts develop, they are usually resected or radiological/endoscopically drained and washed out.111
Neonatal jaundice is usually a transient icterus that occurs during the first week of life in otherwise healthy, fullterm and preterm infants. It is caused by excessive breakdown of the fetal form of haemoglobin, which is a normal process that commences shortly after birth, to replace fetal haemoglobin with adult haemoglobin. This results in the haem component being broken down to bilirubin in relatively large quantities, but the immature liver is unable to metabolise the bilirubin quickly, so it becomes visible in yellow pigmentation of the eyes and skin. Although it is normal for newborns to experience mild jaundice, it requires monitoring in the days after birth for worsening of the condition. PATHOPHYSIOLOGY
The main cause in newborns is the normal breakdown of haemoglobin following birth, which results in increased production of bilirubin. It may also be caused by a different condition known as haemolytic disease of the newborn (ABO blood compatibility), which mainly occurs if the newborn is not the mother’s first baby (see Chapter 17). Serum bilirubin should normally be under 20 µmol/L (see Table 26.5), but in jaundice it becomes much higher. Very high levels of hyperbilirubinaemia are considered pathological. There is a risk of brain damage (kernicterus) as the bilirubin passes across neonatal brain capillaries (the blood–brain barrier) and into brain cells of the basal nuclei. For this reason, persistent or worsening jaundice requires treatment.
jaundice indicate pathological hyperbilirubinaemia. Premature infants with respiratory distress, acidosis or sepsis are at greater risk for encephalopathy and the development of other conditions associated with impaired brain function.108 EVALUATION AND TREATMENT
Evaluation is by measuring serum bilirubin levels. Other causes of jaundice must be eliminated to confirm physiological jaundice. Treatment depends on the degree of hyperbilirubinaemia. Physiological jaundice is usually treated by phototherapy (ultraviolet light), which breaks down the bilirubin. Treatment is administered easily by placing the baby in an incubator or wrapping the baby in a suit to expose them to ultraviolet light (see Fig. 27.38). Pathological jaundice requires an exchange transfusion and treatment of the underlying disorder.
CLINICAL MANIFESTATIONS
Physiological jaundice develops during the second or third day after birth and usually subsides in 1–2 weeks in full-term infants and in 2–4 weeks in premature infants. After this, increasing bilirubin values and persistent
FOCUS O N L E ARN IN G
1 Relate excess cholesterol to the development of cholelithiasis (gallstones). 2 Discuss the diagnosis and management of cholelithiasis. 3 Briefly discuss cholecystitis.
FIGURE 27.38
An infant with jaundice undergoing phototherapy. Phototherapy assists with breakdown of bilirubin.
Pancreatic disorders Pancreatitis
Pancreatitis, or inflammation of the pancreas, is a relatively rare and potentially serious disorder that occurs equally in men and women in their 50s. Pancreatitis is associated with conditions such as alcoholism, biliary tract obstruction
PAEDIATRICS
Paediatrics: neonatal jaundice
CHAPTER 27 Alterations of digestive function across the life span
(particularly due to cholelithiasis), peptic ulcers, trauma and hyperlipidaemia, as well as certain drugs.111 ACUTE PANCREATITIS PATHOPHYSIOLOGY
Acute pancreatitis is usually a mild disease, but about 20% of those with the disease develop a severe pancreatic inflammation requiring hospital care. Alcoholism and biliary tract obstruction because of gallstones are commonly associated with this condition.111 Bile and pancreatic duct obstruction (such as from stones; see Fig. 27.39) impairs the outflow of pancreatic enzymes, allowing them to leak into pancreatic tissue. This causes autodigestion (digestion by the enzymes secreted from the pancreas) and acute pancreatitis. The resulting inflammation entering the bloodstream can cause coagulation abnormalities and injury to vessels and other organs, such as the lungs and kidneys. Myocardial depression and shock can develop and translocation of bacteria may cause sepsis. These systemic effects are major causes of multiple organ involvement, morbidity and mortality.111
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the inflammatory response. Nausea and vomiting are caused by hypermotility or paralytic ileus secondary to the pancreatitis or peritonitis. Abdominal distension accompanies bowel hypermotility and the accumulation of fluids in the peritoneal cavity. Hypotension and shock occur often because plasma volume is lost as enzymes and kinins released into the circulation increase vascular permeability and dilate vessels. Hypovolaemia, hypotension and myocardial insufficiency result. In severe cases, hypovolaemia decreases renal blood flow sufficiently to impair renal function. Transient hyperglycaemia also can occur if glucagon is released from damaged alpha cells in the pancreatic islets (see Chapter 11). Multiple organ failure accounts for most deaths with severe acute pancreatitis. EVALUATION AND TREATMENT
Diagnosis is based on clinical findings, identification of associated disorders and laboratory studies. Elevated pancreatic amylase in serum is a characteristic but is not diagnostic of severity or specificity of disease. Serum lipase
CLINICAL MANIFESTATIONS
2 ALCOHOL • Spasm of hepatopancreatic sphincter • Intraductal protein precipitation • Effects on acini Duodenum
Acini
Bile duct Ampulla of Vater
Pancreatic duct
Blockage of the common bile duct and pancreatic duct Acute alcoholic pancreatic dysfunction leads to
causes
FIGURE 27.39
Acute pancreatitis. The main causes of acute pancreatitis are gallstones and alcohol.
Obstruction of pancreatic enzyme secretions into duodenum
Pancreatic enzymes leak into pancreatic tissue results in Autodigestion of pancreas ends with Acute pancreatitis
1 GALLSTONE IMPACTION • Reflux of bile
leads to
may progress to
Inflammation enters bloodstream
and
Multiple organ failure
FIGURE 27.40
Acute pancreatitis. Pancreatic secretions accumulate, which leads to the pancreatic enzymes becoming activated and pancreatic autodigestion. The severe inflammation in acute pancreatitis may progress to multiple organ failure.
CONCEPT MAP
Epigastric or mid-abdominal pain ranging from mild abdominal discomfort to severe, incapacitating pain is caused by: (1) oedema, which distends the pancreatic ducts and capsule; (2) chemical irritation and inflammation of the peritoneum; and (3) irritation or obstruction of the biliary tract (see Fig. 27.40). Fever and leucocytosis accompany
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elevations are a sensitive marker of pancreatic injury, particularly of acute alcoholic pancreatitis. Elevated serum lactic dehydrogenase and C-reactive protein levels are associated with severe pancreatitis. The goal of treatment for acute pancreatitis is to stop the process of autodigestion and prevent systemic complications. Opioid analgesics may be needed to relieve pain. To decrease pancreatic secretions and ‘rest the gland’, oral food and fluids are withheld and continuous gastric suction is instituted. Nasogastric suction may not be necessary with mild pancreatitis, but it helps to relieve pain and prevent paralytic ileus in individuals who are nauseated and vomiting. Parenteral fluids are essential to restore blood volume and prevent hypotension and shock. Drugs that decrease gastric acid production can decrease stimulation of the pancreas by secretin. Antibiotics may control infection. The risk of mortality increases significantly with the development of infection or pulmonary, cardiac and renal complications.111 CHRONIC PANCREATITIS
Structural or functional impairment of the pancreas leads to chronic pancreatitis. Chronic alcohol abuse is the most common cause, and smoking increases the risk of chronic pancreatitis.112 Chronic pancreatitis causes continuous or intermittent abdominal pain, which usually intensifies after a meal. Occasionally manifestations of pancreatic enzyme deficiency, such as steatorrhoea or a malabsorption syndrome, are present. To correct enzyme deficiencies and prevent malabsorption, oral enzyme replacements are taken before and during meals. Loss of islet cell function can cause type 1 diabetes. Cessation of alcohol intake is essential for the management of chronic pancreatitis. Fibrosis, strictures, continued inflammation, calcification and pancreatic cysts are common lesions of chronic pancreatitis. The cysts are walled-off areas or pockets of pancreatic juice, necrotic debris or blood within or adjacent to the pancreas. Surgical drainage or partial resection of the pancreas may be required to relieve pain and to prevent cystic rupture. Chronic pancreatitis is a risk factor for pancreatic cancer. PANCREATIC CANCER
Pancreatic cancer has a high mortality rate. In 2016 it has been estimated there was 3120 new diagnosis of pancreatic cancer in Australia. One-year survival is 24%, with 5-year survival being only 6%, and it remains the lowest 5-year survival of all cancers.1 If the cancer is unable to be removed and is metastatic, then the goal of treatment is palliation (which means making the patient comfortable rather than being curative). A multidisciplinary team approach that includes surgeon, oncologist, radiation oncologist, nursing staff, dietitian and palliative care, as with all cancer diagnoses, is the best way to treat a person with pancreatic cancer. The cause of pancreatic cancer is not known, but there are modest risks associated with cigarette smoking, certain
dietary factors, obesity, diabetes mellitus and chronic pancreatitis.113 PATHOPHYSIOLOGY
Cancer of the pancreas can arise from exocrine or endocrine cells (exocrine cells release secretions through ducts, while endocrine cells release hormones into the bloodstream). Most pancreatic tumours are adenocarcinomas of the pancreatic ducts (ductal adenocarcinomas). Tumours arising in small ducts invade nearby glandular tissue, penetrate the covering of the pancreas and extend into surrounding tissues. Ductal adenocarcinomas can occur in the head, body or tail of the pancreas, with most occurring in the head. Tumours of the head quickly spread to obstruct the common bile duct and portal vein. Ductal adenocarcinomas arising in the head of the pancreas cause biliary obstruction somewhat early in the disease. Lymphatic invasion occurs early, and rapidly involves local and regional lymph nodes. Venous invasion causes metastases to the liver. Tumour implants on the peritoneal surface can obstruct veins and promote the development of ascites. Individuals with ductal adenocarcinomas in the pancreatic head survive slightly longer than those with cancer of the body or tail of the pancreas, presumably because the symptoms associated with the liver prompt them to seek medical attention earlier. CLINICAL MANIFESTATIONS
Cancer of the body and tail of the pancreas is generally asymptomatic until there is intraductal destruction or the tumour invades adjacent tissue. Often vague back pain is an initial symptom. Jaundice develops in most cases, usually caused by obstruction of the bile duct. Because obstruction impairs enzyme secretion and flow to the duodenum, pancreatic cancer causes fat and protein malabsorption, resulting in weight loss. Distant metastases are found in the neck nodes, the lungs and the brain. Most individuals die of hepatic failure or blockage of the hepatobiliary ducts. EVALUATION AND TREATMENT
Ultrasonography and CT scans may be needed, and a laparoscopy (an incision through the abdominal wall to gain access to the abdominal cavity) is used to establish a definitive diagnosis, evaluate the extent of disease and determine whether palliative bypass surgery is needed. Pancreatic cancer is difficult to treat, as it is non-responsive to many anticancer drugs. Chemotherapy and radiation therapy are used as palliative measures. The surgical option is a Whipple procedure (pancreaticodenectomy) where the head of the pancreas, duodenum, distal part of the stomach and gallbladder are removed. Whipple procedure is complex surgery and has a high morbidity. Because almost all pancreatic cancers are advanced at the time of diagnosis, staging has little relevance in determining treatment.
CHAPTER 27 Alterations of digestive function across the life span
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FOCUS O N L E A R N IN G
1 Explain the pathophysiology of acute pancreatitis. 2 List the symptoms and treatment of acute pancreatitis. 3 Briefly discuss chronic pancreatitis. 4 Discuss the metastasis and mortality rate of pancreatic cancer. 5 Discuss the clinical manifestations and management of pancreatic cancer.
chapter SUMMARY Disorders of the gastrointestinal tract • Cancer of the colon and rectum (colorectal cancer) accounts for approximately 13–15% of the total incidence of cancer in Australia and New Zealand. • Genetics and lifestyle factors may be involved in the development of colorectal cancer. Pre-existing polyps are highly associated with adenocarcinoma of the colon. • Tumours of the right (ascending) colon are usually large and bulky; tumours of the left (descending, sigmoid) colon develop as small, button-like masses. Manifestations of colon tumours include pain, bloody stools and a change in bowel habits. • Rectal carcinoma is located up to 15 cm from the opening of the anus. The tumour spreads transmurally to the vagina in women or the prostate in men. • Population screening for colorectal cancer is being introduced in Australia and New Zealand, with completion of the roll out to be in 2018–2019. • Colorectal cancer can be diagnosed using a faecal occult blood test and colonoscopy, while other procedures may also assist. Treatment is usually surgical removal, with chemotherapy and radiotherapy often used as well. • Cancer of the oesophagus is rare in Australia and New Zealand; however, it has a high morbidity due to the fast spread to other organs. Alcohol and tobacco use, reflux oesophagitis and nutritional deficiencies are associated with oesophageal carcinoma. • Dysphagia is the most common symptom, with reflux and chest pain also common symptoms for oesophageal cancer. Early treatment of tumours that have not spread into the mediastinum or lymph nodes results in a better prognosis. • Gastric carcinoma is associated with high salt intake, food preservatives (such as nitrates) and atrophic gastritis. • Approximately 50% of all gastric cancers are located in the prepyloric antrum. Clinical manifestations (weight
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loss, upper abdominal pain, vomiting, haematemesis, anaemia) develop only after the tumour has penetrated the wall of the stomach. Ulcerative colitis is an inflammatory disease that causes ulceration, abscess formation and necrosis of the colonic and rectal mucosa. Symptoms of ulcerative colitis include cramping pain, bleeding, frequent diarrhoea, dehydration and weight loss. A course of frequent remissions and exacerbations is common. Crohn’s disease is similar to ulcerative colitis, but it affects both the large and the small intestines and ulceration tends to involve all the layers of the lumen. ‘Skip lesion’ fissures and granulomas are characteristic of Crohn’s disease. Abdominal tenderness, diarrhoea and weight loss are the usual symptoms. Irritable bowel syndrome is a functional disorder with no known structural or biochemical alterations. It may manifest as diarrhoea or constipation. Intestinal hypersensitivity and alterations in motility and secretion are associated. Diverticula are outpouchings of colonic mucosa through the muscle layers of the colon wall. Diverticulosis is the presence of these outpouchings; diverticulitis is inflammation of the diverticula. Appendicitis is the most common surgical emergency of the abdomen. Obstruction of the lumen leads to increased pressure, ischaemia and inflammation of the appendix. Without surgical resection, inflammation may progress to gangrene, perforation and peritonitis. Gastritis is acute or chronic inflammation of the gastric mucosa. Regurgitation of bile, use of anti-inflammatory drugs or alcohol and some systemic diseases are associated with gastritis. A peptic ulcer is an area of mucosal inflammation and ulceration caused by excessive secretion of gastric acid
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or disruption of the protective mucosal barrier, or both. There are three types of peptic ulcers: duodenal, gastric and stress ulcers. Gastric ulcers develop near parietal cells, generally in the antrum, and tend to become chronic. Gastric secretions may be normal or decreased and pain may occur after eating. Duodenal ulcers, the most common peptic ulcers, are associated with increased numbers of parietal (acidsecreting) cells in the stomach, elevated gastrin levels and rapid gastric emptying. Pain occurs when the stomach is empty and it is relieved with food or antacids. Duodenal ulcers tend to heal spontaneously and recur frequently. Necrotising enterocolitis is an inflammatory bowel condition occurring mainly in premature babies. The inflammation may be severe and can lead to septicaemia; mortality rates are declining. Deficient lactase production in the brush border of the small intestine inhibits the breakdown of lactose; this condition is known as lactose intolerance. This prevents lactose absorption and causes osmotic diarrhoea. Coeliac disease results when the consumption of gluten in wheat and other grains destroys villi in the small intestine. This can lead to malabsorption of a number of nutrients. The most common symptom of coeliac disease is diarrhoea, due to the large amount of undigested fats (and other substances) in the intestines. Although previously considered a childhood illness, it is now recognised that many cases of coeliac disease are not diagnosed until well into adulthood. Malnutrition is lack of nourishment from inadequate amounts of kilojoules, protein, vitamins or minerals. Starvation is an extreme state of malnutrition. Cachexia is physical wasting associated with chronic disease. Short-term starvation, or lack of dietary intake for 3 or 4 days, stimulates glucose to be produced from glucose stores and non-carbohydrate molecules. Long-term starvation triggers the breakdown of ketone bodies and fatty acids. Eventually proteolysis (protein breakdown) begins and death ensues if nutrition is not restored. Failure to thrive in infants occurs when the growth is less than expected. Various causes include anatomical abnormalities, infection, chronic disease and parental stressors; identification of the cause/s is fundamental to improving infant growth. Gastro-oesophageal reflux is the regurgitation of chyme from the stomach into the oesophagus. An inflammatory response ensues if the oesophageal mucosa is repeatedly exposed to acids and enzymes in the regurgitated chyme. Faecal incontinence is the inability to have a voluntary bowel movement or the inability to control bowel movements. There may be more people affected by this condition than indicated by current statistics, due to embarrassment and underreporting to medical staff. Gastro-oesophageal reflux occurs due to low muscle tone in the gastro-oesophageal sphincter in newborns. It
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may progress to gastro-oesophageal reflux disease. Excessive vomiting, oesophagitis and bleeding may lead to iron deficiency anaemia and poor growth rates. Pyloric stenosis occurs when the opening of the pylorus is narrowed; this impairs the emptying of the stomach into the duodenum. Vomiting occurs immediately after feeding. If the condition can be managed, it may resolve by 6–8 months of age; otherwise surgical options may be necessary. Hiatal hernia is the protrusion of the upper part of the stomach through the hiatus (oesophageal opening in the diaphragm) at the gastro-oesophageal junction. Hiatal hernia can be sliding or para-oesophageal. Intestinal obstruction prevents the normal movement of chyme through the intestinal tract. It can be due to intussusception, volvulus, abdominal hernia or paralytic ileus. Hirschsprung’s disease occurs when the innervation of the digestive system is incomplete, which particularly effects the rectal end of the sigmoid colon. Main symptoms arise due to constipation, and destruction of the mucosal layer occurs. Surgical treatment provides a suitable long-term benefit. Vomiting is the forceful emptying of the stomach by gastrointestinal contraction and reverse peristalsis of the oesophagus. It is usually preceded by nausea and retching, with the exception of projectile vomiting, which is associated with direct stimulation of the vomiting centre in the brain. Constipation is often caused by unhealthy dietary and bowel habits combined with lack of exercise. Constipation can also result from a disorder that impairs intestinal motility or obstructs the intestinal lumen. Diarrhoea can be caused by excessive fluid drawn into the intestinal lumen by osmosis (osmotic diarrhoea), excessive secretion of fluids by the intestinal mucosa (secretory diarrhoea), bile salt malabsorption or excessive gastrointestinal motility. Diarrhoea is of particular concern in young children, who are susceptible to changes in fluid balance. Severe dehydration from diarrhoea can be fatal. Childhood diarrhoea is often caused by rotavirus. Diarrhoea in children requires particularly close monitoring, as it can quickly lead to fatality due to severe dehydration. Causes of diarrhoea in children include infectious agents (bacterial or viral) or conditions such as lactose intolerance. Dysphagia is difficulty swallowing. It can be caused by a mechanical or functional obstruction of the oesophagus. Functional obstruction is an impairment of oesophageal motility. Anorexia (loss of appetite), vomiting, constipation, diarrhoea and evidence of gastrointestinal bleeding are clinical manifestations of many disorders of the gastrointestinal tract. Obvious manifestations of gastrointestinal bleeding are haematemesis (vomiting of blood), melaena (dark, tarry stools) and haematochezia (frank bleeding from the rectum). Occult bleeding can be detected only by testing stools or vomitus for the presence of blood.
CHAPTER 27 Alterations of digestive function across the life span
Disorders of the hepatobiliary system and pancreas • Fatty deposition resulting from alcohol consumption contributes to alcoholic liver disease, which can progress from fatty liver to alcoholic hepatitis and finally to alcoholic cirrhosis. • Alcoholic cirrhosis impairs the hepatocytes’ ability to metabolise and remove a range of potentially harmful substances from the bloodstream. • Alcoholic liver disease is reversible in the early stages, so cessation of alcohol consumption is vital to limit worsening of the condition. • Clinical manifestations of alcoholic liver disease include ascites, gastrointestinal haemorrhage, portal hypertension, hepatic encephalopathy and oesophageal varices. • Viral hepatitis is an infection of the liver caused by a strain of the hepatitis virus — hepatitis A, B and C are most common in Australia and New Zealand. • Although they differ with respect to modes of transmission and severity of acute illness, all types of viral hepatitis can cause hepatic cell necrosis, Kupffer cell hyperplasia and infiltration of liver tissue by mononuclear phagocytes. These changes obstruct bile flow and impair hepatocyte function. • The clinical manifestations of viral hepatitis depend on the stage of infection. Fever, malaise, anorexia and liver enlargement and tenderness characterise the pre-icteric phase (stage 1). Jaundice and hyperbilirubinaemia mark the icteric phase (stage 2). During the recovery phase (stage 3), symptoms resolve. Recovery takes several weeks. • Chronic hepatitis is a complication of hepatitis B or hepatitis C virus. It causes widespread hepatic necrosis and is often fatal. • Metastatic invasion of the liver is more common than primary cancer of the liver. • Primary liver cancers are associated with chronic liver disease (cirrhosis, hepatitis B). Hepatocellular carcinomas arise from the hepatocytes, whereas cholangiocellular carcinomas arise from the bile ducts. Primary liver cancer spreads to the heart, lungs, brain, kidneys and spleen through the circulation. • Portal hypertension is an elevation of portal venous pressure, caused by increased resistance to venous flow in the portal vein, including the sinusoids and hepatic vein. • Portal hypertension is the most serious complication of liver disease because it can cause potentially fatal complications, such as bleeding varices, ascites and hepatic encephalopathy. • Ascites is the accumulation and sequestration of fluid in the peritoneal cavity, often as a result of portal hypertension and decreased concentrations of plasma proteins. • Hepatic encephalopathy is impaired cerebral function caused by blood-borne toxins (particularly ammonia)
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not being metabolised by the liver. Toxin-bearing blood may bypass the liver in collateral vessels opened as a result of portal hypertension or diseased hepatocytes may be unable to carry out their metabolic functions. Manifestations of hepatic encephalopathy range from confusion and asterixis (flapping tremor of the hands) to loss of consciousness, coma and death. Jaundice (icterus) is a yellow or greenish pigmentation of the skin or sclera of the eyes caused by increases in plasma bilirubin concentration (hyperbilirubinaemia). Obstructive jaundice is caused by obstructed bile canaliculi (intrahepatic obstructive jaundice) or obstructed bile ducts outside the liver (extrahepatic obstructive jaundice). Bilirubin accumulates proximal to sites of obstruction, enters the bloodstream and is carried to the skin and deposited. Prehepatic jaundice is caused by destruction of red blood cells at a rate that exceeds the liver’s ability to metabolise bilirubin. Although this is a normal process in the newborn, it must be monitored for worsening or persistence to avoid kernicterus (brain damage caused by the bilirubin). Neonatal jaundice is common in the newborn, due to breakdown of fetal haemoglobin that causes the level of bilirubin to rise. Although this improves within several days in most infants, it needs to be closely monitored for worsening, as high levels of bilirubin are harmful to the brain. Phototherapy is an effective, non-invasive treatment. Cholelithiasis (the formation of gallstones) is a common disorder of the gallbladder. Gallstones form in the bile as a result of the aggregation of cholesterol crystals (cholesterol stones) or precipitates of unconjugated bilirubin (pigmented stones). Gallstones that fill the gallbladder or obstruct the cystic or common bile duct cause abdominal pain and jaundice. Cholecystitis is an inflammation of the gallbladder. It is usually associated with obstruction of the cystic duct by gallstones. Pancreatitis (pancreatic inflammation) is a serious but relatively rare disorder. Injury to the pancreatic ducts or acini permits leakage of digestive enzymes into pancreatic tissue where they become activated and begin the process of autodigestion, inflammation and destruction of tissues. Release of pancreatic enzymes into the bloodstream or abdominal cavity causes damage to other organs. The main risk factor known for pancreatic cancer is heavy cigarette smoking. Most tumours are adenocarcinomas that arise in the exocrine cells of ducts in the head, body or tail of the pancreas. Symptoms of pancreatic cancer may not be evident until the tumour has spread to surrounding tissues. Treatment is palliative and mortality is nearly 100%.
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CASE STUDY
A DULT Cathryn is a 56-year-old female who has separated from her husband after 32 years of marriage. She has been living on her own for the last 18 months after her youngest child left home. Cathryn is finding it difficult to cope with her loneliness and is drinking four bottles of wine a night. Cathryn often passes out on the lounge, is late for work and has been having more days off as sick. Cathryn is not eating much and friends/family have noticed a general decline in her appearance. Cathryn is admitted to hospital when she fractured her arm after a fall while she was intoxicated.
1
How many standard drinks is Cathryn consuming each night and what is the recommended amount of alcohol for a female? 2 Cathryn is at risk of liver disease. Explain further. 3 What major complications of liver disease may Cathryn experience if she does not reduce her alcohol intake? 4 Explain what her family and friends may be noticing in her appearance and general health.
CASE STUDY
A GEING James is a 78-year-old diagnosed with pancreatic cancer. James lives alone but has a supportive daughter. He has had weight loss of 6 kg in the last 2 months. He has painless jaundice, experiences some back pain and feels nauseous most of the time. James sees you at pre-admission clinic before his planned Whipple procedure.
1
Describe the possible treatment plans for James. (Hint: Discussion options include those plans which are palliative, those which are curative.) 2 Describe the general features of pancreatic cancer. 3 James is worried about his weight loss. Suggest ways he can help maintain his weight through his treatment. 4 James also asks about his postoperative care. Explain the complications of this major surgery.
REVIEW QUESTIONS 1 Name the methods of bowel assessment that allow for removal of polyps at the same time as visualisation in colorectal cancer. 2 Explain why it is advisable to remove benign polyps from the colon. 3 Discuss how inflammatory bowel disease and irritable bowel syndrome differ. In what ways are they similar? 4 Describe how coeliac disease can lead to lactose intolerance. 5 Explain the pathophysiology of pyloric stenosis.
6 Outline why dysphagia is an important symptom to consider for the populations of Australia and New Zealand. 7 Explain why diarrhoea can be a serious condition for infants. 8 Discuss how the liver metabolises (breaks down) alcohol. 9 Compare the modes of transmission for viral hepatitis A, B and C. 10 Explain the development of portal hypertension.
Key terms afferent arteriole, 861 aldosterone, 868 angiotensin I, 871 angiotensin II, 871 angiotensin-converting enzyme (ACE), 871 angiotensin-converting enzyme (ACE) inhibitors, 872 angiotensinogen, 871 antidiuretic hormone (ADH), 866 bladder, 876 calyces, 858 collecting duct, 866 cortex, 858 creatinine, 875 detrusor muscle, 876 distal convoluted tubule, 866 diuretic, 868 efferent arteriole, 861 erythropoietin, 870 filtrate, 860 glomerular filtration, 863 glomerular filtration membrane, 860 glomerular filtration rate (GFR), 870 hilum, 858 juxtaglomerular apparatus, 862 kidneys, 858 loop of Henle, 866 medulla, 858 micturition, 876 nephron, 858 oliguria, 868 peritubular capillaries, 861 proximal convoluted tubule, 864 renal autoregulation, 870 renal capsule, 858 renal corpuscle, 858 renal pelvis, 858 renin, 871 renin-angiotensin-aldosterone system, 871 tubular reabsorption, 863 tubular secretion, 863 urea, 874 ureters, 875 urethra, 876 urinalysis, 873 vitamin D, 869
CHAPTER
The structure and function of the urinary system
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Deanne Hryciw Chapter outline Introduction, 858 The structure of the kidneys, 858 External anatomy, 858 Internal anatomy, 858 Blood supply to the kidneys and nephrons, 860 The juxtaglomerular apparatus, 862 The function of the kidneys, 862 Urine formation, 862 Urine concentration, 867 Renal hormones, 869 Glomerular filtration rate, 870
Urine, 872 Acidification of urine, 872 Measures of renal function, 873 Urinary structures, 875 The ureters, 875 The bladder, 876 The urethra, 876 Micturition, 876 Ageing and the urinary system, 878
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Introduction The kidneys are the main organs of the urinary system and they are primarily responsible for the excretion of waste products from the body. These waste products include metabolites formed during chemical reactions, toxins in the blood and excess electrolytes that are eliminated from the body in the form of urine. The kidneys maintain a stable internal environment for optimal cell and tissue metabolism by filtering the blood and eliminating only the undesirable components, which means that most of the fluid is returned to the bloodstream. Therefore, not only do the kidneys produce urine, they also assist in facilitating a stable blood environment by contributing to homeostasis of the overall blood volume. The formation of urine is achieved through the processes of glomerular filtration, and tubular reabsorption and secretion within the kidney. Urine formation is a complex process that involves many steps, yet the fundamental principles of fluid and solute movement, such as filtration, diffusion and active transport should be familiar to you (see Chapter 3). The kidney also has an endocrine function and secretes the hormones renin, erythropoietin, and 1,25-dihydroxyvitamin D3 for regulation of blood pressure, erythrocyte production, and calcium metabolism, respectively. In times of severe fasting, the kidney can also produce glucose from amino acids, performing the process of gluconeogenesis. The other major component of the urinary system is the urinary bladder, which temporarily stores the urine that it receives from the kidneys. There are also tubes that transport urine between these structures, including two ureters that permit urine flow between the two kidneys and bladder and a urethra that travels from the bladder to outside the body. However, the kidneys are integral to homeostatic functions other than urine production. They are centrally involved in balancing electrolyte and water transport, conserving nutrients and regulating acids and bases. They also have an endocrine function and secrete hormones that are involved in blood pressure regulation, erythrocyte production and calcium metabolism. In males only, the urinary system is anatomically linked with the reproductive system, but this is discussed in Chapter 31. We commence our exploration of the urinary system by looking at the anatomy of the kidneys.
The structure of the kidneys External anatomy
The kidneys are two bean-shaped organs located on the posterior abdominal wall outside the peritoneal cavity. The kidney beans that some people eat are very similar in shape to the actual kidneys, hence the name. The kidneys lie on either side of the vertebral column (spine) with their upper and lower poles extending from near the twelfth thoracic vertebra to the third lumbar vertebra (see Fig. 28.1). An adult kidney weighs approximately 130–150 g and is 11 cm
long, 5–6 cm wide and 3–4 cm thick. The shape of the kidney arises because the lateral surface is convex and the medial surface is concave with a cleft in the middle called the hilum, where blood vessels, nerves and lymphatic vessels enter and exit the kidney, and the joining tube to the bladder, the ureter, exit the kidney. Each kidney is surrounded by a layer of fibrous connective tissue in a capsule (the renal capsule), which is embedded in a mass of fat. The capsule and this perirenal fat layer are covered with a double layer of renal fascia, fibrous tissue that attaches the kidney to the posterior abdominal wall. The cushion of fat, the ribs and the position of the kidney between the abdominal organs and muscles of the back protect the kidneys from trauma (see Fig. 28.2). The right kidney is slightly lower than the left; it is displaced downwards by the superior position of the liver.
Internal anatomy
The kidney has three distinct sections, when viewing a frontal section: the cortex, medulla and pelvis. The outer section of the kidney is called the cortex, while the medulla forms the inner part of the kidney and consists of regions call pyramids, which are cone-shaped structures. The renal columns separate the pyramids and the papillae are the inward projections of each pyramid. The pyramids extend into the renal pelvis, which has a striped appearance. The minor and major calyces are chambers that receive urine and form the entry into the renal pelvis (see Fig. 28.2). The pelvis connects to the ureters for urine to flow into the bladder for storage. These structures are organised into lobes, which consist of a pyramid and the overlying cortex. There are about 14 lobes in each kidney.
The nephrons
The nephron is the structural and functional unit of the kidney (see Fig. 28.3). Each kidney contains approximately 1.2 million nephrons. The nephrons are the microscopic units that produce urine. We can actually survive with only one kidney, and a considerable number of nephrons need to be damaged before insufficient urine is produced, demonstrating that nephrons are remarkably efficient units at filtering waste. The nephron is a tubular structure, which commences with a funnel-shaped unit called the glomerular capsule (or Bowman’s capsule) at one end. Inside this capsule is a clumped network of capillaries called the glomerulus, where blood enters the nephron to commence the filtration process. Collectively, these structures are termed the renal corpuscle (consisting of the glomerular capsule and glomerulus). The glomerular capsule has two layers: a parietal (outer) layer and a visceral (inside) layer. The parietal layer is the external component and is composed of simple squamous epithelium. The visceral layer attaches to the glomerular capillaries and has specialised epithelial cells called podocytes. These cells allow the movement of fluid from the capillaries and into the capsule (discussed below). The space between these layers is known as the glomerular space.
CHAPTER 28 The structure and function of the urinary system
A
Spleen
Adrenal gland Liver
B
Renal artery Renal vein
Twelfth rib
Left kidney
Right kidney
Abdominal aorta Inferior vena cava
Ureter Urinary bladder
Common iliac artery and vein
859
Eleventh rib
Lower edge of pleura
Twelfth rib
Left kidney
Right kidney
Spinous process of first lumbar vertebra
Spinous process of fourth lumbar vertebra
Urethra
C Kidney Renal pelvis
Ureter Urinary bladder
FIGURE 28.1
Organs of the urinary system. A Anterior view of kidneys, ureters, bladder and urethra. Other anatomical structures are also shown in reference to the urinary system. B Posterior view of the position of the kidneys in relation to the ribs and vertebrae. C X-ray with contrast showing the position and size of the urinary organs.
The glomerular capsule is continuous with a series of tubes called the proximal convoluted tubule, the loop of Henle (also known as the nephron loop), and the distal convoluted tubule. The proximal and distal components refer to their location relative to the renal corpuscle, with the loop of Henle connecting these two tubules. The distal convoluted tubule drains into the collecting duct, which contributes to the formation of urine. The proximal and distal convoluted tubules are twisted and folded back, while the loop of Henle is considerably longer and has two limbs — a descending arm and an ascending arm. In addition, the renal tubules are lined with a single layer of epithelial cells. The structure and function of these epithelial cells are slightly different along the length of the tubules, which
permits specific functions in the production of urine. This is discussed later in the chapter when urine production is explained. Urine production starts at the glomerular capsule and continues through the proximal convoluted tubule, the loop of Henle, the distal convoluted tubule and the collecting duct. The kidney has two major types of nephrons: cortical and juxtamedullary (juxta meaning ‘near’; see Fig. 28.4). Cortical nephrons (85% of all nephrons) are located in the cortex and extend only partially into the medulla. Juxtamedullary nephrons lie close to and extend deep into the medulla and are important in the kidney’s production of concentrated urine. The major structural difference between the types of nephrons is the length of the loop of
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A
Pyramid in renal medulla
B Capsule (fibrous) Renal column Cortex
Renal cortex Renal papilla
Renal papilla of pyramid
Minor calyces
Renal sinus
Major calyces Renal artery
Hilum
Renal pelvis
Renal vein Minor calyx
Renal pelvis
Renal column Medullary pyramid
Ureter
FIGURE 28.2
Cross-section of the kidney. A Schematic of the internal structures of the kidney. B Photograph of a cross-section of a human kidney.
Henle. In cortical nephrons, the loop is short, whereas in juxtamedullary nephrons the loop may extend the whole depth of the medulla. Mesangial cells (shaped like smooth muscle cells) and the mesangial matrix lie between and support the capillaries. Mesangial cells have phagocytic ability similar to monocytes, release inflammatory cytokines, and can contract to regulate glomerular capillary blood flow.1,2
The glomerular filtration membrane
The glomerular filtration membrane filters blood components from the capillary into the glomerular capsule. The membrane has three components: (1) the endothelium of the capillary; (2) the visceral layer of the glomerular capsule with podocytes; and (3) a basement membrane between these two layers (see Fig. 28.5). The capillary endothelium is composed of cells in continuous contact with the basement membrane of the glomerular capsule and contains pores. These pores are numerous and are called fenestrae (from the Latin word for window). These fenestrations allow plasma to flow through, but blood proteins cannot as they are too large. The basement membrane, which is a selectively permeable network of proteins between the capillary and the podocytes, further prevents proteins from entering the capsule. The podocytes have extensions known as foot processes; between these are gaps known as filtration slits that attach to the basement
membrane forming an elaborate network of intercellular clefts.1,2 The fluid flows through these filtration slits into the glomerular capsule and forms the primary urine, called filtrate. These sophisticated structures separate the blood of the glomerular capillaries from the fluid (filtrate) in the glomerular capsule.
Blood supply to the kidneys and nephrons
The kidneys are highly vascular organs, meaning that they have a high blood flow and there are many blood vessels within the kidneys (see Fig. 28.6). The kidneys receive about 25% of total cardiac output — or approximately 1000 mL to 1200 mL of blood per minute. This is necessary to allow adequate filtration of the blood and this process needs to be continuous. When this blood flow is reduced, the kidneys can be injured and if the blood flow is severely restricted, this can lead to acute kidney injury (Chapter 30). Blood flow to the kidneys and nephrons is shown in Fig. 28.7. The blood vessels of the kidney closely parallel nephron structure. The major vessels, listed in the order through which blood flows through the kidney, are as follows: 1 Renal arteries. The renal arteries arise from the abdominal aorta, divide into anterior and posterior branches at the renal hilum, then subdivide into lobar arteries supplying
CHAPTER 28 The structure and function of the urinary system
Efferent Glomerulus Glomerular capsule arteriole
B
861
Proximal convoluted tubule
Juxtaglomerular apparatus
A Medulla
Afferent arteriole
Papilla
Distal convoluted tubule
Renal pelvis Calyx
Ureter Peritubular capillaries
Collecting tubule
Loop of Henle
FIGURE 28.3
The location and components of the nephron. A Magnified wedge cut from a renal pyramid showing the nephron’s structures. B Schematic of the nephron including the blood supply and the tubules down to the collecting tubule.
blood to the lower, middle and upper thirds of the kidney. 2 Interlobar arteries. These arteries are more subdivisions that travel down renal columns between the pyramids towards the cortex. 3 Arcuate arteries.These arteries are branches of the interlobar arteries at the cortical medullary junction, which arch over the base of the pyramids and run parallel to the surface of the kidney. From these arises the arteriole that enters the glomerular capsule, called the afferent arteriole (afferent meaning ‘carrying towards’), which connects to the glomerular capillaries, where filtration occurs. After the capillaries exit the capsule, they form the efferent arteriole (efferent meaning ‘carrying away’). The afferent and efferent arterioles are unique in the body because this is the only time that arterioles both feed and drain a capillary. 4 Glomerular capillaries. Four to eight vessels are arranged in a fist-like structure, arise from the afferent arteriole and empty into the efferent arteriole, which carries blood to the peritubular capillaries.
Peritubular capillaries. The efferent arteriole forms a network of capillaries that intertwine with the tubules of the nephron. These are termed the peritubular capillaries; they are a low-pressure system that permits reabsorption of fluid and solute from the tubules. In this way, all the structures of the nephron have a close relationship with capillaries — the glomerular capsule has the glomerular capillaries, while the remaining structures are associated with the peritubular capillaries. 6 Vasa recta. This network of capillaries forms loops and closely follows the loop of Henle. It is the only blood supply to the medulla. 7 Renal veins. These veins follow the arterial path and have the same names as the corresponding arteries; they eventually empty into the inferior vena cava. The venous system is essentially the reverse of the arterial supply: the peritubular capillaries drain into an arcuate vein joining to an interlobar vein and then into the renal vein, which eventually empties into the inferior vena cava. Note that the lymphatic vessels tend also to follow the distribution of the blood vessels. 5
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The juxtaglomerular apparatus
Cortex
Another important anatomical component of the nephron is the juxtaglomerular apparatus. A group of specialised cells known as juxtaglomerular cells (which release a hormone called renin; see later in the chapter) are located Cortical nephron Efferent arteriole Afferent arteriole
Juxtamedullary nephron
around the afferent arteriole where it enters the renal corpuscle (see Fig. 28.8). These cells lie within the arteriole wall; they detect the blood pressure within the vessel and contain granules that secrete renin when stimulated. Located within the distal tubule are the macula densa (sodium-sensing cells), which detect the amount of sodium within the distal tubule. Together, the juxtaglomerular cells and macula densa cells form the juxtaglomerular apparatus, which is important in sensing the properties of fluid flowing through that region. The juxtaglomerular apparatus is vitally important in the control of blood pressure and the rate at which glomerular filtration occurs.3,4 FOCU S ON L EA RN IN G
Medulla
1 Describe the location of the kidneys. Interlobar Artery Vein Collecting duct
Vasa recta
Thick loop of Henle
2 Discuss the function of the nephrons. 3 Explain why large molecules in the blood, like proteins, are not filtered at the glomerulus. 4 Describe the path of blood from the aorta to the nephrons.
Thin loop of Henle
5 Describe the location of the juxtaglomerular apparatus.
The function of the kidneys We now turn our attention to kidney physiology and the formation of urine.
FIGURE 28.4
Cortical and juxtamedullary nephrons. Note the length of the loop of Henle and the vasa recta, the long blood vessels that intertwine.
Urine formation
The formation of urine involves many steps. The kidneys are relatively non-selective in what they filter from the blood. Except for large molecules like proteins, the majority of fluid and solutes are filtered into the nephrons, then must
FIGURE 28.5
The filtration membrane of the glomerulus. A The arrangement of the glomerulus and glomerular capsule showing the podoctyes. B An electron micrograph showing a cross-section through the filtration barrier. The endothelium on the inside of the capillary has large multiple fenestrations (see asterisks) and the multiple foot processes of the podocyte, which are separated by filtration slits (arrows). Large red arrows indicate the direction of fluid flow from capillary into the glomerular capsule.
CHAPTER 28 The structure and function of the urinary system
863
Right main renal artery
FIGURE 28.6
Blood vessels within the kidneys. A Renal angiogram. B Diagram of renal blood vessels.
Vena cava
Aorta
Arcuate vein
Proximal Arcuate Afferent convoluted artery arteriole tubule
Distal convoluted tubule
Efferent arteriole
Petitubular capillaries
Interlobular vein
Glomerulus
Interlobular artery Collecting tubule Renal vein
Renal artery
Glomerular Vasa capsule recta
Loop of Henle
FIGURE 28.7
Blood supply to the kidney and nephron. The renal artery provides the arterial blood to the kidneys for filtration and processing. A small branch from the renal artery becomes the afferent arteriole, which enters the glomerulus for filtration. The blood flow exits the glomerulus as the efferent arteriole, which follows the nephron as the peritubular capillaries. These peritubular capillaries then become venous, and the renal vein exits the kidneys transporting the blood which has been fully processed by the kidneys.
be returned to the bloodstream. The sophistication with the process is the balancing act by the nephrons to control both the volume of urine produced and the concentration of solutes in the urine. There are three main processes in the formation of urine: 1 glomerular filtration: filtration of plasma at the glomerulus
tubular reabsorption: reabsorption of different substances along tubular structures 3 tubular secretion: secretion of solutes into the tubules. These processes are summarised in Fig. 28.9. We now explore how these processes work and coordinate to produce urine. We start with the glomerulus, where the first process occurs. 2
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Part 4 Alterations to body maintenance
Glomerular filtration
Distal convoluted tubule Macula densa
H2O
Filtration is a passive process whereby fluid and solutes move across a membrane (see Chapter 3). The initial fluid which enters the glomerular capsule from the blood is known as filtrate (fluid and solutes that are filtered), and it is subsequently modified along the length of the nephron to become urine. Fluid and solutes are forced across the glomerular filtration membrane by hydrostatic pressure (blood pressure); the filtrate contains electrolytes (such as sodium, chloride and potassium) and other molecules (such as creatinine, urea and glucose) in the same concentrations as in plasma. While large proteins cannot cross the glomerular filtration membrane, some small proteins (amino acids) may be filtered. The size and electrical charge of a substance affects its ability to be filtered at the glomerulus. Like other capillary membranes, the glomerulus is freely permeable to water and relatively impermeable to large substances such as plasma proteins. However, the glomerulus is more efficient at filtering fluid than other capillaries because of the fenestrations and the higher pressure in the glomerular capillaries. This allows more substances to exit the capillaries at the nephrons than at other capillaries in the body. The hydrostatic pressure within the capillaries is the major force for moving water and solutes across the filtration membrane and into the glomerular capsule (see Fig. 28.10). Two forces oppose the filtration effects of the glomerular capillary hydrostatic pressure: (1) the hydrostatic pressure in the glomerular space; and (2) the oncotic pressure of the glomerular capillary blood. Because the fluid in the glomerular capsule normally contains only small amounts of protein, it does not usually have a large oncotic influence on the plasma of the glomerular capillary. The combined effect of forces favouring and forces opposing filtration determines the filtration pressure. The net filtration pressure is the sum of forces favouring and opposing filtration. The estimated values contributing to the forces of filtration are presented in Fig. 28.10. Overall, there is a net outward pressure that allows substances to move from the capillary into the glomerular capsule.
NH3
Tubular reabsorption
Juxtaglomerular cells
Efferent arteriole
Afferent arteriole
Glomerulus
Glomerular capsule
Podocytes (visceral cells)
Parietal epithelial cells
Proximal convoluted tubule
FIGURE 28.8
The juxtaglomerular apparatus. The juxtaglomerular cells of the afferent arteriole are granular cells within the wall of the arteriole. The macula densa are cells located in the ascending limb of the loop of Henle, adjacent to the juxtaglomerular cells. Collectively, they form the juxtaglomerular apparatus.
Glomerulus
Peritubular capillaries Distal tubule
Na+
H2O Glomerular capsule Glucose
Proximal tubule K+ NH3
H
+
Loop of Henle Filtration Reabsorption Secretion
Collecting duct
FIGURE 28.9
A summary of urine formation. Includes the processes of filtration, reabsorption and secretion. These are represented by the coloured arrows.
Thus far, blood has entered the glomerulus, via the afferent arteriole, and the majority of plasma has filtered across into the glomerular capsule. From here, the filtrate, which is actually primary urine, flows into the proximal convoluted tubule. Fortunately, nearly all the filtered plasma (99%) is reabsorbed into the blood — otherwise, we would very quickly deplete our blood volume! In fact, by the end of the proximal convoluted tubule, about 60–70% of the filtered water has been reabsorbed and large amounts of electrolytes (such as sodium, potassium, bicarbonate, calcium and phosphate) and other molecules (such as glucose and amino acids) have also been reabsorbed. Tubular reabsorption along the tubules is due to processes such as simple diffusion, facilitated diffusion, active transport, co-transport and osmosis (see Chapter 3). The
CHAPTER 28 The structure and function of the urinary system
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FIGURE 28.11
Reabsorption at the proximal convoluted tubule. 1 Sodium (Na+) is actively reabsorbed using an ATP pump. 2 Electrolytes and other solutes are reabsorbed using facilitated diffusion and are greatly enhanced by the sodium concentration changes due to active transport. 3 Water moves via osmosis in the same direction as the solute. Therefore, most of the electrolytes and water are reabsorbed by the time the filtrate leaves the proximal convoluted tubule. FIGURE 28.10
Glomerular filtration pressures. The larger arrows represent the hydrostatic pressure within the capillary and the smaller arrows are forces opposing the hydrostatic pressure: hydrostatic pressure in the glomerular capsule and blood oncotic pressure. This results in a net fluid pressure that forces fluid out of the capillary. Pressures are approximate values only.
pressure in the peritubular capillaries is low so that filtrate will be reabsorbed from the tubules. Some molecules, particularly glucose, are reabsorbed using active transport which requires specific protein carriers to return filtered glucose to the blood. Because there are only a certain number of protein carriers available, reabsorption can be limited. Glucose should not normally appear in the urine because it is able to be fully reabsorbed. When it does appear in urine it is often because there is too much glucose in the filtrate. The transporters cannot keep up and some glucose will not be reabsorbed. This phenomenon is referred to as the transport maximum. We turn now to how reabsorption occurs in the different sections of the tubules, starting with the proximal convoluted tubule. THE PROXIMAL CONVOLUTED TUBULE
The proximal tubular lumen consists of one layer of cuboidal cells. This is the only surface inside the nephron where the cells are covered with abundant microvilli (forming a brush border). This greatly expands the surface area of the tubule and enhances its reabsorptive capacity. The most important electrolyte that is reabsorbed is sodium. The
reabsorption of sodium occurs by active transport using the sodium–potassium–ATP pump. While this pump requires energy in the form of ATP, it greatly enhances the movement of other electrolytes and water out of the proximal convoluted tubule and back into the peritubular capillaries (see Fig. 28.11). Water, most electrolytes (potassium, chloride, calcium and phosphate) and organic substances (glucose and amino acids) are co-transported with sodium, which means that when sodium is reabsorbed, other substances are also reabsorbed. The movement of other substances does not require ATP and therefore is very efficient. The osmotic force generated by active sodium transport promotes the passive diffusion of water out of the tubular lumen and into the peritubular capillaries (remember the general rule that where sodium goes, water follows — on the condition that the membrane must actually be permeable to both sodium and water). Passive transport of water is further enhanced by the elevated oncotic pressure of the blood in the peritubular capillaries, which is created by the previous filtration of water at the glomerulus. As the filtrate moves through the proximal convoluted tubule, approximately 65% of water is reabsorbed. In a healthy person, glucose is able to filter at the glomerulus and is then completely reabsorbed in the proximal convoluted tubule, such that glucose does not appear in the urine. While the positively charged sodium ions leave the tubular lumen during reabsorption, negatively charged chloride ions passively follow to maintain electroneutrality.
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Part 4 Alterations to body maintenance
Lumen
Tubule cells
Blood
1 CO2 diffuses into tubular cell
H+ secreted into urine
Na+
4
Na+ and
H+ + HCO3–
2 CO2
HCO3– reabsorbed
Carbonic anhydrase
CO2 + H2O
1
3
2 CO2 combines with H2O to form H+ and HCO3–, by carbonic anhydrase
3 HCO3– reabsorbed into blood with Na+
4 H+ secreted into filtrate and then urine
FIGURE 28.12
Tubular reabsorption of bicarbonate. Tubule cells reabsorb carbon dioxide, and using carbonic anhydrase, they transport bicarbonate through to the tubular capillaries and hydrogen ions into the urine.
Because the proximal tubular cell has a limited permeability to chloride, chloride reabsorption lags behind sodium. Hydrogen ions are actively exchanged for sodium ions. The hydrogen ions (H+) then combine with bicarbonate (HCO3-). Bicarbonate is completely filtered at the glomerulus, and approximately 90% is reabsorbed in the proximal tubule. In the tubular lumen, hydrogen and bicarbonate ions form carbonic acid (H2CO3), which rapidly breaks down, or dissociates, to carbon dioxide (CO2) and water (H2O). CO2 then diffuses into the tubular cell, where carbonic anhydrase again catalyses the CO2 and H2O to form HCO3- and H+. The H+ is secreted again into the filtrate, and HCO3- combines with sodium and is transported to the peritubular capillary blood. Bicarbonate is thus conserved, and the hydrogen is reabsorbed as water. Therefore, these ions normally do not contribute to the urinary excretion of acid or the addition of acid to the blood (Fig. 28.12). THE LOOP OF HENLE
The proximal tubule joins the loop of Henle, which has descending and ascending arms that project down into the medulla. The tube then loops and becomes a thickening ascending segment that extends toward the cortex. The descending arm has a thin segment composed of thin squamous cells with no active transport capabilities. However, this section is very permeable to water and
water moves out via osmosis — approximately 15% of water is reabsorbed in the loop of Henle. In contrast, the ascending loop is not permeable to water, but allows sodium to move out using both active and passive transport mechanisms. Another important function of the loop of Henle is the production of a protein uromodulin which binds to pathogens to prevent urinary tract infection, protects the epithelium of the urinary tract from injury, and protects against kidney stone formation.5 THE DISTAL CONVOLUTED TUBULE AND COLLECTING DUCT
By the time the filtrate has entered the distal convoluted tubule, the majority of water and solute reabsorption has occurred. The distal convoluted tubule and collecting duct are involved in adjusting the solute concentration and the amount of water, and this is mainly done under hormonal control. The distal convoluted tubule is poorly permeable to water but readily reabsorbs ions and contributes to the dilution of the tubular fluid. The end of the distal convoluted tubule and the collecting duct are permeable to water as controlled by antidiuretic hormone (ADH: diuresis = production of urine, so antidiuresis = less production of urine). This means that in the presence of ADH, water is reabsorbed from the urinary filtrate so that
CHAPTER 28 The structure and function of the urinary system
more water returns to the blood (see below). Alternatively, in someone who is well-hydrated, ADH is not released and in the kidneys the excess water remains in the filtrate through the collecting duct and exits the body with the urine. Sodium is readily reabsorbed by the later segment of the distal convoluted tubule and collecting duct under the regulation of the hormone aldosterone. Potassium is actively secreted in these segments and is also controlled by aldosterone and other factors related to the concentration of potassium in body fluids.
Tubular secretion
The final process in the production of urine is tubular secretion (see Fig. 28.9). This occurs when toxins and byproducts of metabolism are moved into the tubules from the peritubular capillaries for elimination. It is essentially reabsorption in reverse and is a valuable method for allowing additional substances to be moved from the blood into the filtrate. Remember that the process of filtration occurs only at the glomerular capsule, so in order for other substances to pass from the blood into urinary filtrate after that, secretion is necessary. Furthermore, filtration is a general, non-selective process whereby many substances enter the urinary filtrate, but secretion along the tubules is a selective process whereby substances that need to be removed from the blood can become part of the urine. Secretory transport mechanisms exist for some metabolic byproducts as well as some drugs and chemical products. Examples include creatinine and penicillin. These secretory mechanisms eliminate drugs and other chemical products from the body. When the renal tubules are damaged, metabolic byproducts and drugs may accumulate in the blood (due to impaired secretion), causing toxic levels. A variety of substances may be secreted, including creatinine, urea, excess hydrogen ions (acid), potassium and ammonia. Furthermore, the kidneys are an important organ in removing drugs from the body; these drugs are secreted in the tubules to enter the urinary filtrate.
FO CUS O N L E A R N IN G
1 Describe the main mechanisms involved in the production of urine. 2 Discuss how glomerular filtration occurs. 3 Explain the different processes of reabsorption in the tubules. 4 Discuss how active transport of sodium facilitates the movement of other electrolytes and water. 5 Describe the regions of the tubules where water is reabsorbed. 6 Describe tubular secretion and what substances are secreted.
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Urine concentration
Urine can be hypotonic, isotonic or hypertonic, but body fluids must stay constant with an osmolality of approximately 300 mOsm/kg. The kidneys have a sophisticated mechanism whereby they can regulate urine concentration and volume. This is achieved principally by the juxtamedullary nephrons, which have long loops of Henle that project down into the medulla. The structural features of the medullary loops of Henle allow the kidneys to concentrate urine and retain water for the body. There exists an osmotic gradient from the cortex to the medulla, where the osmolality of the interstitial fluid becomes progressively more concentrated the deeper into the medulla. Therefore, the increased length of the longer loops of Henle means that there is more distance for water reabsorption to occur, which results in more concentrated urine. In addition, the transition of the filtrate into the final urine reflects the concentrating ability of the loops. It should be noted that the efficiency of water reabsorption is related to the length of the loops: the longer the loops, the greater the ability to concentrate the urine. Final adjustments in urine composition are made by the distal convoluted tubule and collecting duct according to body needs. Urine concentration or dilution occurs principally in the loop of Henle, distal tubules, and collecting ducts. The efficiency of water reabsorption (conservation) is related to the length of the hairpin loops of the nephron which enter the medulla: the longer the loops, the greater the ability to concentrate the urine. The transition of the filtrate into the final urine reflects the concentrating ability of the loops.
RESEARCH IN F
CUS
Fructose and dehydration in hot climates An epidemic in Central America as well as Egypt, India and Sri Lanka has emerged in the last decade that is known as chronic kidney disease (CKD) of unknown origin (CKDu). CKDu is particularly prevalent in male agricultural workers and leads to substantial morbidity and mortality. It is thought that excessive heat exposure and dehydration combined with strenuous physical labour are the central elements to the development of CKDu. Another potential risk factor for CKDu is pesticide exposure and CKDu presents typically between the 3rd and 5th decade of life. CKDu is characterised by low-grade non-nephrotic proteinuria, hyperuricaemia and/or hypokalaemia. In addition, patients with CKDu have tubulointerstitial disease and glomerular damage. The underlying mechanism is unknown. However, a study in mice has found that dehydration increases the production of fructose (sugar) in the kidney tubules. Fructose in the tubules increases the release of oxidants and inflammatory mediators, leading to kidney damage. Therefore, in these populations, it is important that cycles of excessive heat exposure and dehydration be avoided and that regular access to water, rest and shade is available during each workday to assist in the maintenance of normal kidney function.
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Antidiuretic hormone
remains in the bloodstream, to lessen the hypertension), as well as to draw in some fluid from surrounding tissues in sites of oedema. Diuretics are divided into four general categories: (1) osmotic diuretics that increase water loss by osmosis; (2) carbonic anhydrase inhibitors that inhibit carbonic anhydrase — an enzyme that causes urine to become more acidic by also causing reabsorption of sodium; thus
Angiotensinogen
Aldosterone
Aldosterone is produced and secreted by the adrenal cortex under the regulation of the renin-angiotensin-aldosterone system (see later this chapter). One main role for aldosterone is the stimulation of the distal tubule and collecting duct to reabsorb sodium, which promotes water reabsorption.
Atrial natriuretic peptide
Atrial natriuretic peptide (ANP) is secreted from cells in the right atrium of the heart. When right atrial pressure rises, ANP inhibits secretion of renin, inhibits angiotensin-induced secretion of aldosterone, relaxes vascular smooth muscle, and inhibits sodium and water absorption by kidney tubules. The result is decreased blood volume and blood pressure. Natriuretic hormones are also produced by other tissues including the ventricular myocardium, brain and vascular system and have effects on heart tissue, vasodilation, and bone growth.6
Diuretics as a factor in urine flow
A diuretic is any agent that enhances the flow of urine. Diuretics are commonly used to treat hypertension and oedema caused by heart failure, cirrhosis and renal failure. Diuretics are useful in these conditions, as they cause fluid to be lost from the body in the urine (as a result, less fluid
FIGURE 28.13
The effect of renin release on blood pressure, blood volume and urine output.
CONCEPT MAP
The distal convoluted tubule in the cortex receives the hypo-osmotic urine from the ascending limb of the loop of Henle. The concentration of the final urine is controlled by ADH, which is secreted from the posterior lobe of the pituitary gland. The osmoreceptors in the hypothalamus sense changes in blood osmolality and, when osmolality increases, ADH is released. ADH is also released when renin causes the activation of angiotensin II by stimulating the hypothalamus (see Fig. 28.13; the complete description of the renin-angiotensin-aldosterone system appears later in the chapter). Other external stimuli, such as surgery, pain, exercise and heat exposure, cause ADH release, as the body will want to retain water content in these instances. ADH increases water permeability and reabsorption in the last segment of the distal convoluted tubule and along the entire length of the collecting duct, which pass through the medulla. The water diffuses out of the tubule and returns to the blood. The excreted urine can be very concentrated, such that the volume is normally reduced to about 1% of what was filtered at the glomerulus. Therefore, ADH causes an individual to produce concentrated urine. ADH secretion is therefore one cause of oliguria—diminished excretion of urine, at less than 400 mL/day. In the absence of ADH, water diuresis — an increase in excretion of highly dilute urine — takes place. The distal convoluted tubules and collecting duct become impermeable to water. Water remains in the tubular lumen and is excreted as a dilute and large volume of urine. Because ADH has no effect on sodium reabsorption, sodium continues to be actively transported from the distal tubule.
CHAPTER 28 The structure and function of the urinary system
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TABLE 28.1 The action of diuretic DIURETIC
SITE OF ACTION
ACTION
SIDE EFFECTS
Osmotic diuretic Mannitol
Proximal convoluted tubule
Freely filtered but not reabsorbed; osmotically Hypokalaemia, dehydration attracts water and diminishes sodium reabsorption
Carbonic anhydrase inhibitors Acetazolamide
Proximal convoluted tubule
Inhibits carbonic anhydrase; blocks hydrogen Hypokalaemia, systemic ion secretion and reabsorption of sodium and acidosis, alkaline urine bicarbonate
Inhibitors of sodium/chloride reabsorption Thiazides
Between the end of the ascending loop and the beginning of the distal convoluted tubule
Blocks sodium and chloride reabsorption; mildly suppresses carbonic anhydrase
Hypokalaemia, metabolic alkalosis
Frusemide
Thick ascending limb of the loop of Henle
Blocks active transport of chloride, sodium and potassium
Hypokalaemia, uric acid retention
Increases rate of urine formation
Aldosterone antagonists/potassium-sparing diuretics Spironolactone Distal convoluted tubule/collecting Inhibits aldosterone, blocks sodium duct reabsorption and results in potassium retention
Hyperkalaemia, nausea, confusion, gynaecomastia
Amiloride
Nausea, vomiting, headache, skin rash
Distal convoluted tubule/collecting Blocks sodium reabsorption and inhibits duct potassium excretion
inhibiting this allows sodium and the water that follows to exit the body; (3) inhibitors of loop sodium or chloride transport (which decrease reabsorption and therefore increases urine volume); and (4) aldosterone antagonists and potassium-sparing diuretics — aldosterone increases sodium and water reabsorption; preventing aldosterone actions inhibits reabsorption. Aldosterone antagonists and potassium-sparing diuretics are usually placed together as many of them share the same properties. The physiological mechanisms related to each category are summarised in Table 28.1. The relevant physiology relating to many of these drugs is explained later in the renin-angiotensinaldosterone system. Unfortunately, some individuals have used diuretic medications to promote weight loss, as they cause dehydration that will lower the total body weight. However, such practices which promote dehydration are unsafe and should not be used to achieve weight loss. In addition to medications, some diuretics are consumed in the diet (e.g. alcohol and caffeine). These also have the ability to enhance urinary flow. F O CUS O N L E A R N IN G
1 Discuss the effect of antidiuretic hormone on urine volume. 2 List the different types of diuretics.
Renal hormones
Certain hormones are either activated or produced by the kidney. These hormones have significant systemic effects and include urodilatin, the active form of vitamin D, and erythropoietin.
Urodilatin
Urodilatin, a natriuretic peptide, is produced by the distal tubule and collecting ducts when there is increased circulating volume and increased blood pressure. It inhibits sodium and water resorption from the medullary part of the collective duct, producing diuresis.
Vitamin D
Vitamin D is a hormone that can be obtained in the diet or produced by the action of ultraviolet radiation on cholesterol in the skin. These forms of vitamin D3 (cholecalciferol) are inactive and require two steps to establish a metabolically active form. The first step occurs in the liver and the second in the kidneys. Vitamin D is necessary for the absorption of calcium and phosphate by the small intestine. The renal hydroxylation step is stimulated by parathyroid hormone (see Chapter 29). A decreased plasma calcium level (less than 2.5 mmol/L) stimulates the secretion of parathyroid hormone. Parathyroid hormone then stimulates a sequence
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of events that help restore plasma calcium toward normal levels: • calcium mobilisation from bone • production of 1,25-dihydroxyvitamin D3 • absorption of calcium from the intestine • increased renal calcium reabsorption • decreased renal phosphate reabsorption. Serum phosphate fluctuations also influence the renal hydroxylation of vitamin D. Decreased levels of serum phosphate stimulate active 1,25-dihydroxyvitamin D3 formation and increased levels inhibit formation. This results in compensatory changes in phosphate absorption from bone and intestine. Individuals with renal disease have a deficiency of 1,25-dihydroxyvitamin D3 (1,25-OH2D3; calcitriol) and manifest symptoms of disturbed calcium and phosphate balance (see Chapter 29). Therefore, normal kidney function is required for the activation of vitamin D.
Erythropoietin
Oxygen-sensing erythropoietin-producing cells are located in the juxtamedullary cortex.7 Erythropoietin stimulates the bone marrow to produce red blood cells in response to tissue hypoxia and may have tissue protective effects.7 (Erythrocyte production is discussed in Chapter 16.) The stimulus for erythropoietin release is decreased oxygen delivery in the kidneys. The anaemia of chronic kidney disease, in which kidney cells have become nonfunctional, can be related to the lack of this hormone.8
Glomerular filtration rate
As already mentioned, the kidneys usually receive 1000–1200 mL of blood per minute. With a normal haematocrit (concentration of red blood cells in the blood) of 45%, about 600–700 mL of blood flowing through the kidneys per minute is plasma. From the renal plasma flow, 20% (approximately 120–140 mL/min) is filtered at the glomerulus and passes into glomerular capsule. The amount of fluid filtered over time is known as the glomerular filtration rate (GFR) and it is measured in millilitres per minute (mL/min). The GFR is directly related to the perfusion pressure of the glomerular capillaries; therefore as the blood pressure increases, so does the GFR and, as the pressure decreases, the GFR is also reduced. The normal GFR in adults is approximately 120–125 mL/min. Note that these values are combined for both kidneys and, in a healthy person, each kidney receives approximately half of the blood flow and contributes half of the GFR. The remaining 80% (about 480 mL) of plasma flows through the efferent arterioles to the peritubular capillaries. The ratio of glomerular filtrate to renal plasma flow per minute (125/600 = 0.20) is called the filtration fraction. Normally all but 1 to 2 mL of the glomerular filtrate is reabsorbed from nephron tubules and returned to the circulation by the peritubular capillaries. The GFR is directly related to renal blood flow, which is regulated by intrinsic autoregulatory mechanisms, by
neural regulation, and by hormonal regulation. In general, blood flow to any organ is determined by the arteriovenous pressure differences across the vascular bed. If mean arterial pressure decreases or vascular resistance increases, renal blood flow declines. The total volume of fluid filtered by the glomeruli averages 180 L per day or approximately 120 mL/min, which is a phenomenal amount considering the size of the kidneys. Because only about 1.5 L of urine is excreted per day, 99% of the filtrate is reabsorbed into the peritubular capillaries and returned to the blood. The factors determining the GFR are directly related to the pressures that favour or oppose filtration. For example, if the afferent arteriole constricts, blood flow decreases with a corresponding drop in glomerular pressure. The GFR then decreases and body fluids are conserved, meaning that less fluid is excreted in the urine and more is retained in the blood. Conversely, constriction of the efferent arteriole increases the net filtration pressure and the GFR increases. When both afferent and efferent arterioles constrict, little change occurs in filtration pressure, but renal blood flow is reduced and so is the GFR. Pathophysiological conditions such as kidney stones can obstruct the outflow of urine. This can cause a retrograde increase in pressure at the glomerular capsule and a decrease in the GFR. Excessive loss of protein-free fluid from vomiting, diarrhoea, use of diuretics or excessive sweating can increase glomerular capillary oncotic pressure and decrease the GFR. Renal disease can also cause changes in pressure relationships by altering capillary permeability and the surface area available for filtration (these issues are discussed in more detail in Chapter 30). The GFR is directly related to renal blood flow. However, it is advantageous for the kidneys to have a constant blood pressure and flow. Therefore, there are mechanisms that control renal blood flow and hence GFR. These mechanisms can be separated into intrinsic and extrinsic controls.
Intrinsic control
In the kidneys, a local mechanism tends to keep the rate of renal blood flow and therefore the GFR fairly constant over a range of arterial pressures between 80 mmHg and 180 mmHg (see Fig. 28.14). This occurs because smooth muscle in the arteriole wall will contract (causing vasoconstriction) when the systemic blood pressure increases and will relax (causing vasodilation) when the systemic blood pressure drops. Therefore, both the renal blood flow and the GFR are relatively constant. This is called renal autoregulation and it is crucial to the GFR and hence urine output. The purpose of autoregulation of blood flow is to prevent large changes in the GFR when there are increases or decreases in systemic blood pressure. This enables the kidneys to still be effective in filtering the blood to maintain homeostasis, despite the alterations in blood delivery to the kidneys. Solute and water excretion and thus blood volume are regulated when arterial pressure changes.9
CHAPTER 28 The structure and function of the urinary system
Flow rate (mL/min)
renal blood flow
glomerular filtration rate
0
50
100
150
200
Arterial blood pressure (mmHg) FIGURE 28.14
Autoregulation of renal blood flow. Blood flow and the GFR are kept constant when arterial pressure is approximately between 80 mmHg and 180 mmHg. However, decreases in renal blood flow directly affect the GFR.
Another mechanism assists renal autoregulation, which is also known as tubuloglomerular feedback. As the GFR in an individual nephron increases or decreases, the macula densa cells in the distal convoluted tubule (of the juxtaglomerular apparatus) sense the increasing or decreasing amounts of filtered sodium. When the GFR and sodium content increases, the macula densa cells stimulate afferent arteriolar vasoconstriction, which causes a decrease in the GFR. The opposite occurs with decreases in the GFR and sodium at the macula densa. By these mechanisms, renal blood flow is autoregulated, irrespective of systemic blood pressure, and the GFR keeps relatively stable. Together, these processes are vital for ensuring that the blood is undergoing constant filtering by the kidney.
Extrinsic control
The extrinsic control mechanisms that control the GFR work to maintain a stable and constant systemic blood pressure. Two mechanisms are responsible for extrinsic control: the sympathetic nervous system and hormonal control as the renin-angiotensin-aldosterone system. SYMPATHETIC NERVOUS SYSTEM CONTROL
The blood vessels of the kidneys are innervated by the autonomic nervous system through sympathetic fibres that cause vasoconstriction and decrease renal blood flow. The afferent and efferent arterioles are richly innervated. There is no significant parasympathetic innervation. When systemic arterial pressure decreases to below 80 mmHg, increased renal sympathetic nerve activity activates the carotid sinus and the baroreceptors of the aortic arch (see Chapter 22). This stimulates vasoconstriction
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of the afferent arteriole and decreases both renal blood flow and the GFR. The decreased renal blood flow also reduces excretion of sodium and water, promoting an increase in blood volume and thus an increase in systemic pressure. Exercise, body position, and hypoxia also influence renal blood flow. Exercise and change of body position activate renal sympathetic neurons and cause mild vasoconstriction. This mechanism is particularly important in many hospitalised patients. Hypoxia (low tissue oxygen levels) influences renal blood flow by stimulating the chemoreceptors of the carotid and aortic bodies. This decreases renal blood flow due to sympathetic stimulation. Haemorrhage also induces intense sympathetic stimulation and vasoconstriction, and both the GFR and blood flow are reduced. Therefore, patients with hypoxia or haemorrhage can experience substantial changes in their blood flow to the kidneys, which can have deleterious effects on renal function. Remember that if the kidneys are unable to adequately filter the blood, then homeostasis of the blood cannot be maintained, and this can have a significant impact on health. THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM
The major hormonal regulator of renal blood flow is the renin-angiotensin-aldosterone system, which can increase systemic arterial pressure and change renal blood flow (see Fig. 28.15). Renin is an enzyme formed and stored in the cells of the arterioles of the juxtaglomerular apparatus (see Fig. 28.8). Several complex physiological mechanisms stimulate the release of renin, including decreased blood pressure in the afferent arterioles (which reduces the stretch of the juxtaglomerular cells), decreased sodium chloride concentration in the distal convoluted tubule and sympathetic nerve stimulation of β (beta)-adrenergic receptors on the juxtaglomerular cells.10 Renin is released from the juxtaglomerular cells into the blood and acts on the plasma protein angiotensinogen, which is produced by the liver. This interaction converts angiotensinogen to angiotensin I. An enzyme called angiotensin converting enzyme (ACE), which is found in the capillaries of the lungs, converts angiotensin I to angiotensin II. Angiotensin II has a number of effects, chiefly to increase systemic blood pressure and restore plasma volume. It is a powerful vasoconstrictor that causes the smooth muscle in the arterioles to constrict. Although angiotensin II is effective in increasing systemic blood pressure, it is degraded rapidly and therefore its effect is only temporary. Angiotensin II activates the secretion of other hormones, namely aldosterone and ADH. Aldosterone, released from the adrenal cortex, acts on the distal convoluted tubule to reabsorb water and sodium — when sodium is reabsorbed, water is reabsorbed too, as water usually follows sodium. This causes an increase in blood volume and a subsequent increase in blood pressure. ADH is released from the hypothalamus, stimulating the thirst centre and increasing water reabsorption at the distal convoluted tubule and collecting duct. This reabsorption of water also causes an increase in intravascular volume and assists in maintaining
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Kidney (juxtaglomerular cells)
Adrenal cortex
Lungs Angiotensin-converting enzyme, ACE Angiotensin II Angiotensin I Aldosterone
Liver
Kidney
Renin Angiotensinogen
Arterioles
Blood vessel
Vasoconstriction
FIGURE 28.15
The renin-angiotensin-aldosterone system. In response to a decline in blood volume or blood pressure, the kidneys secrete renin. The release of renin leads to conversion of angiotensinogen to angiotensin I, which is subsequently converted to angiotensin II. This acts on the adrenal glands to promote secretion of aldosterone. Aldosterone has three main functions: promoting reabsorption of sodium, promoting reabsorption of water, and promoting secretion of potassium. The effects include increased blood volume and blood pressure, which decreases urinary output.
water balance throughout the body. Therefore, the release of renin causes many physiological effects that work to increase blood pressure to normal and restore water balance. The renin-angiotensin-aldosterone system is a vital link in the intimate relationship between the cardiovascular and urinary systems. It is of note that a large percentage of individuals with hypertension control their blood pressure pharmacologically by taking medications called angiotensin converting enzyme (ACE) inhibitors. ACE inhibitors are also used to manage and prevent heart failure, and in people with diabetes, to slow the progression of renal damage. These drugs work by blocking the conversion of angiotensin I to angiotensin II, thereby causing vasodilation and a reduction in blood pressure. ACE inhibitors have names that are easy to remember by the ending ‘-pril’ — for example, captopril, enalapril and ramipril. Individuals who are taking ACE inhibitors often complain of a cough. This is thought to be related to the suppression of the angiotensin converting enzyme in the lungs.
Urine
F OCU S O N L E ARN IN G
Urine is normally clear yellow or amber in colour. It obtains its yellowish colour from a pigment of haemoglobin breakdown. Changes in colour often occur due to drugs, foods or vitamin supplements. Cloudiness may indicate the presence of bacteria, cells or high solute concentration. The pH ranges from 4.6 to 8.0, but it is normally acidic, providing protection against bacteria. Because the kidneys have such an important role in removing excess acid from the blood, it is expected that the urine will be acidic. Specific gravity is a measure of substance concentration. Distilled water that has no solutes has a specific gravity of 1.000. In contrast, any substance that contains solute, such as urine, will have a greater weight than distilled water and the specific gravity will be greater than 1.000. The specific gravity of urine ranges from 1.001 to 1.035, depending on the amount of solutes. For instance, the first passing of urine in the morning after waking will have a higher specific gravity than that obtained after drinking a large volume of water. The odour of urine is slightly aromatic, but urine can become pungent if left exposed to air. This is caused by an increase in ammonia due to bacterial contamination.
1 Discuss how renal autoregulation maintains a constant glomerular filtration rate.
Acidification of urine
2 Explain how the release of renin restores blood pressure and plasma volume to normal levels.
Hydrogen is secreted by the distal tubule and combines with non-bicarbonate buffers (i.e. ammonium and phosphate) for the elimination of acids in the urine. The distal tubule
CHAPTER 28 The structure and function of the urinary system
thus contributes to the regulation of acid–base balance by excreting hydrogen ions into the urine and by adding new bicarbonate to the plasma. The mechanism is similar to the conservation of bicarbonate by the proximal tubule, except that the hydrogen ion is excreted in the urine and influences acid–base balance (Fig. 28.16). (The specific Distal tubule cells
CO2
(dibasic phosphate)
H2CO3
CO2+H2O
HCO3
H+
HCO3
Na+
−
Na2HPO4
[Na2H H+ PO4]
−
NaHCO3
NaH 2 PO 4
NaHCO3
(monobasic phosphate)
A Bases Acids Buffers
Renal tubule cells
Blood capillary Glutamine (amino acid = contains NH2)
Glutamine
NH2
H+
(ammonia secreted into tubule) NH3 NaCl
NH3 H2CO
HCO3-
Na+ + ClNH3Cl-
NaHCO3 (basic salt absorbed into blood)
B
NaHCO3
NH4+ NH4Cl (weak acid salt = dissociates to form a few H+)
Tubular urine
FIGURE 28.16
Acidification of urine by tubule excretion of phosphate and ammonia. A Acidification of urine by excretion of H+ via phosphate buffers. B An amino acid moves into the tubule cell and forms ammonia (NH3) which is secreted into the urine and combines with H+ to form ammonium ion (NH4+) and an ammonium salt (NH4Cl). In exchange, the tubule cell absorbs a basic salt (mainly NaHCO3) into the blood from the urine.
873
mechanisms of acid–base balance and acid excretion are described in Chapter 29.) Urea is a major constituent of urine. The glomerulus freely filters urea, and tubular reabsorption depends on urine flow rate, with less reabsorption at higher flow rates. Approximately 50% of urea is excreted in the urine, and 50% is recycled within the kidney. This recycling contributes to the osmotic gradient within the medulla and is necessary for the concentration and dilution of urine. Because urea is an end product of protein metabolism, individuals with protein deprivation cannot maximally concentrate their urine.
Measures of renal function
To adequately assess renal function, determining the GFR would be appropriate. If the GFR is lowered, the production of urine is affected and therefore the body’s ability to excrete waste products is impaired. However, it is difficult to directly measure GFR; rather, an estimate GFR (eGFR) is based on the excretion of creatinine. In Australia all biochemistry results report eGFR.11 In clinical practice, eGFR leads to the diagnosis of renal impairment in many people. This may be due to a variety of reasons, but the main causes are type 2 diabetes mellitus or hypertension. Other causes include hypovolaemia (see Chapter 29), an alteration to renal blood flow such as bleeding, direct damage to the kidneys (infection and glomerular diseases), obstruction of the urinary structures that transport urine (kidney stones) and the ageing process. One of the first measures of renal function is the amount of urine produced. The volume of urine produced is crucial to adequate clearance and excretion of waste products. For instance, if there is damage to the kidneys, usually urine output (mL/hour) will be affected and the volume reduced. Therefore, a simple measure can inform the clinician that there may be an alteration to renal function. In addition, the chemical and physical composition of urine and blood provides vital clues to how well the kidneys are excreting waste. In the following sections we look at three common tests used to assess renal function: urinalysis (analysis of the urine) and two blood measures — urea and creatinine.
Urinalysis
Urinalysis provides the composition of the urine and therefore indicates how effectively the kidneys are processing waste. The test usually consists of a chemical reagent dipstick that is placed in fresh urine. The microscopic and chemical properties of the urine are determined by the change in colour of the reagent dipstick. The usual tests measure pH, red blood cells, white blood cells, protein, glucose, specific gravity and ketone bodies. Normal urine does not contain glucose or blood cells and only occasionally contains traces of protein, usually in association with rigorous exercise. However, detection of glucose, blood, protein or ketone bodies in urine should be investigated further (see Table 28.2).
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TABLE 28.2 Normal renal function tests TEST
NORMAL VALUE
INTERPRETATION
Colour
Amber–yellow
Drugs and foods may change colour
Turbidity
Clear
Purulent matter will make cloudy
pH
4.6–8.0
Bacteria create an alkaline urine
Specific gravity (density of distilled water = 1.000)
Represents concentrating ability or density of urine in relation to density of water (i.e. higher when contains glucose or protein; lower with dilute urine)
Adults
1.010–1.025
Infants
1.010–1.018
Blood
Negative
Bleeding along urinary tract
Bacteria
None
Infection
Red blood cells
Negative
Bleeding along urinary tract
White blood cells
Negative
Urinary tract infection
Crystals
Negative
May have potential for stones
Fat
Negative
Can be associated with nephrosis
Casts
Occasional
A few are normal, may represent renal disease
Bilirubin
Negative
Increases may cause dark orange colour
Ketones
Negative
Represents an increase in fat metabolism
Glucose
Negative
Usually signifies hyperglycaemia, may indicate diabetes mellitus
Protein
Negative-trace
Dysfunction of the glomerulus
3.0–8.0 mmol/L
Elevated with diseased kidneys
Urine
Microscopic urine
Urinary chemistry
Normal serum values Urea Creatinine
Elevated with decreased GFR
Adult male
0.06–0.12 mmol/L
Adult female
0.05–0.11 mmol/L
Child < 12 years
0.04–0.08 mmol/L
Potassium
3.8–4.9 mmol/L
Urea
Urea is found in both urine and the blood. It is formed due to protein metabolism in the liver. However, it is excreted by the kidneys, and therefore increases in urea in the blood indicate that renal function is not optimal. Urea is a major constituent of urine along with water. The glomerulus freely filters urea, and tubular reabsorption depends on urine flow rate, with less reabsorption at higher flow rates. The concentration of urea in the blood reflects glomerular filtration and urine-concentrating capacity.
Elevated in renal failure
Urea is filtered at the glomerulus and therefore the blood concentration of urea increases when glomerular filtration drops. In addition, because urea is reabsorbed by the blood through the permeable tubules, the blood concentration of urea rises in states of dehydration, acute kidney injury and chronic kidney disease when passage of fluid through the tubules slows. Urea also changes as a result of altered protein intake and protein catabolism. In isolation, it is not a reliable indicator of renal function. The normal range for urea in the blood of an adult is 3–8 mmol/L.
CHAPTER 28 The structure and function of the urinary system
Creatinine
Creatinine is a natural substance and byproduct of muscle metabolism and is released into the blood at a relatively constant rate (regardless of the level of physical activity). Creatinine is freely filtered at the glomerulus and therefore, like urea, the level of creatinine closely matches the GFR. Creatinine clearance provides a good measure of the GFR because only one blood sample is required in addition to a 24-hour volume of urine. The normal level of creatinine in the plasma is 50–120 µmmol/L (which is the equivalent of 0.05–0.12 mmol/L); however, this is dependent on the muscle mass of the individual and males have slightly higher values than females. The serum creatinine value is used in conjunction with the patient’s age and sex to calculate the eGFR.11 Patients with suspected kidney damage will have their creatinine and urea blood levels measured to ascertain the level of renal dysfunction and also to indicate when to provide therapies, such as dialysis (see Box 28.1).
F O CUS O N L E A R N IN G
1 Describe the features of urine. 2 Discuss how measures of urea and creatinine in the blood provide indications of GFR and kidney function.
Urinary structures The ureters
The urine formed by the nephrons flows from the distal convoluted tubule and collecting duct through the renal papillae (projections of the duct) and into the calyces and is collected in the renal pelvis (see Fig. 28.2). From the renal pelvis, urine is funnelled into the ureters (see Fig. 28.17). The word ureter comes from the Greek word ‘to make water’. The ureters are thin tubes that transport urine from the kidneys to the bladder. Each adult ureter is approximately 30 cm long and is composed of long, intertwining muscle bundles. The lower ends pass obliquely through the posterior aspect of the bladder wall. Contraction of the bladder during emptying compresses this end of the ureter, preventing urinary reflux. The close approximation of muscle cells permits the direct transmission of electrical stimulation and the resulting peristaltic activity (like the intestines in the digestive system) propels urine into the bladder. Peristaltic activity is affected by urine volume such that increasing flow rates increase peristalsis. Peristalsis is maintained even when the ureters are denervated (does not have a nerve supply), so ureters can be transplanted. The upper part of the ureter is innervated by the tenth thoracic nerve roots, with referred pain to the umbilicus. The innervation of lower segments arises from the sacral nerves, with referred pain to the vulva or penis.
BOX 28.1
875
Dialysis
When the kidneys are damaged or diseased such that metabolic waste is not cleared from the blood and urine production reduces, kidney failure may ensue. Kidney failure usually occurs when renal function declines by about 85–90%. If this does occur, there are two treatment options: dialysis and kidney transplant. Dialysis refers to the artificial cleaning of the blood and it provides a substitution for the kidneys, without performing all renal processes — for instance, the production of renal hormones. Once dialysis commences, it continues for the individual’s life, or until a kidney transplant is performed. There are two types of dialysis: • In haemodialysis blood is passed via an extracorporeal circuit (occurring outside the body) to an artificial kidney, which is a filter called a dialyser. The blood is passed through the dialyser (which contains fibres) at a high flow rate and only the fluid content of the blood (plasma) moves through fine pores without the movement of blood cells, similar to the glomerulus of the nephron. At the same time, fluid called dialysate is passed around these fibres, without coming into contact with the blood. This enables the balancing of metabolites and electrolytes in the blood; the fluid essentially washes the blood such that elevated values are returned to homeostatic balance. Blood is then returned to the individual. A complete cycle of haemodialysis usually takes about 4 hours, and occurs about 3 times per week. • In peritoneal dialysis, dialysate flows via gravity into the individual’s peritoneal cavity via a catheter that is permanently inserted into the peritoneal space. The peritoneal cavity acts as a reservoir for fluid and provides an excellent filter for the removal of metabolites and excess fluid via the process of diffusion. In this type of dialysis the individual’s peritoneal cavity acts as the kidney. The fluid sits in the cavity for a period of time and is then drained out via the same catheter. There are disadvantages and advantages to both types of dialysis. For example, haemodialysis requires the individual to be attached to a dialysis machine for many hours while the blood is continuously washed. The individual must restrict their fluid, sodium and potassium intake between dialysis treatments. Peritoneal dialysis requires a large volume of fluid to reside in the peritoneal cavity, which can provide a heavy feeling to many individuals; however, dietary restrictions are not as strict compared with haemodialysis. The options for individuals are based on both medical and lifestyle considerations.
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FIGURE 28.17
Ureters shown with dye. The renal pelvis can be seen and the long slender ureters arising from them (arrows).
Ureter
Cut edge of peritoneum Smooth muscle Trigone
Opening of ureter
Epithelium
Opening of ureter Internal urinary sphincter
FIGURE 28.18
The urinary bladder. The urinary bladder is the site for storing urine. Urine empties into the urinary bladder through the two ureters, which pass behind the bladder and open into the inferior section of the bladder. Urine empties from the urinary bladder through the urethra.
The bladder
The urinary bladder is a bag made of smooth muscle fibres that is a temporary storage area for urine (see Fig. 28.18). It would be inappropriate to continually pass urine, as it is constantly being formed; therefore, the bladder stores urine until ready for urination. The bladder is situated in the pelvic cavity, behind the symphysis pubis. The position of the bladder varies with age and gender. In females, it is in an anterior position compared to the vagina and uterus. In males, it is anterior to the rectum. The bladder is lined
with transitional epithelium (cells that can change shape; see Chapter 3) and as it fills with urine, the walls distend and the layers of transitional epithelium slide past each other and become thinner. This epithelium maintains an important barrier function to prevent movement of water and solutes between the urine and the blood.12 The smooth muscle layer is called the detrusor muscle and it is important in the process of passing urine (see below — micturition), and the trigone is a smooth triangular area between the openings of the two ureters and the urethra. The bladder has a profuse blood supply, accounting for the bleeding that readily occurs with trauma, surgery or inflammation. The bladder can greatly expand and hold large volumes of urine. In most cases, when the bladder contains approximately 500 mL of urine, the individual will have the urge to urinate. However, the bladder can hold considerably more urine and in some cases has a volume in excess of 1 L. You may well have experienced this — the bladder can be palpated and in some cases seen as the distension moves superiorly into the abdominal cavity. If there is a reduction in the volume of urine that is voided, a bladder ultrasound can be performed to determine residual urine volume.
The urethra
The urethra extends from the inferior side of the bladder to the outside of the body. A ring of smooth muscle forms the internal urethral sphincter at the junction of the urethra and the bladder. The external urethral sphincter is composed of skeletal muscle and is under voluntary control. The entire urethra is lined with mucus-secreting glands. The female urethra is short (3 to 4 cm) compared with the male urethra (18 to 20 cm); for this reason, females are more prone to urinary tract infections. In males, the urethra has three segments: (1) the prostatic urethra is closest to the bladder — it passes through the prostate gland and contains the openings of the ejaculatory ducts (note that the prostatic urethra ‘tunnels’ through the prostate gland without mixing with the contents of the prostate gland); (2) the membranous urethra passes through the floor of the pelvis; and (3) the cavernous segment forms the remainder of the tube — it is surrounded by erectile tissue and contains the openings of the bulbourethral mucous glands.
Micturition The process of emptying urine from the bladder is called micturition (see Fig. 28.19). This term is not used extensively in clinical practice — terms such as ‘voiding’ and ‘urinating’ are more commonly used. The process is involuntary in children and in some older individuals, and in pregnancy micturition may be affected. There are a number of stages to micturition and it commences when the bladder wall is stretched due to urine
CHAPTER 28 The structure and function of the urinary system
877
filling the bladder. When the bladder accumulates 250 to 300 mL of urine, this initiates the micturition reflex, which is controlled by the micturition centre in the pons. Nerve impulses, stimulated by mechanoreceptors responding to the stretching of tissue, are sent to the sacral level of the spinal cord. The innervation of the bladder and internal urethral sphincter is supplied by parasympathetic fibres of the autonomic nervous system. This sends action potentials along the parasympathetic neurons that contract the detrusor muscle of the bladder. At the same time, the internal urethral sphincter relaxes and the individual feels the urge to void. Impulses from higher brain centres inhibit the relaxing of the external urinary sphincter and while the individual has the urge to void, conscious control inhibits micturition. Small children are unable to control when they empty their bladders, as they have not yet learnt how to perform this conscious control. As urine accumulates in the bladder, the urge to void becomes greater; at an appropriate time, conscious control allows relaxation of the external urinary sphincter and urine flows out. During micturition, contraction of the bladder compresses the lower end of the ureters, preventing reflux, which is important in preventing infections.
FIGURE 28.19
Micturition. 1 As the bladder fills with urine it causes stretch receptors on the bladder wall to initiate action potentials. 2 Nerve impulses are sent to the sacral region (S2–S4) of the spinal cord with increasing frequency as the bladder fills. 3 Parasympathetic fibres at the sacral level are activated, causing the detrusor muscle to contract. 4 As urine continues to fill the bladder, nerve impulses are sent with increased frequency to the pons (micturition centre) and the cerebral cortex, which ascertains the urge to urinate. 5 Signals sent back to the sacral region inhibit the external sphincter and the individual can consciously prevent urination. 6 When the individual wants to urinate, nerve impulses are transmitted to the pontine micturition centre, coordinating the detrusor muscle to contract and simultaneously reducing nerve impulses to the internal and external sphincters, which cause them to relax and the individual passes urine.
FOCU S ON L EA RN IN G
1 Describe the urinary structures and how they are connected. 2 Explain the micturition reflex and how urine is passed from the bladder.
Renal development occurs late in pregnancy. At birth, the renal blood flow and GFR increase due to a decrease in vascular resistance, and the loss of excretion of wastes via the placenta. The kidneys occupy a large region of the posterior abdominal wall. The ureters are shorter in children compared to adults. Glomerular filtration in infants does not reach adult values until 1–2 years of age, and newborns have a decreased ability to efficiently remove excess water and solutes. Their shorter loops of Henle also decrease concentrating ability and produce more dilute urine than that produced by adults. Risks
for metabolic acidosis are increased during the first few months of life while the mechanisms for excreting acid and retaining bicarbonate are maturing. These normal developmental processes result in a narrow safety margin for fluid and electrolyte balance when there is any disturbance such as diarrhoea, infection, improper feeding or fluid replacement. An increased risk of toxicity accompanies drug administration. Low-birth weight infants are at increased risk for low nephron numbers and chronic kidney disease as adults.
PAEDIATRICS
Paediatrics and the urinary system
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Part 4 Alterations to body maintenance
Ageing and the urinary system
CONCEPT MAP
Decreased renal blood flow
Decreased size and weight of nephrons
Decreased bladder innervation
or excessive water loads. Tubular transport changes with ageing. Reabsorption of glucose, bicarbonate and sodium may be delayed and drugs eliminated by the kidneys can accumulate in the plasma, causing toxic reactions; drug dosage should be carefully evaluated. Impairment in renal blood flow, hormonal regulatory systems and use of medications may alter sodium and water balance. Furthermore, the elderly often have impaired thirst, and water intake may alter water balance. The presence of comorbid conditions, such as hypertension and diabetes mellitus, accelerates the decline of renal function. The effects of ageing on the urinary system are summarised in Fig. 28.20.
Decreased bladder capacity
Increased urinary muscle weakness
leads to Decreased GFR
Decreased size and weight of kidney
Change in structure of female urethra causes
Decreased sensation of filling
Decreased sphincter tone manifests as
manifests as
manifests as Decreased excretory and reabsorptive capabilities of tubules
Increased risk of incontinence
Difficulty starting urinary stream
results in
Decreased excretion of drugs and metabolites
Decreased secretion of H+
Decreased urine concentration
FIGURE 28.20
The effects of ageing on urinary and renal function.
Increased renal threshold of glucose
Decreased glycosuria
Loss of diurnal excretory pattern manifests as Nocturia
AGEING
Throughout the life span, renal changes occur in response to an increased workload. Structural changes commonly occur in the kidney with ageing, including loss of renal mass, arterial sclerosis, an increased number of sclerotic glomeruli, loss of tubules, and interstitial fibrosis. Specifically, kidneys undergo atrophy (a decrease in size). In addition, there is a loss of nephrons due to a change in renal blood flow. Nephron loss accelerates between 40 and 80 years of age. These changes contribute to a slow decline in GFR in most individuals, but generally it is not significant enough to lead to severe loss of renal function. As the number of nephrons decreases and degenerative changes occur, nephrons are less able to concentrate urine and less able to tolerate dehydration
CHAPTER 28 The structure and function of the urinary system
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chapter SUMMARY The structure of the kidneys • The kidneys are paired structures lying bilaterally between the twelfth thoracic and third lumbar vertebrae. • The right kidney is slightly lower than the left; it is displaced downwards by the superior position of the liver. • Each kidney is composed of an outer cortex and an inner medulla. • The calyces join to form the renal pelvis, which is continuous with the upper end of the ureter. • The nephron is the urine-forming unit of the kidney and is composed of the glomerulus, proximal convoluted tubule, loop of Henle, distal convoluted tubule and collecting duct. Each kidney contains approximately 1.2 million nephrons. • The glomerulus contains loops of capillaries. The capillary walls serve as a filtration membrane for the formation of primary urine. • The proximal convoluted tubule is lined with microvilli to increase surface area and enhance reabsorption. • The hairpin loop of Henle transports solutes and water, contributing to the production of concentrated urine as more reabsorption of water occurs here. • The renal arteries supply blood to the nephrons via the interlobar and arcuate arteries. The afferent arteriole connects to the glomerular capillaries; the efferent arteriole arises from the glomerular capillaries and forms the peritubular capillaries, where reabsorption takes place. • The juxtaglomerular apparatus is a group of specialised cells that release renin. These cells detect blood pressure changes within the afferent vessel and are integral to blood pressure control and the glomerular filtration rate.
The function of the kidneys • The major function of the nephrons is urine formation, which involves the processes of glomerular filtration, tubular reabsorption and tubular secretion. • Glomerular filtration is favoured by capillary hydrostatic pressure and opposed by oncotic pressure in the capillary and hydrostatic pressure in glomerular capsule. The net filtration pressure is the sum of forces favouring and opposing filtration and there is a net outward pressure that allows substances to move from the capillary into the glomerular capsule. • The proximal convoluted tubule reabsorbs about 60– 70% of the filtered sodium and water and 90% of other electrolytes.
• About 15% of water is reabsorbed in the loop of Henle. • The distal convoluted tubule and collecting duct adjust the solute concentration and the amount of water that needs to be reabsorbed. In addition, sodium is reabsorbed by the distal convoluted tubule and collecting duct under the regulation of the hormone aldosterone. Potassium is actively secreted in these segments and is also controlled by aldosterone. • Tubular secretion is the final process in the formation of urine. Toxins and byproducts of metabolism are moved from the peritubular capillaries into the tubules for elimination. It is essentially reabsorption in reverse. • The concentration of the final urine is a function of the level of antidiuretic hormone, which stimulates the distal convoluted tubule and collecting duct to reabsorb water. • Renal blood flows at about 1000–1200 mL/min (20–25% of cardiac output). • The glomerular filtration rate is the filtration of plasma per unit of time (mL/min) and is directly related to the perfusion pressure of renal blood flow. • The glomerular filtration rate is approximately 120 mL/ min and 99% of filtrate is reabsorbed. • Blood flow through the glomerular capillaries is maintained at a constant rate in spite of a wide range of arterial pressures. • Autoregulation of renal blood flow and neural regulation of vasoconstriction maintain a constant GFR. • Renin is an enzyme secreted from the juxtaglomerular apparatus and causes the generation of angiotensin, a potent vasoconstrictor. This occurs when renin acts on angiotensinogen, which permits the conversion of angiotensinogen to angiotensin I. Angiotensin converting enzyme converts angiotensin I to angiotensin II, increasing systemic blood pressure and restoring plasma volume. The renin-angiotensin-aldosterone system is thus a regulator of renal blood flow.
Urine • Urine is normally clear yellow or amber in colour and its pH ranges from 4.6 to 8.0. Urine is slightly aromatic in odour but can become pungent if exposed to air due to an increase in ammonia from bacterial contamination. • Urinalysis is performed to measure both microscopic and chemical properties of the urine. It is used to provide clues about the cause of the renal dysfunction. • Both the plasma urea and creatinine concentration levels provide a good indication of glomerular function. Urea is an indicator of hydration status; creatinine is measured to monitor progressive renal dysfunction.
Continued
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Part 4 Alterations to body maintenance
• Creatinine, a substance produced by muscle, is measured in both plasma and urine to calculate a commonly used clinical measurement of the glomerular filtration rate.
• Control of the micturition reflex occurs when conscious control of the external sphincter takes place and urine is released from the bladder.
Urinary structures
Paediatrics and the urinary system
• The ureters are thin tubes that extend from the renal pelvis to the posterior wall of the bladder. Urine flows through the ureters by means of peristaltic contraction of the muscles. • The bladder is a bag that acts as a temporary storage area for urine. It is composed of the detrusor and trigone muscles and is innervated by parasympathetic fibres. • The urethra extends from the inferior side of the bladder to the outside of the body. It is short in females (3–4 cm) compared with in males (18–20 cm).
• Infants and children have more dilute urine than do adults because of higher blood flow and shorter loops of Henle. • Children are more affected than adults by fluid imbalances resulting from diarrhoea, infection or improper feeding because of their limited ability to quickly regulate changes in pH or osmotic pressure.
Micturition • When accumulation of urine reaches approximately 250– 300 mL, mechanoreceptors in the bladder wall, which respond to the stretching of tissue, stimulate the micturition reflex.
Ageing and the urinary system • Older adults have a decreased ability to concentrate urine and are less able to tolerate dehydration or water loads because they have fewer nephrons. • Response to acid–base changes and reabsorption of glucose are delayed in older adults. • In older adults, drugs eliminated by the kidneys can accumulate in the plasma, causing toxic reactions.
CASE STUDY
A DULT Angela is studying nursing at university and is trying to work out why urine volume varies according to the volume of fluids ingested and the level of physical activity of the individual. A simple practical experiment was conducted in the laboratory where three individuals had to drink 1 L of water, drink 1 L of water and exercise for 30 minutes, or just exercise for 30 minutes without ingesting any water. All the individuals had to measure the volume of their urine every 30 minutes for the next 2 hours. (The assumption was made that all individuals were normally hydrated and had normal renal function). Angela noticed that the individual who drank water only produced the largest volume of urine, followed by the individual who exercised and drank fluid, with the exerciseonly individual producing the lowest volume of urine.
1 2
3 4
5
Name the hormone responsible for the increase in urine volume and explain its actions. Describe why the individuals who drank the water (one exercising, the other not) had different urine volumes. Discuss why the individual who exercised only but did not ingest water still produced urine. Discuss whether there would have been differences in the volume of urine produced if the individual who exercised and drank fluid had ingested a drink with a high sodium concentration. Explain any differences in the osmolality of the urine for the three different individuals.
CASE STUDY
A GEING Joseph is 85 years old, living at home with his wife. He is a non-smoker (although he did smoke cigarettes heavily until 10 years ago) and has complained to his doctor of needing to urinate frequently. Recently his doctor has been concerned about his increasing blood pressure and his obesity which may increase his risk of developing chronic kidney disease.
1
Describe the physiological mechanisms that have led to an increase in urine output in the elderly. 2 Explain how increased urine output reflects changes in the nephron. 3 Identify the risk factors likely to reduce renal function. What is the physiological mechanism for this?
CHAPTER 28 The structure and function of the urinary system
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REVIEW QUESTIONS 1 Explain the anatomical location of the kidneys and the components that allow urine to be transported out of the body. 2 Describe the features of a nephron, with particular reference to the glomerulus and tubules. 3 Describe the glomerular filtration membrane and how fluid moves through it. 4 Outline the locations of the juxtaglomerular apparatus and macula densa, and the significance of their position in the nephron. 5 Discuss the differences between glomerular filtration, tubular reabsorption and tubular secretion.
6 Explain how concentrated urine is formed. 7 Discuss the role of antidiuretic hormone in urine concentration and the conditions that promote its release. 8 Outline how renin released at the afferent arteriole increases systemic blood pressure. 9 Describe the composition of urine and explain what is measured in urinalysis. 10 Describe how urine flows from the ureters to the bladder and passes through the urethra during micturition.
Key terms
CHAPTER
29
Fluids and electrolytes, acids and bases Deanne Hryciw and Ann Bonner
Chapter outline Introduction, 883 Fluid balance, 883 The distribution of body fluids, 883 Water intake and output, 883 Water movement between the plasma and interstitial fluid, 884 Water movement between the interstitial fluid and intracellular fluid, 885 Alterations in water movement, 885 Electrolyte balance, 889 Sodium, chloride and potassium balance, 889
882
Alterations in sodium, chloride and water balance, 891 Alterations in potassium balance, 895 Calcium, phosphate and magnesium, 899 Acid–base balance, 901 Acid and pH, 901 Buffer systems, 902 Acid–base imbalances, 904 Ageing and the distribution of body fluids, 906
acidaemia, 904 acidosis, 901 aldosterone, 889 alkalaemia, 904 alkalosis, 901 anuria, 898 blood pressure, 884 buffers, 902 capillary hydrostatic pressure, 884 capillary oncotic pressure, 885 compensation, 902 correction, 902 dehydration, 893 extracellular fluid (ECF), 883 first spacing, 887 hypercalcaemia, 899 hyperkalaemia, 898 hypernatraemia, 892 hypervolaemia, 888 hypocalcaemia, 899 hypocapnia, 905 hypochloraemia, 894 hypokalaemia, 895 hypomagnesaemia, 901 hyponatraemia, 893 hypophosphataemia, 899 hypovolaemia, 887 interstitial fluid, 883 interstitial hydrostatic pressure, 885 interstitial oncotic pressure, 885 intracellular fluid (ICF), 883 intravascular fluid, 883 lymphoedema, 887 metabolic acidosis, 905 metabolic alkalosis, 906 oedema, 885 oliguria, 898 osmoreceptors, 888 polyuria, 892 respiratory acidosis, 904 respiratory alkalosis, 905 second spacing, 887 third spacing, 887 total body water, 883
CHAPTER 29 Fluids and electrolytes, acids and bases
Introduction The cells of the body live in a fluid environment with an electrolyte and acid–base concentration maintained within a narrow range. Changes in electrolyte concentration affect the electrical activity of nerve and muscle cells and cause movement of fluid in or out of cells. Alterations in acid–base balance disrupt cellular functions. Fluid fluctuations also affect blood volume and cellular function. Disturbances in these functions are common, particularly in those who are hospitalised, and can progress to become life threatening. Understanding how alterations occur and how the body compensates or corrects the disturbance is important for understanding many pathophysiological conditions. Balance of fluids and electrolytes is controlled mainly by the renal system, so that a healthy kidney is essential to maintaining homeostasis. Important hormones that act on the kidneys such as antidiuretic hormone (ADH) and the renin-angiotensin-aldosterone system are essential to normal fluid and electrolyte balance. Hormone disturbances are likely to interfere with fluid and electrolyte balance (refer to Chapter 11). Acid–base balance is extremely well controlled in the body. Normally, blood pH is maintained within a very narrow range and corrections are implemented if pH starts to fall outside the normal range. Both the lungs and the kidneys are critical organs in maintaining acid–base balance.
Fluid balance
883
the fluid within cells, which is about two-thirds of total body water. Extracellular fluid (ECF) is all the fluid outside the cells, which constitutes the remaining fluid volume and is further divided into smaller compartments: the interstitial fluid (the space between the cells and outside the blood vessels) and the plasma or intravascular fluid (see Fig. 29.1). Note that the plasma volume of 3.5 L shown in Fig. 29.1 is substantially lower than the average total blood volume of 5 L, as the blood volume consists of plasma (the liquid component of blood) plus the cellular components. Additional smaller compartments of extracellular fluid include lymph, cerebrospinal fluid, synovial fluid, sweat, urine, and pleural, peritoneal, pericardial and intraocular fluids. Although the amount of fluid within the various compartments is relatively constant, water and electrolytes are exchanged between the compartments to maintain their unique compositions. The percentage of total body water varies with the amount of body fat and age. Because fat is water repelling (hydrophobic), very little water is contained in adipose (fat) cells. The constant balancing between body compartments allows the body to maintain homeostasis.
Water intake and output
The distribution and the amount of total body water change with age (see the Paediatrics and Ageing sections below), and although daily fluid intake may fluctuate widely, the body regulates water volume within a relatively narrow range. The primary sources of body water are fluid intake, usually by drinking, ingestion of water from food and water
The distribution of body fluids
All fluids within the body compartments constitute the total body water, which is about 60% of adult body weight (see Table 29.1) but is higher in infants. The volume of total body water is usually expressed as a percentage of body weight in kilograms — 1 L of water weighs 1 kg and hence the total volume of body water for a 70 kg male is about 42 L. It is important to consider that data on the ‘average’ body size are based on a 70 kg male, which is not a particularly large person. Fluid levels are actually lower in those who are obese (refer to Table 29.1), as a result of the lower proportion of fluid stored in fat cells as well as an increase of surface area for sweat loss; hence, those who are obese are more susceptible to dehydration. Body fluids are distributed among functional compartments or spaces. Intracellular fluid (ICF) comprises all
TABLE 29.1 Total body water percentage in relation to body weight BODY BUILD
ADULT MALE
ADULT FEMALE
INFANT
Normal
60
50
70
Lean
70
60
80
Obese
50
42
60
FIGURE 29.1
The distribution of body fluids. The majority of the total body water is located within the cells in the intracellular fluid. The extracellular fluid is located mainly in the interstitial fluid compartment and plasma.
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Part 4 Alterations to body maintenance
H2O
H2O
Water gained from metabolism 10%
Water lost through faeces and sweat
12% Water vapour lost through lungs
30%
28%
Water gained in moist food
Water lost through skin
60% (1500 mL)
60% (1500 mL)
Water gained in drinks
Water lost in urine
Intake (2500 mL)
Output (2500 mL)
FIGURE 29.2
Water balance.
obtained from the metabolism of food. Normally, most water is lost through urine, with lesser amounts lost through faeces, sweat and lungs (insensible water loss) (see Fig. 29.2). Overall, approximately 2.5 L of fluid enters and exits the circulation per day; this balance of input and output maintains homeostasis.
Water movement between the plasma and interstitial fluid
Water crosses cell membranes easily for exchange between fluid compartments. The distribution of water and the movement of nutrients and waste products between the capillary and interstitial spaces occur as a result of changes in hydrostatic pressure (pushes water) and osmotic (oncotic) pressure (pulls water) at the arterial and venous ends of
the capillary. Although water, sodium, and glucose readily move across the capillary membrane, plasma proteins do not cross the capillary membrane due to their large size. These proteins, particularly albumin, maintain effective osmolality by generating plasma oncotic pressure. Importantly, hypoalbuminaemia, the result of a decline in albumin production, is clinically common as it occurs in acute or prolonged illness. Water crosses cell membranes easily to be exchanged between fluid compartments. As blood flows from the arterial to the venous end of the capillary, four main forces determine whether fluid moves (1) out of the capillary and into the interstitial space or (2) back into the capillary from the interstitium: • Capillary hydrostatic pressure, (otherwise known as the blood pressure) is present within all blood vessels.
CHAPTER 29 Fluids and electrolytes, acids and bases
This pressure tends to force water outwards from the capillary to the interstitial space. • Capillary oncotic pressure occurs as proteins tend to attract fluid; there is a high level of protein in the blood and hence there is a reasonable amount of oncotic pressure, which draws water from the interstitial space into the capillary. The additional forces in the interstitium tend to be quite low: • Interstitial hydrostatic pressure, due to the presence of fluid within the interstitium, facilitates the inward movement of water from the interstitial space into the capillary, as well as into the lymphatic vessels (as explained below). • Interstitial oncotic pressure, due to proteins in the interstitium, osmotically attracts water from the capillary into the interstitial space. We will now consider Starling’s law of the capillary, which explains how these forces interact in the movement of fluid back and forth across the capillary wall, which results in net filtration: Net filtration = Forces favouring filtration − Forces opposing filtration Forces favouring filtration = Capillary hydrostatic pressure and interstitial oncotic pressure Forces opposing filtration = Capillary oncotic pressure and interstitial hydrostatic pressure
At the arterial end of the capillary, capillary hydrostatic pressure exceeds capillary oncotic pressure and so fluid exits the capillary and moves into the interstitial space (see Fig. 29.3). At the venous end of the capillary, capillary
885
hydrostatic pressure is actually less than at the arterial end, mainly due to the rapid exit of water from the arterial end. Capillary oncotic pressure is the same at the venous and arterial ends, as the amount of protein in the vessel does not change. As a result, capillary oncotic pressure exceeds capillary hydrostatic pressure at the venous end and so fluid is attracted back into the capillary (see Fig. 29.3). The pressure of fluid within the interstitial space is extremely low (about 10 mmHg), as the fluid that is not drawn back into the bloodstream is constantly drained by the lymphatic vessels. Because albumin does not normally cross the capillary membrane, interstitial oncotic pressure is normally minimal. A reasonably large volume of approximately 3 L is drained from the interstitium by the lymphatic system per day. Similarly, oncotic pressure within the interstitial space is also very low, as there is very little protein in this area. Therefore, it is the pressures within the capillary that determine whether fluid exits or enters the bloodstream.
Water movement between the interstitial fluid and intracellular fluid
Water moves from the interstitial space into the cells primarily as a function of osmotic forces. The oncotic force of proteins, which is relatively constant within the cell, draws water into the intracellular fluid. Water moves freely by diffusion through the lipids of the cell membrane and through aquaporins, which are water channel proteins that provide permeability to water.1 Sodium is responsible for the ECF osmotic balance, and potassium maintains the ICF osmotic balance. The osmotic force of ICF proteins and other non-diffusible substances is balanced by the active transport of ions out of the cell. Water crosses cell membranes freely, so the osmolality of the total body water is normally at equilibrium. Normally the ICF is not subject to rapid changes in osmolality, but when ECF osmolality changes, water moves from one compartment to another until osmotic equilibrium is re-established. This means that if the cell is low in fluid, it is easily corrected by fluid crossing the cell membrane and entering the cell, so homeostasis of fluid balance at the cell is maintained (see Fig. 29.4). On the other hand, if the total body fluid volume is low, water will exit the cells. Unfortunately, even the sensitive neurons of the brain cannot be protected from this water loss, which may explain why some people experience headache when they have not consumed enough water. This can progress to more severe symptoms if the lack of fluid is not addressed.
Alterations in water movement Oedema
FIGURE 29.3
Water movement between the plasma and the interstitial space.
Oedema, from the Greek word ‘to swell’, is the excessive accumulation of fluid within the interstitial spaces. The forces that promote fluid movement from the capillaries into the tissues are increased capillary hydrostatic pressure, lowered plasma oncotic pressure, increased capillary membrane permeability and lymphatic channel obstruction (see Fig. 29.5).2
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blood vessel ↓ capillary oncotic pressure
BA normal amount of water
results in
results in
↑ fluid exits the blood
↓ fluid drawn back into blood
causes water enters to restore homeostasis
oedema
BB
causes ↑ fluid exits the blood
cell is deficient in water, so water enters cell
results in
BC water exits to restore homeostasis
causes
↑ capillary permeability
causes ↓ lymphatic drainage
results in
↓ lymphatic vessel destruction
FIGURE 29.5
Mechanisms of increased interstitial fluid, causing oedema.
cell has too much water, so water exits cell
FIGURE 29.4
Water movement between the extracellular fluid (plasma and interstitial space surrounding the cells) and the intracellular fluid. In A, a normal amount of water is inside the cell. In B, a low intracellular fluid volume draws water from the plasma and interstitium, while in C a high intracellular fluid volume requires water to be moved to the plasma.
PATHOPHYSIOLOGY
Conditions that cause increased sodium and water retention lead to increased blood volume, which increases blood hydrostatic pressure, thereby contributing to oedema. Hypertension (which is common in Australia and New Zealand; see Chapter 23), heart failure and renal failure are common causes of oedema. Hydrostatic pressure increases as a result of venous obstruction, or sodium and water retention. Venous obstruction, particularly in the lower limbs, may result from decreased venous return due to lack of use of the skeletal muscle pump during standing, or while remaining seated on long-haul flights. This causes blood hydrostatic pressure to increase prior to the obstruction, pushing fluid from the capillaries into the
interstitial spaces and causing oedema. Thrombophlebitis (inflammation of veins), hepatic obstruction, tight clothing around the extremities, and prolonged standing are common causes of venous obstruction. Congestive heart failure, renal failure, and cirrhosis of the liver are associated with excessive sodium and water retention, which cause plasma volume overload, increased capillary hydrostatic pressure, and oedema. Even in healthy people oedema can occur; for example, when you have been standing upright for a lengthy period of time your feet swell as fluid moves into the interstitial spaces but is not reabsorbed at the same rate. Upon moving or lying down the fluid will quickly reabsorb and the swelling in your feet will subside. It is when oedema is in greater amounts and is associated with underlying disease that it is of most concern. Decreases in the amount of protein in the blood will lower plasma oncotic pressure. The decreased oncotic attraction of fluid within the capillaries causes filtered capillary fluid to remain in the interstitial spaces, resulting in oedema. This may occur with decreased plasma albumin (the main plasma protein) production, due to liver disease or protein malnutrition. Plasma proteins are also lost in some kidney diseases (see Chapter 30), serous drainage from open wounds, haemorrhage and burns.
CONCEPT MAP
↑ capillary hydrostatic pressure (hypertension)
interstitial fluid
Increased capillary permeability is an important part of the inflammatory process, as it allows leucocytes to exit the blood and reach the tissues. This increased permeability also occurs with trauma such as burns or crushing injuries, cancer and allergic reactions. Proteins escape from the vascular space, which draws fluid into the interstitial spaces, leading to oedema. The lymphatic system normally collects and drains interstitial fluid and a small amount of proteins. When lymphatic channels are blocked or surgically removed, proteins and fluid accumulate in the interstitial spaces causing lymphoedema.3 For example, lymphoedema of the arm or leg occurs after surgical removal of the axillary or femoral lymph nodes, respectively, for treatment of cancer. Inflammation or tumours may cause lymphatic obstruction, leading to oedema of the involved tissues.4 CLINICAL MANIFESTATIONS
Oedema may be localised or generalised. Localised oedema is usually limited to a site of trauma, as in a sprained ankle or the swelling of an area after surgery. Another kind of localised oedema occurs within organ systems and is usually a serious pathophysiological condition. These types of localised oedema include cerebral oedema, pulmonary oedema, pleural effusion (fluid accumulation in the pleural space around the lungs), pericardial effusion (within the membrane around the heart) and ascites (accumulation of fluid in the peritoneal space). Generalised oedema is manifested by a more uniform distribution of fluid in the interstitial spaces. Dependent oedema, in which fluid accumulates in gravity-dependent areas of the body, might signal more generalised oedema. Dependent oedema appears in the feet and legs when standing and in the sacral area and buttocks when supine (lying face up). It can be identified by pressing on tissues overlying bony prominences — a pit left in the skin indicates oedema, known as pitting oedema (see Fig. 29.6). Oedema is usually apparent as weight gain, swelling and puffiness, tight-fitting clothes and shoes, limited movement of affected joints and symptoms associated with the underlying condition. Fluid accumulations make it more difficult for nutrients and waste products to diffuse between the capillaries and tissues. Blood flow may also be impaired. Therefore, wounds heal more slowly and, with prolonged oedema, the risks of infection and pressure injuries over bony prominences increase. Oedema of specific organs, such as the brain, lung, or larynx, can be life threatening. EVALUATION AND TREATMENT
The underlying cause of the oedema should be determined and treated. Oedema may be treated symptomatically until the underlying disorder is corrected. Elevating the feet assists in lessening lower limb oedema. Restricting sodium and fluid intake and using diuretics to promote fluid excretion by the kidneys are often helpful.
CHAPTER 29 Fluids and electrolytes, acids and bases
A
887
BB
FIGURE 29.6
Pitting oedema in a patient with cardiac failure. A The limb is oedematous and when fingertip pressure is applied a depression appears in the tissue. B A depression (‘pit’) remains in the oedema for some minutes after firm fingertip pressure is applied.
Fluid spacing
When the distribution of fluid is normal between the intracellular and extracellular fluids, this is known as first spacing. In the development of oedema, second spacing occurs, as there is an excess of fluid located in the interstitial spaces. This excess fluid in the interstitium can be treated by changing pressures (such as elevating the limb to enhance venous return and lymphatic drainage) or using diuretic agents that cause water loss from the plasma, hence drawing the excess fluid from the interstitium back to the plasma. Alternatively, fluid may accumulate in an area that is not able to be drained easily; for example, fluid will pool around the damaged tissue of a burns site. Because this is not a normal fluid compartment that is exchanged with other body fluids, this is known as third spacing (see Fig. 29.7). It is difficult to return third space fluid to the body circulation. Dehydration may result, as fluid in the third space is not available for the circulation. Importantly, increasing fluid intake to correct the dehydration can worsen the third space fluid. Large amounts of water in the third space are difficult to treat. A main concern when large amounts of fluid accumulate in the third space is the risk of hypovolaemia and circulatory shock (see Chapter 23).
Water balance
Water balance is important in maintaining appropriate blood volume; blood volume is linked with blood pressure, such that a low blood volume (hypovolaemia) causes hypotension; this is compensated for by tachycardia in the otherwise healthy person. Fluid loss (dehydration) may occur from vomiting, diarrhoea or excessive sweating. For example, fluid is lost in someone with diarrhoea, as it passes through the intestines too quickly to be absorbed to replenish the blood volume. Fluid can also move from the plasma into
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Part 4 Alterations to body maintenance Normal
Red blood cells within small blood vessel
Third spacing
Increased red blood cells
Intracellular space Fluid escapes from blood into extracellular space
Extracellular space FIGURE 29.7
Fluid movements in third spacing. In normal tissue, the amount of fluid in the extracellular space is normal. However, in third spacing, excess fluid moves into the extracellular space, which accordingly increases in size and becomes the third space.
FIGURE 29.8
Diarrhoea causes fluid to exit the body rapidly, so that it cannot be absorbed into the bloodstream.
the cells lining the intestines to replace the fluid loss, which may result in hypovolaemia (see Fig. 29.8). Tachycardia is one way for the body to maintain homeostasis of blood flow to tissues until the overall water balance can be increased. Alternatively, hypervolaemia (increased blood volume), seen after an excessive intake of water, can cause hypertension and bradycardia. Water balance is regulated by antidiuretic hormone (ADH), which is secreted when the total plasma concentration (osmolality) increases or the circulating blood volume or blood pressure decreases. Increased plasma concentration occurs with either water deficit or sodium excess. The increased concentration stimulates hypothalamic osmoreceptors. In addition to causing thirst, these osmoreceptors signal the posterior pituitary gland to
release ADH. Thirst stimulates water drinking (see Fig. 29.9). In addition to causing thirst, these osmoreceptors signal the posterior pituitary to release ADH, which increases the reabsorption of water by the kidneys, so that water is retained rather than being lost in the urine (see Chapter 28). Urine concentration increases and the reabsorbed water increases the plasma volume, which in turn decreases plasma concentration, returning it towards normal. Water is the most effective fluid for rehydrating, as other fluid choices such as caffeinated drinks, alcohol and sugary soft drinks may actually contribute to dehydration (see Fig. 29.9). With further fluid loss (dehydration) from vomiting, diarrhoea, or excessive sweating, a decrease in blood volume and blood pressure often occurs. Other receptors are activated in addition to the hypothalamic osmoreceptors. Volume-sensitive receptors in the right and left atria of the heart and thoracic vessels, as well as the baroreceptors (nerve endings that are sensitive to changes in stretch and pressure) found in the aorta and carotid sinus become activated. These receptors stimulate the release of ADH from the pituitary gland, which then promotes the restoration of plasma volume and blood pressure. FOCU S ON L EA RN IN G
1 Describe the different body fluid compartments and the approximate proportion of fluid inside each one. 2 Discuss the pressures involved in the movement of water between the plasma, interstitial fluid, lymphatic vessels and intracellular fluid. 3 Explain how an increase in capillary hydrostatic pressure causes oedema, and how a decrease in capillary oncotic pressure causes oedema. 4 Describe what is meant by fluid being in the third space. 5 Discuss how water balance is controlled.
CHAPTER 29 Fluids and electrolytes, acids and bases
↓ Blood volume
↑ Sodium
CONCEPT MAP
↓ Body water
results in ↑ Blood sodium concentration stimulates Osmoreceptors in hypothalamus
stimulates
stimulates Thirst
inhibits the
Posterior pituitary release of ADH
Increased fluid intake
which targets
conscious choice of fluid type Alcohol, coffee
Kidneys reabsorb more water
causes
889
which results in
Less urine Increased blood volume and decreased blood sodium concentration
Soft drinks (sugary)
Water
Draws fluid into digestive tract Worsens the blood sodium concentration
Fluid lost in faeces
which results in
FIGURE 29.9
Mechanisms of fluid replacement to increase blood volume and decrease blood concentration. Note that the fluid that is consumed may not always be particularly useful in causing rehydration.
Electrolyte balance Sodium, chloride and potassium balance
The kidneys and hormones have a central role in maintaining sodium and water balance. Because water follows the osmotic gradients established by changes in sodium concentration, sodium and water balance are intimately related. Sodium and potassium are regulated by the renal effects of aldosterone.
Sodium
Sodium (Na+) is the main extracellular fluid ion and accounts for 90% of the ECF cations (positively charged ions). In conjunction with the constituent anions (negatively charged ions) chloride and bicarbonate, sodium regulates extracellular osmotic forces and therefore is a key regulator of water balance. Sodium is important in other functions, including
working with potassium and calcium in neuron signalling and regulating the acid–base balance (see Acid–base balance below), participation in cellular chemical reactions, and transport of substances across the cellular membrane. The distribution of electrolytes in body compartments is summarised in Table 29.2. The kidneys, in response to neural and hormonal mediators, maintain normal plasma sodium concentration within a narrow range (135–145 mmol/L), which is primarily via tubular reabsorption. After being filtered at the kidneys, the reabsorption of sodium through the kidney tubules is tightly controlled. Hormonal regulation of sodium balance is mediated by aldosterone produced and secreted from the adrenal cortex as a component of the renin-angiotensinaldosterone system. Aldosterone secretion is influenced by both circulating blood volume and plasma concentrations of sodium and potassium (aldosterone is secreted when sodium levels are decreased or potassium levels are increased). Aldosterone increases the reabsorption of sodium
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TABLE 29.2 The distribution of electrolytes in body compartments EXTRACELLULAR FLUID (MMOL/L)
INTRACELLULAR FLUID (MMOL/L)
Sodium
135–145
10
Potassium
3.5–5.0
150–160
ELECTROLYTES
Cations
Calcium
2.15–2.60
0
0.8–1.0
24
Bicarbonate
22–32
12
Chloride
95–110
4
Phosphate
0.8–1.5
100
16
65
Magnesium Anions
Proteins
aldosterone
sodium reabsorption water reabsorption potassium secretion (retention) (retention) (excretion) FIGURE 29.10
The effects of aldosterone on the kidneys.
and the secretion of potassium by the kidneys. As a result, sodium concentration of the extracellular fluid is enhanced and potassium is excreted with the urine (see Fig. 29.10; a full discussion of the important renin-angiotensinaldosterone system can be found in Chapter 28). When circulating blood volume or blood pressure is reduced, sodium levels are decreased or potassium levels are increased, renin produced by juxtaglomerular cells of the kidney, is released into the blood. Renin stimulates the formation of angiotensin I (from angiotensinogen). Angiotensin converting enzyme (ACE) in pulmonary vessels converts angiotensin I to angiotensin II, which stimulates the secretion of aldosterone and also causes vasoconstriction. The aldosterone then promotes renal sodium and water reabsorption, which increases blood volume (see Box 29.1). Aldosterone also causes excretion of potassium. Vasoconstriction elevates the systemic blood pressure and restores renal perfusion (blood flow). This restoration inhibits the further release of renin. In addition, other substances known as natriuretic peptides are released by the heart when there is an increase in blood volume and hence pressure, which may occur with heart failure or when there is an increase in mean arterial pressure.5 Atrial natriuretic peptide (ANP) is released
General rules relating sodium, chloride, potassium and water movement
BOX 29.1
1 Where sodium goes, water follows. 2 Where sodium goes, chloride follows. 3 Where sodium goes, potassium goes in the opposite direction. These rules apply on the condition that: • the membrane of the particular cell crossing must be permeable to allow both substances to cross • the individual is healthy.
by the atria, while brain natriuretic peptide (BNP, named because it was first identified in the brain) is released by the myocardial ventricles. These natriuretic peptides decrease the release of renin, thus increasing sodium and water excretion, and they also cause vasodilation. As a result, blood volume and blood pressure are decreased. Natriuretic peptides are sometimes called a ‘third factor’ in sodium regulation (increased glomerular filtration rate is considered the first factor and aldosterone the second factor).
Chloride
Chloride (Cl–) is in a high concentration in the extracellular fluid and its negative charge allows it to interact with the positively charged sodium to balance the electrical charge in the form of sodium chloride (NaCl, which is table salt). The transport of chloride is generally passive and follows the active transport of sodium, so that increases or decreases in sodium are proportional to changes in chloride. The concentration of chloride tends to be the ‘opposite’ to the concentration of bicarbonate (HCO3–), the other major extracellular anion, so that when there are high amounts of chloride, there are low concentrations of bicarbonate, and vice versa.
Potassium
Potassium (K+) is the major intracellular electrolyte; it is positively charged and is essential for normal cellular function (see Box 29.2). Most potassium (98%) of the body is located within cells. The intracellular fluid concentration of potassium is 150–160 mmol/L, while the extracellular fluid concentration is 3.5–5.0 mmol/L. The difference in concentration is maintained by the sodium–potassium pump (which requires ATP to pump the electrolytes against their concentration gradients), which returns 3 molecules of sodium to the extracellular fluid and 2 molecules of potassium to the intracellular fluid with each cycle (see Chapter 3). As the predominant intracellular ion, potassium exerts a major influence in regulating intracellular fluid concentration. In addition, potassium has a vital role in neuronal function, as it is essential for maintaining the resting membrane potential and mediating the action
CHAPTER 29 Fluids and electrolytes, acids and bases
BOX 29.2
891
TABLE 29.3 Water and solute imbalances
There’s no K in potassium
Have you ever wondered why the symbol for potassium is K, yet there is no ‘K’ in potassium? This is because the symbols for the chemical elements are based on Latin words. Fortunately, the names of some chemical elements in English are similar to Latin, so learning their symbols is somewhat easier. ENGLISH
LATIN
SYMBOL
Sodium
Natrium
Na+
Potassium
Kalium
K+
Calcium
Calcium
Ca2+
Chloride
Chlorum
Cl–
potential for the transmission of nerve impulses. It is also essential for neural control and muscular function of cardiac, skeletal and smooth muscle contractions. For this reason, disturbances in the potassium balance require urgent medical attention, as disruptions to neurons and cardiac muscle are life threatening. The kidneys are the most efficient regulator of potassium balance. Potassium is freely filtered at the glomerulus of the nephron, with most potassium subsequently being reabsorbed into the blood, mainly by the proximal convoluted tubule. However, potassium is also secreted by the kidneys as well — when plasma potassium concentration increases from increased dietary intake or shifts of potassium from the ICF to the ECF occur, potassium is secreted into the urine by the distal tubules. The fact that potassium is filtered, reabsorbed and secreted by the kidneys indicates that it is tightly regulated in the blood. Changes in the rate of filtrate (urine) flow through the kidneys also influence potassium secretion. When the flow rate is high, as with the use of diuretics, potassium is secreted into the urine. The gut may also sense the amount of K+ ingested and stimulate renal K+ excretion.2 Besides conserving sodium, aldosterone also regulates potassium levels. When plasma potassium concentration increases, aldosterone is released, stimulating the excretion of potassium into the urine by the kidneys. Aldosterone also increases the secretion of potassium from the sweat glands. Changes in the acid–base balance (or pH) also affect the potassium balance, as hydrogen ions (H+) inside the cell cause potassium to shift out of the cell to the extracellular fluid to maintain the balance of cations across the cell membrane (see later section on acid–base balance). Potassium tolerance is the ability of the body to adapt to increased levels of potassium intake over time. A sudden increase in potassium may be fatal (e.g. excess administered intravenously), but if the intake of potassium is slowly increased (particularly dietary sources), the kidneys can increase urinary excretion and maintain the potassium balance.
TONICITY
MECHANISM
Isotonic imbalance
Gain or loss of extracellular fluid resulting in a concentration equivalent to a 0.9% sodium chloride (table salt) solution (normal saline); no shrinking or swelling of cells
Hypertonic imbalance
Imbalance that results in an extracellular fluid concentration more than 0.9% sodium solution (i.e. water loss or solute gain); cells shrink in a hypertonic fluid
Hypotonic imbalance
Imbalance that results in an extracellular fluid concentration less than 0.9% sodium solution (i.e. water gain or solute loss); cells swell in a hypotonic fluid
Alterations in sodium, chloride and water balance
Alterations in sodium and water balance are closely related. Water imbalance may develop with gains or losses of sodium. Likewise, sodium imbalance occurs with alterations in body water volume. Generally, these alterations can be classified as changes in tonicity — the change in the concentration of solutes with relation to water (see Chapter 3). Alterations can therefore be classified as isotonic, hypertonic or hypotonic (see Table 29.3).
Isotonic alterations
Total body water changes may be accompanied by proportional changes in electrolytes, so that osmolality remains within the normal range of 280–300 mOsm/kg.3 For example, if an individual loses pure plasma or extracellular fluid, the fluid volume is depleted but the concentration and type of electrolytes remain in the normal range. The term isotonic refers to a solution that has the same concentration of solutes as the normal plasma concentration. HYPOVOLAEMIA
Hypovolaemia (isotonic fluid loss) is a low extracellular fluid volume (and hence low blood volume), which is caused by insufficient fluid intake, haemorrhage, severe wound drainage, excessive diaphoresis (sweating), vomiting or diarrhoea, or high doses of diuretic medications. This results in a decrease in the extracellular fluid volume, with weight loss, dryness of skin and mucous membranes, and decreased urine output. In hypovolaemia, both the fluid and extracellular sodium are lost together, as compared with dehydration, which is just the loss of water. Indicators of hypovolaemia include a rapid heart rate, flattened neck veins and normal or decreased blood pressure. In severe states, hypovolaemic shock can occur (see Chapter 23). Controlled rehydration using fluid and sodium is implemented with isotonic solutions of electrolytes and
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glucose given orally, intravenously or in some cases subcutaneously (hypodermoclysis). HYPERVOLAEMIA
Hypervolaemia (isotonic fluid excess) is a high extracellular fluid volume (and increased blood volume), which is most commonly the result of excessive administration of intravenous fluids (saline), hypersecretion of aldosterone (causing retention of sodium and water) or the effects of corticosteroid drugs (which cause renal reabsorption of sodium and water). As plasma volume expands, hypervolaemia develops with weight gain. The diluting effect of excess plasma volume leads to a decreased haematocrit and decreased plasma protein concentration, which can be ascertained using blood tests. The neck veins may distend and the blood pressure increases. Increased capillary hydrostatic pressure leads to oedema. Ultimately, pulmonary oedema and heart failure may develop. Fluid intake should be restricted to correct the hypervolaemia.
Hypertonic alterations
Hypertonic fluid refers to fluid where the solute concentration is higher than in the blood (and thus the solution also has less water than the blood). Within the body, such alterations develop when the concentration of the extracellular fluid is elevated above normal osmolality (greater than 300 mOsm/ kg).3 The most common causes are increased concentration of sodium (hypernatraemia) or deficit of extracellular fluid water. In both instances, the extracellular fluid hypertonicity seen in the plasma attracts water from the intracellular spaces, causing intracellular fluid dehydration. HYPERNATRAEMIA PATHOPHYSIOLOGY
Hypernatraemia occurs when serum sodium levels exceed 145 mmol/L. Hypernatraemia may be caused by either an acute gain in sodium or a net loss of water (see Fig. 29.11). Although sodium is mainly in the extracellular fluid, increased levels of sodium cause intracellular dehydration, as fluid will move out of the cells and into the extracellular fluid. This movement of water may cause hypervolaemia; however, if there is also an accompanying water loss with the hypernatraemia, both intracellular and extracellular dehydration may occur. Because chloride follows sodium, hypernatraemia is accompanied by hyperchloraemia (elevated chloride levels); however, no specific symptoms are associated with chloride excess. Increased sodium retention commonly occurs as a result of oversecretion of aldosterone (as in primary hyperaldosteronism) or oversecretion of adrenocorticotropic hormone (ACTH), which also causes increased secretion of aldosterone (as in Cushing’s syndrome). Less commonly there may be inappropriate administration of hypertonic saline solution (e.g. as sodium bicarbonate for treatment of acidosis during cardiac arrest). Dehydration, particularly in the elderly, is a common finding. Increased sodium concentration due to water deprivation or water loss is associated with fever or
Na Na+
Na+
volume of water in the extracellular fluid
+
Na+
normal sodium concentration
Na+ loss of water
Na+
Na+
Na+ Na+
Na+
gain of sodium Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+
FIGURE 29.11
Hypernatraemia may result from either loss of water or a gain in sodium in the extracellular fluid.
respiratory infections, which increase the respiratory rate and enhance water loss from the lungs. Similarly, profuse sweating can increase fluid loss. Elderly patients have a decreased thirst mechanism, making them more vulnerable to the effects of fluid loss, as insufficient water intake means that fluid is not being replaced. Decreased secretion of ADH (due to diabetes insipidus) or its decreased effectiveness (due to renal disease) can lead to insufficient retention of fluid by the kidneys, resulting in water loss. On the other hand, diabetes mellitus leads to glucose passing into the urinary filtrate — this glucose attracts water and hence water is lost from the body in urine. Polyuria (increased urinary volume above the normal 1.5 L per day), profuse sweating, and diarrhoea also cause water loss in relation to sodium. Insufficient water intake can cause hypernatraemia, particularly in individuals who are comatose, confused, immobilised, or are receiving gastric feedings. High amounts of dietary sodium rarely cause hypernatraemia in a healthy individual, as excess sodium is eliminated from the body by the kidneys. However, a high-sodium diet is not advised for those with illness or the majority of the population as this may contribute to hypertension. High sodium levels can occur with oversecretion of aldosterone, leading to increased sodium retention by the kidneys; this is associated with hypervolaemia as water is reabsorbed with the sodium. Because chloride follows sodium, hyperchloraemia (elevation of serum chloride concentration above 105 mmol/L) often accompanies hypernatraemia, as well as plasma bicarbonate deficits as in metabolic acidosis. There are no specific symptoms or treatment for chloride excess.
CLINICAL MANIFESTATIONS
The higher concentration of sodium in the extracellular fluid draws water out of the cells and intracellular dehydration ensues. This results in hypervolaemia and intracellular dehydration. Thirst, fever, dry mucous membranes and restlessness are associated with hypernatraemia as a result of water loss. Clinical manifestations include weight gain, bounding pulse (strong pulse), and increased blood pressure. Lethargy and irritability are also early symptoms, while the more serious central nervous system symptoms are quite late symptoms of hypernatraemia. These are related to alterations in membrane potentials and shrinking of brain cells and include muscle twitching and hyperreflexia (hyperactive reflexes), convulsions, coma and cerebral haemorrhage from stretching of veins. Rapid isotonic fluid replacement should be avoided, especially in the elderly, as it increases the risk of heart failure. EVALUATION AND TREATMENT
Investigations should be directed at assessing the presence of diabetes insipidus and appropriate treatment. The treatment of hypernatraemia is to give oral fluids or isotonic sodium-free fluid (5% dextrose in water) until the serum sodium level returns to normal. Fluid replacement must be administered slowly to avoid serious complications such as cerebral oedema or death.4 WATER DEFICIT PATHOPHYSIOLOGY
Dehydration refers to water deficit, but the term dehydration is commonly also used to indicate both sodium and water loss.5 Pure water deficits (hyperosmolar or hypertonic dehydration) are rare because most people have access to water. Individuals who are comatose or paralysed continue to have insensible water losses through the skin and lungs with a minimal obligatory formation of urine. Hyperventilation caused by fever can contribute to water deficit. The most common cause of water loss is increased renal excretion of water due to impaired function or diabetes insipidus (decreased ADH; see Chapter 11). CLINICAL MANIFESTATIONS
Marked water deficit is manifested by symptoms of dehydration: thirst, dry skin and mucous membranes, elevated temperature, weight loss and concentrated urine (with the exception of diabetes insipidus, when the urine is dilute). Skin turgor (ability to move back into normal place when pinched) may be normal or decreased. Symptoms of hypovolaemia include tachycardia, weak pulses and postural hypotension (a decrease in blood pressure with movement from lying or sitting to standing). EVALUATION AND TREATMENT
An elevated haematocrit and increased serum sodium concentration are associated with moderate water loss in addition to clinical signs and symptoms. Comparing plasma and urinary osmolarity assists in determining the magnitude of dehydration. In addition, physical examination and patient
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history are important in ascertaining dehydration causation. Determining the cause, such as assessing the patient for diabetes insipidus, directs treatment. Oral or intravenous rehydration therapy may be sufficient, although some patients may require administration of an antidiuretic hormone agent. Fluid replacement must be administered slowly enough to prevent very rapid movement of water into brain cells, which causes cerebral oedema, seizures, brain injury, and death. When intravenous replacement is required, 5% dextrose in water should be used because pure water lyses red blood cells.
Hypotonic alterations
Hypotonic fluids are those that have a lower solute concentration (are more dilute) than the blood. Hypotonic imbalances occur when the concentration of the extracellular fluid is less than normal (less than 280 mOsm/kg).3 The most common cause is sodium deficit (hyponatraemia) or water excess. Either leads to intracellular overhydration and cell swelling (oedema). When there is a sodium deficit, less water is required in the extracellular fluid and hence water moves into the cells where the osmotic pressure is greater. The plasma volume then decreases, leading to symptoms of hypovolaemia. With water excess, increases in both the intracellular and the extracellular fluid volume occur, causing symptoms of hypervolaemia and water intoxication with cerebral and pulmonary oedema. HYPONATRAEMIA PATHOPHYSIOLOGY
Hyponatraemia develops when the serum sodium concentration falls below 135 mmol/L. It occurs frequently among hospitalised elderly individuals. This may result from insufficient sodium due to sodium loss from the body or inadequate sodium intake, or dilution of the body’s sodium level by water excess (see Fig. 29.12). Sodium depletion usually causes hypo-osmolality with movement of water into cells. Pure sodium deficits are usually caused by vomiting, diarrhoea, gastrointestinal drainage or burns, or are due to renal losses of sodium from the use of diuretics. Inadequate intake of dietary sodium is rare but possible in individuals on low-sodium diets or if fasting. Insufficient aldosterone secretion allows both sodium and water to be lost from the body by the kidneys. Hyponatraemia is also a common adverse effect of diuretics, particularly the loop diuretics (such as frusemide), which cause excretion of water and sodium. Hypochloraemia (low blood chloride) may also occur with hyponatraemia, as chloride is associated with sodium. Dilutional hyponatraemia occurs when the amount of sodium is diluted by the amount of water. This is one reason why patients are not rehydrated intravenously using water only — saline is infused, as it replaces both sodium and water simultaneously. Nevertheless, hyponatraemia is the most common electrolyte abnormality observed in patients in hospital and this can be attributable to intravenous fluid administration without sufficient sodium.6 For instance,
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replacement of fluid loss with intravenous 5% dextrose in water can be detrimental, as the glucose is metabolised to carbon dioxide and water, leaving a water solution that has a diluting effect. For this reason, most hospital patients receive a mixture of intravenous fluids if they cannot take Na+
Na Na+ +
Na
+
normal sodium concentration
Na+ gain of water Na+
loss of sodium
Na+ Na+ Na
+
Na+ Na+
Na+
Na+
fluids orally, and these will replace both water and sodium deficits. Excessive sweating may stimulate thirst and the intake of large amounts of water, which dilute sodium. Hyponatraemia can also result from the syndrome of inappropriate antidiuretic hormone secretion (see Chapter 11), such that increased amounts of retained water dilute the sodium. During renal failure or heart failure, renal excretion of water is impaired, resulting in hyponatraemia (see Fig. 29.13). Also, hyperglycaemia in diabetes mellitus increases extracellular fluid concentration and attracts water out from the intracellular fluid; this in turn dilutes the concentration of sodium and other electrolytes. Hypochloraemia, a low level of serum chloride (less than 97 mmol/L), usually occurs with hyponatraemia or an elevated bicarbonate concentration, as in metabolic alkalosis (see Acid–base balance below). Sodium deficit related to restricted intake, use of diuretics, and vomiting is accompanied by chloride deficiency. Cystic fibrosis is characterised by hypochloraemia (see Chapter 25). Treatment of the underlying cause is required. CLINICAL MANIFESTATIONS
FIGURE 29.12
Hyponatraemia may result from either gain of water or loss of sodium from the extracellular fluid, thereby decreasing the sodium concentration.
Deficits of sodium alter the cell’s ability to depolarise and repolarise normally and hence can have severe implications for neuronal and muscular action potentials (see Chapters 6 and 20). Behavioural and neurological changes characteristic of hyponatraemia include lethargy, confusion, apprehension, depressed reflexes, seizures and finally coma.
CONCEPT MAP
Heart failure manifests as detected as
leads to
Decreased cardiac output leads to
Decreased blood volume by baroreceptors causes Increased secretion of ADH
causes
Decreased renal blood flow
Sympathetic nervous system causes vasoconstriction
leads to stimulates Thirst
contributes to
Decreased renal excretion of water contributes to
Water retained in body by kidneys manifests as Increased body water, oedema, hyponatraemia
FIGURE 29.13
The relationship between heart failure and hyponatraemia.
contributes to
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895
Muscle twitching and weakness are common. Hyponatraemia often indicates that the fluid volume is increased (hypervolaemia), which can lead to increased intracranial volume and life-threatening brain swelling. Pure sodium losses that cause hypovolaemia have symptoms of hypotension, tachycardia and decreased urine output. Weight gain, oedema and ascites are characteristic of hyponatraemia with normal or increased blood volume.
sodium level will be reduced. The haematocrit is reduced from the dilutional effect of water excess. Fluid restrictions are necessary until the underlying cause is adequately treated. As the extracellular solutes are diluted in the excess water, electrolytes including sodium may need correction when neurologic manifestations are severe.9
EVALUATION AND TREATMENT
FOCU S ON L EA RN IN G
The cause of hyponatraemia must be determined and treatment planned accordingly. Hypertonic saline solutions are used cautiously with severe symptoms such as seizures, and must be given slowly to prevent osmotic demyelination syndrome in the brain. Simply restricting the amount of water ingested in these patients usually alleviates the sodium imbalance and is a common treatment. Fluid should not be administered if the patient has accompanying oedema.7 If the hyponatraemia is accompanied by a decrease in fluid volume, then fluid volume replacement with normal saline may be used. Restriction of water intake is required in most cases of dilutional hyponatraemia because body sodium levels may be normal or increased even though serum sodium levels are low. Serum sodium concentration must be monitored.8
1 Briefly describe how sodium, chloride and potassium are normally kept in balance.
WATER EXCESS PATHOPHYSIOLOGY
Hypokalaemia
When the body is functioning normally, it is almost impossible to retain an excess of total body water, because any increase in water consumption is soon balanced by an increase in the excretion of water by the kidneys. Some individuals with psychogenic disorders develop water intoxication from compulsive water drinking. Acute kidney injury, severe congestive heart failure and liver cirrhosis can contribute to water excess, as can intravenous infusion of 5% dextrose in water. Decreased urine formation from renal disease or decreased renal blood flow contributes to water excess. The overall effect is dilution of the extracellular fluid, with water also moving into the intracellular spaces by osmosis. Water excess is usually accompanied by hyponatraemia. Excess retention of water also occurs with the syndrome of inappropriate secretion of antidiuretic hormone (see Chapter 11), whereby the kidneys are prevented from excreting excess water and hence water is retained in the body. CLINICAL MANIFESTATIONS
The symptoms of water excess are related to the rate at which water is increased, known as water loading. Acute excesses cause confusion and convulsions. Weakness, nausea, muscle twitching, headache and weight gain are common symptoms of long-term water accumulation. EVALUATION AND TREATMENT
Correct diagnosis of the cause of the water excess is essential to guiding treatment. Serum and urine osmolalities are decreased because water will be in excess of sodium. Urine
2 Compare isotonic fluid volume alterations with hypovolaemia and hypervolaemia. 3 Describe what happens to the fluid in cells as a result of hypernatraemia. 4 Briefly list some common causes of water deficit. 5 Discuss the process of hyponatraemia. 6 List some causes of water excess. Why is the healthy body unable to remain in a state of water excess?
Alterations in potassium balance PATHOPHYSIOLOGY
Potassium deficiency, or hypokalaemia, develops when the serum potassium concentration falls below 3.5 mmol/L. In clinical practice, the intracellular level of potassium cannot be measured accurately, but generally, lowered serum potassium indicates loss of total body potassium. Therefore, with potassium loss from the extracellular fluid, the concentration gradient change favours movement of potassium from the cells to the extracellular fluid. The intracellular/extracellular fluid concentration ratio is maintained, but total body potassium is depleted (see Fig. 29.14). Factors contributing to the development of hypokalaemia include reduced intake of potassium, increased entry of potassium into cells, and increased losses of body potassium. Dietary deficiency of potassium is rare but may occur in elderly individuals with both low protein intake and inadequate intake of fruits and vegetables and in individuals with alcoholism or anorexia nervosa. Generally, reduced potassium intake becomes a problem when combined with other causes of potassium depletion. Renal potassium losses occur with increased secretion of potassium by the distal tubule. Many kidney diseases reduce the ability to reabsorb sodium. Use of potassium-wasting diuretics, excessive aldosterone secretion, increased distal tubular flow rate, and low plasma magnesium concentration may all contribute to urinary losses of potassium. The elevated flow of bicarbonate at the distal tubule during alkalosis also contributes to renal excretion of potassium because the increased tubular lumen electronegativity attracts potassium. Many diuretics inhibit
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A 12 potassium
8 potassium
loss of 5 potassium
B 12 potassium
3 potassium remaining
shift out 3 potassium
C 9 potassium
6 potassium
FIGURE 29.14
Hypokalaemia. A Normal intracellular and extracellular levels of potassium, with a concentration gradient established. B Loss of 5 potassium from the extracellular fluid causes 3 potassium from inside the cell to shift out. C Although the overall numbers of potassium are now lessened, the concentration gradient from inside to outside of the cell remains normal, due to the potassium shift from the intracellular fluid to the extracellular fluid. Note: the numbers used are arbitrary.
the reabsorption of sodium chloride, causing the diuretic effect. The distal tubular flow rate then increases, promoting potassium excretion. If sodium loss is severe, the compensating aldosterone secretion may further deplete potassium stores. Primary hyperaldosteronism with excessive secretion of aldosterone from an adrenal adenoma (tumour) also causes potassium wasting. The disordered sodium reabsorption produces a diuretic effect, and the increased distal tubule flow rate favours the secretion of potassium. Magnesium deficits increase renal potassium secretion and promote hypokalaemia. Many diuretics, such as frusemide, are potassium-wasting as they cause potassium excretion by the kidneys and hence contribute to hypokalaemia. For example, diuretics that inhibit the reabsorption of sodium chloride cause sodium and water to be excreted — this increased fluid volume passing through the kidney tubules prevents adequate reabsorption of potassium (resulting in renal potassium excretion). Similarly, renal diseases also cause increased fluid excretion, which limits the ability to retain potassium in the body. Several antibiotics are known to cause hypokalaemia by increasing the rate of potassium excretion.
Hypokalaemia can also develop without losses of total body potassium. For example, potassium shifts from the extracellular fluid into cells in exchange for hydrogen to maintain plasma acid–base balance during respiratory or metabolic alkalosis (see Acid–base balance below). Potassium shifts from the intracellular fluid to the extracellular fluid in conditions such as diabetic ketoacidosis: the increased hydrogen ions (H+) decrease the pH of the extracellular fluid making it more acidic. This causes acid to move into the cell and, as a consequence, potassium exits the cell. A normal level of potassium is maintained in the plasma as potassium continues to be lost in the urine, causing a deficit in total body potassium. Insulin stimulates the sodium–potassium pump, thereby stimulating potassium entry into cells. Severe, even fatal, hypokalaemia may occur if insulin is used to treat diabetic emergency of hyperglycaemia without also providing potassium supplements. Thus, total body potassium depletion becomes evident when insulin treatment and rehydration therapy are initiated. Potassium replacement is instituted cautiously to prevent hyperkalaemia. Losses of potassium from body stores are usually caused by gastrointestinal and renal disorders. Diarrhoea, intestinal drainage tubes or fistulae and laxative abuse also result in hypokalaemia. Normally, only small amounts (5 to 10 mmol) of potassium are excreted in the faeces each day, but with diarrhoea, the loss of fluid and electrolytes, including potassium, can be substantial (100 to 200 mmol per day). Vomiting or continuous drainage is often associated with potassium depletion, partly because of the potassium lost from the gastric fluid but principally because of renal compensation for volume depletion and the metabolic alkalosis (elevated bicarbonate levels) that occurs from sodium, chloride and hydrogen ion losses (see Acid–base balance below). Conditions that cause high aldosterone secretion (described above) also result in renal losses of potassium. CLINICAL MANIFESTATIONS
Mild losses of potassium are usually asymptomatic. Neuromuscular and cardiac effects of hypokalaemia are evident with severe loss of potassium. Neuron and muscular excitability decreases, causing skeletal muscle weakness, smooth muscle atony, cardiac arrhythmias, glucose intolerance and impaired urinary concentrating ability.10 A wide range of other dysfunctions may result from potassium deficiency (see Table 29.4), as potassium is the main intracellular ion. Symptoms occur in relation to the rate of potassium depletion. Slow losses of potassium may allow potassium to gradually shift from the intracellular fluid to the extracellular fluid, restoring the potassium concentration gradient towards normal, with less severe neuromuscular changes. With acute and severe losses of potassium, changes in neuromuscular excitability are more profound. Skeletal muscle weakness occurs initially in the larger muscles of the legs and arms and ultimately affects the diaphragm and depresses ventilation. Paralysis and respiratory arrest can
CHAPTER 29 Fluids and electrolytes, acids and bases
TABLE 29.4 Clinical manifestations of potassium alterations ORGAN SYSTEM
HYPOKALAEMIA
HYPERKALAEMIA
Cardiovascular
Arrhythmias
Arrhythmias
Electrocardiogram changes
Bradycardia
Cardiac arrest Weak irregular pulse
Heart block Cardiac arrest
Lethargy
Anxiety
Fatigue
Tingling
Confusion
Numbness
Paraesthesias Gastrointestinal
Nausea and vomiting Decreased motility Distension
Nausea and vomiting Diarrhoea
Normal PR interval Normal P wave
Slightly prolonged PR interval Slightly peaked P wave
Water loss
Oliguria
Thirst
Kidney damage
Kidney damage Flaccid paralysis Respiratory arrest Constipation
Prominent U wave
Shallow T wave
Hyperkalaemia Tall, peaked T wave
Wide, flat P wave Prolonged PR interval
Inability to concentrate urine Weakness
ST depression
Decreased R wave amplitude
Ileus
Skeletal and smooth muscle
U wave shallow Normal Rounded, QRS normal-size if present T wave
Colicky pain
Decreased bowel sounds Kidneys
Normokalaemia
Hypokalaemia
Postural hypotension Nervous
897
Widened QRS
Depressed ST segment
FIGURE 29.15
Early: hyperactive muscles Late: weakness and flaccid paralysis
Bladder dysfunction
occur. Loss of smooth muscle tone is manifested by constipation, intestinal distension, anorexia, nausea and vomiting. The cardiac effects of hypokalaemia are related also to changes in membrane excitability. Because potassium contributes to the repolarisation phase of the action potential, hypokalaemia delays ventricular repolarisation. Various dysrhythmias may occur, including sinus bradycardia, atrioventricular block and paroxysmal atrial tachycardia. The characteristic changes in the ECG reflect delayed repolarisation — for instance, the amplitude of the T wave decreases, the amplitude of the U wave increases and the ST segment is depressed (see Fig. 29.15). In severe states of hypokalaemia, P waves peak and the QRS complex is
Electrocardiography (ECG) changes with potassium imbalance.
prolonged. Hypokalaemia also increases the risk of toxicity caused by digoxin (see Chapter 23). A wide range of metabolic dysfunctions may result from potassium deficiency (see Table 29.4). Carbohydrate metabolism is affected because hypokalaemia depresses insulin secretion and alters hepatic and skeletal muscle glycogen production. Renal function is impaired, with a decreased ability to concentrate urine. Polyuria (increased urine volume) and polydipsia (increased thirst) are associated with decreased responsiveness to ADH. Long-term potassium deficits lasting more than 1 month may damage renal tissue, with interstitial fibrosis and tubular atrophy. EVALUATION AND TREATMENT
The diagnosis of hypokalaemia is significantly related to the health history and the identification of disorders associated with potassium loss or shifts of extracellular potassium to the intracellular space. Treatment involves an estimation of total body potassium losses and correction of acid–base imbalances. Further losses of potassium should be prevented and the individual should be encouraged to eat foods rich in
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potassium (fruit and vegetables). Intravenous replacement is controlled carefully (maximal safe rate of 20 mmol/hr) because potassium is irritating to blood vessels, and there is the need to avoid potentially fatal effects of potassium excess. Serum potassium values are monitored until normokalaemia is achieved. Electrocardiography (ECG) allows for monitoring of cardiac function during hypokalaemia. Oral or intravenous potassium chloride replacement is instituted cautiously to prevent hyperkalaemia. Including foods higher in potassium can be used for those at risk of continual hypokalaemia.
( 41.5 mmol/L)
Hypermagnesaemia (serum concentrations > 1.0 mmol/L)
Causes of excess
Hyperparathyroidism; bone metastases with calcium resorption from breast, prostate, renal, and cervical cancer; sarcoidosis; excess vitamin D; many tumours that produce PTH
Acute kidney injury or chronic kidney disease with significant loss of glomerular filtration; treatment of metastatic tumours with chemotherapy that releases large amounts of phosphate into serum; long-term use of laxatives or enemas containing phosphates; hypoparathyroidism
Usually renal insufficiency or failure; also excessive intake of magnesium-containing antacids, adrenal insufficiency
Effects of excess
Many nonspecific; fatigue, weakness, lethargy, anorexia, nausea, constipation; impaired renal function, kidney stones; dysrhythmias, bradycardia, cardiac arrest; bone pain, osteoporosis
Symptoms primarily related to low serum calcium levels (caused by high phosphate levels) similar to results of hypocalcaemia; when prolonged, calcification of soft tissues in lungs, kidneys, joints
Skeletal smooth muscle contraction; excess nerve function; loss of deep tendon reflexes; nausea and vomiting; muscle weakness; hypotension; bradycardia; respiratory distress
Deficit
Hypocalcaemia (serum calcium concentration < 2.10 mmol/L)
Hypophosphataemia (serum phosphate concentration < 0.8 mmol/L)
Hypomagnesaemia (serum magnesium concentration < 0.8 mmol/L)
Causes of deficit
Related to inadequate intestinal absorption, deposition of ionised calcium into bone or soft tissue, blood administration, or decreases in PTH and vitamin D; nutritional deficiencies occur with inadequate sources of dairy products or green leafy vegetables
Most commonly by intestinal malabsorption related to vitamin D deficiency, use of magnesium- and aluminum-containing antacids, longterm alcohol abuse, and malabsorption syndromes; respiratory alkalosis; increased renal excretion of phosphate associated with hyperparathyroidism
Malnutrition, malabsorption syndromes, alcoholism, urinary losses (renal tubular dysfunction, loop diuretics)
Effects of deficit
Increased neuromuscular excitability; tingling, muscle spasm (particularly in hands, feet, and facial muscles), intestinal cramping, hyperactive bowel sounds; severe cases show convulsions and tetany; prolonged QT interval, cardiac arrest
Conditions related to reduced capacity for oxygen transport by red blood cells and disturbed energy metabolism; leucocyte and platelet dysfunction; deranged nerve and muscle function; in severe cases, irritability, confusion, numbness, coma, convulsions; possibly respiratory failure (because of muscle weakness), cardiomyopathies, bone resorption (leading to rickets or osteomalacia)
Behavioural changes, irritability, increased reflexes, muscle cramps, ataxia, nystagmus, tetany, convulsions, tachycardia, hypotension
deficiency of magnesium can cause disturbances throughout body cells. HYPOMAGNESAEMIA
Hypomagnesaemia (deficiency of magnesium) is linked to cardiovascular disease and is common in approximately 10% of hospitalised patients, even being apparent in 40% of hospitalised patients who have other disturbances in electrolyte balance.15 Renal losses of magnesium are the most common cause and relate to kidney dysfunction and diuretic use. Hypomagnesaemia is also common following surgery,16 as well as in alcoholism. Symptoms include irritability and muscle cramps, leading to convulsions and hypotension. Intravenous replacement of magnesium is usually necessary and can rectify cardiac arrhythmias and assist with ATP production. However, the recommended dosage for administration is variable.
F O CUS O N L E A R N IN G
1 Discuss what metabolic dysfunctions occur in potassium deficiency and in potassium excess. 2 Explain how you can have hypokalaemia but not a deficit in total body potassium. 3 What is the most prominent ECG change associated with hyperkalaemia? With hypokalaemia? 4 Briefly explain why alterations in (a) calcium, (b) phosphate and (c) magnesium are important.
CHAPTER 29 Fluids and electrolytes, acids and bases
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to neurons. For this reason, multiple systems control acid–base balance in the body. The concentration of hydrogen ions (H+) in body fluids is very small — approximately 0.0000001 mg/L. This number may be expressed as 10−7 mg/L, and is indicated as pH 7.0. The term pH represents the acidity or alkalinity of a solution. As the pH changes 1 unit (e.g. from pH 7.0 to 6.0), the hydrogen ion concentration changes tenfold. The greater the amount of hydrogen ions, the more acidic the solution and the lower the pH. Similarly, the lower the hydrogen ions, the more alkaline the solution and the higher the pH (see Chapter 1). The concentration of acid or hydrogen ions in the blood is maintained in a narrow pH range of 7.35 to 7.45. A pH of less than 7.35 is defined as acidosis and a pH greater than 7.45 is defined as alkalosis (alkaline meaning the same as a base, the opposite to an acid) (see Table 29.6). Changes in pH are life threatening; for instance, a blood pH of 6.8 is too acidic to sustain the body and a pH of 7.8 is too alkaline (see Fig. 29.16). Certain conditions can greatly displace blood pH. One example is when exercising and approaching exhaustion, such as during a maximal exercise test. The severe metabolic effects can drive the blood pH below 7. However, in comparison to disease states, this effect is only temporary and the body will rapidly correct the body’s pH back to homeostatic balance. Furthermore, the individual will not be able to continue with the exercise due to the metabolic imbalance.
TABLE 29.6 pH of body fluids
Acid–base balance Acid–base balance must be regulated within a narrow range for the body to function normally. Slight changes in amounts of hydrogen ions can significantly alter biological processes in cells and tissues.17 Hydrogen ions are needed to maintain membrane integrity and the speed of metabolic enzyme reactions. Neurons are particularly susceptible to changes in acid levels and their function is altered if the acid–base balance is not maintained. Most pathological conditions disturb acid–base balance, producing conditions possibly more harmful than the disease process itself.
Acid and pH
Acidic substances are produced by normal body processes. For example, cells that operate using aerobic metabolism (requiring oxygen) produce carbon dioxide as a byproduct, which is then converted into acidic molecules (see below). In addition, cells that use anaerobic metabolic processes (without oxygen) also produce acid — in this case, lactic acid. Body acids are formed as end products of the metabolism of protein, carbohydrate and fat. This must be balanced by the amount of basic or alkaline substances in the body to maintain normal pH, as changes in acid levels alter body processes, as well as being particularly harmful
BODY FLUID
PH
FACTORS AFFECTING PH
Gastric juices
1.0–3.0
Hydrochloric acid production
Urine
5.0–6.0
H+ ion excretion from waste products
Arterial blood
7.35–7.45 pH is slightly higher because there is less carbonic acid
Venous blood
7.37
pH is slightly lower because there is more carbonic acid
Cerebrospinal fluid
7.32
Decreased bicarbonate and higher carbon dioxide content decrease pH
7.8–8.0
Contains bicarbonate produced by exocrine cells
Pancreatic fluid
death 6.8
acidosis
normal 7.35 7.45
alkalosis
death 7.8
FIGURE 29.16
Normal pH range is 7.35 to 7.45. Below this is acidosis, and above this alkalosis. Changes in pH that cannot be corrected are fatal.
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The lungs and kidneys are the major organs involved in regulating acid–base balance. These systems work together to regulate short- and long-term changes in acid–base status. We now examine how these systems work to achieve pH homeostasis.
excess acid. This occurs mainly inside cells where the level of protein is high:
Buffer systems
This means that the acid inside the cells can be buffered by the high level of intracellular protein. Haemoglobin, apart from its vital roles in oxygen and carbon dioxide transport, is also an excellent intracellular buffer. It is a protein and can therefore bind with acid hydrogen:
Buffering occurs in response to changes in acid–base status. Buffers are substances that can absorb excessive acid (hydrogen ion, H+) or base (hydroxyl ion, OH–) and prevent significant fluctuations in pH. The buffer systems are located in both the intracellular and the extracellular fluid compartments and they function at different rates (see Table 29.7). The most important plasma buffer systems are carbonic acid–bicarbonate and the protein haemoglobin. Phosphate and protein are the main intracellular buffers. Ammonia and phosphate are important renal buffers. Acid–base fluctuations are essentially controlled on three levels: (1) by protein buffers; (2) by the lungs; and (3) by the kidneys. The protein buffering system consists of substances that are present in the blood that are able to provide short-term, immediate balancing of acid–base changes. The lungs then contribute and are efficient in removing acid, which is related to respiratory processes — namely, due to carbon dioxide levels. Finally, the kidneys are responsible for the main, longer-term control of acid– base balance and are able to remove excess acid (or base) from a variety of sources. These three systems contribute to acid–base homeostasis. Renal and respiratory adjustments to changes in pH are known as compensation. The respiratory system compensates for changes in pH by increasing or decreasing carbon dioxide by changing ventilation. The renal system compensates by producing more acidic or more alkaline urine. Correction occurs when the values for both components of the buffer pair (carbonic acid and bicarbonate) return to normal levels.
Protein buffering
Proteins have negative charges that allow them to combine with hydrogen ions, which are positively charged, to buffer
attraction protein − → ← + acid
attraction haemoglobin − → ← + acid
Haemoglobin is also critical for being able to buffer carbon dioxide — when carbon dioxide is combined with water, it forms carbonic acid, which then splits into hydrogen ion (acid) and bicarbonate ion (see Fig. 29.17). This occurs in a number of processes as part of acid–base balance and it is the most important relationship to remember, as it allows you to see that carbon dioxide actually leads to acid production. This process occurs inside red blood cells, where the hydrogen ion can bind with haemoglobin, thereby buffering the blood. Haemoglobin not saturated with oxygen (in the venous blood) is actually a better buffer than haemoglobin saturated with oxygen (arterial blood) — this is particularly useful, as it is the venous blood that collects the acid produced from cells. In this manner, the acid can be buffered in the blood, until it can be transported to the lungs for elimination. Finally, cells can exchange acid and potassium. When acid levels rise, accumulation of hydrogen ions inside the cell causes potassium to exit the cell to maintain a balance of positive ions in the cell (Fig. 29.18). This occurs in part because of a decrease in sodium–potassium ATP pump activity with acidosis. However, decreased intracellular potassium also results in decreased renal secretion of potassium, contributing to hyperkalaemia which may lead to serious pathophysiological conditions (see previous section). On the other hand, alkalosis causes decreased
Erythrocyte
TABLE 29.7 Buffer systems BUFFER SYSTEM
MECHANISM
RATE
Protein buffer and ionic shifts
Protein buffers bind acid; exchange of intracellular potassium and sodium for hydrogen
2–4 hours
Lungs
Minutes– Regulates retention or elimination of carbon dioxide hours and therefore carbonic acid concentration
Kidneys
Bicarbonate reabsorption and regeneration, ammonia formation, phosphate buffering
Hours–days
CO2
+ H2O
H2CO3
water
carbonic acid
Carbon dioxide
+ H+ HCO3– hydrogen bicarbonate ion (acid) ion (base)
FIGURE 29.17
Carbon dioxide combines with water to form carbonic acid, which then splits into hydrogen ion (acid) and bicarbonate ion (base).
CHAPTER 29 Fluids and electrolytes, acids and bases
CO2 + H2O increasing levels of H+
H2CO3
May increase plasma K+ levels and lead to serious conditions
H+
903
+ HCO3–
+Cl–
+Na+
=HCl
=NaHCO3
FIGURE 29.19
K+ exit
Increased levels of carbon dioxide result in increased levels of acid being produced (and a lowered pH). In this figure, note that the bicarbonate ion combines with sodium to form sodium bicarbonate. It is also possible for the bicarbonate ion to combine with potassium and magnesium, which have lesser roles in acid–base balance. HCl = hydrochloric acid; NaHCO3 = sodium bicarbonate.
FIGURE 29.18
Acidosis can cause potassium to exit from the cell. This allows the level of positive charge to remain normal within the cell. However, it may result in hyperkalaemia.
Respiratory membrane Erythrocyte
H+
+
Alveoli
diffuses out
HCO3–
H2CO3
CO2
+
H2O
CO2 exhaled
FIGURE 29.20
In the lungs, acid is converted back to carbon dioxide to be exhaled.
intracellular hydrogen, so potassium enters the cell and the kidney increases potassium secretion, which may lead to hypokalaemia. (Review hyperkalaemia and hypokalaemia in the previous section.)
Carbonic acid–bicarbonate buffering
Carbonic acid (H2CO3) and bicarbonate ion (HCO3-) form in important buffering system for changes in acid–base balance (refer to equation in Fig. 29.17). This carbonic acid–bicarbonate buffer pair operates in both the lung and the kidney and is a major extracellular buffer. The lungs can decrease the amount of carbonic acid by blowing off carbon dioxide and leaving water. The kidneys can reabsorb bicarbonate or regenerate new bicarbonate from carbon dioxide and water. The relationship between bicarbonate and carbonic acid is usually expressed as a ratio. Normal bicarbonate level is about 24 mmol/L, and normal carbonic acid level is about 1.2 mmol/L (when the arterial CO2 partial pressure [PaCO2] is 40 mmHg), producing a 20 : 1 ratio and the normal pH of 7.4. These two systems are very effective together because the lungs can adjust acid concentration rapidly and bicarbonate is easily reabsorbed or regenerated by the kidneys. Renal and respiratory adjustments to primary changes in pH are known as compensation. The respiratory system compensates for changes in pH by increasing or decreasing
the concentration of carbon dioxide by changing ventilation. The renal system compensates by producing more acidic or more alkaline urine. Correction occurs when the values for both components of the buffer pair (carbonic acid and bicarbonate) return to normal levels.
Respiratory buffering
Carbon dioxide, produced from cellular processes, combines with water (present as body fluid, inside and outside of cells) in the manner described above. Increases in carbon dioxide contribute directly to increased amounts of acid and hence lowered pH (see Fig. 29.19). This carbonic acid–bicarbonate buffer system is a major extracellular buffer, which works with the respiratory system (discussed in Chapter 24). Once the haemoglobin carrying its hydrogen ion returns to the lungs, the acid can be eliminated from the body by the steps occurring in reverse — this results in the formation of carbon dioxide, which is removed from the body simply by exhaling (see Fig. 29.20). Carbonic acid (H2CO3) readily dissociates into carbon dioxide (CO2) and water (H2O), in the presence of carbonic anydrase (an enzyme). The carbon dioxide is then eliminated by pulmonary ventilation. The lungs are able to remove excess carbon dioxide in this way relatively quickly, by simply increasing the respiratory rate. These changes are detectable after a few minutes.
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Renal buffering
Renal buffering, although slower in comparison with respiratory buffering, is able to buffer larger loads of acid. Thus, the kidneys main role in acid–base balance is involved in long-term regulation. They have the ability to make relatively large changes as necessary to restore the balance. The nephrons are able to remove acid from the blood, as well as produce new bicarbonate ions for the blood, to enable more buffering ability in the blood. The distal tubule of the kidney regulates acid–base balance by secreting hydrogen into the urine and reabsorbing bicarbonate. Hydrogen phosphate (HPO4-) and ammonia (NH3) are two important renal buffers. The renal buffering of hydrogen ions requires the use of carbon dioxide (CO2) and water (H2O) to form carbonic acid (H2CO3). Fig. 29.21 shows how carbon dioxide diffuses from the blood into the kidney tubule cells and is then secreted into the urinary filtrate. Here, the acid is combined with other molecules to form carbonic acid, which exits the body in urine. At the same time, the kidneys regenerate new bicarbonate from carbon dioxide and water. The enzyme carbonic anhydrase catalyses the reaction. The hydrogen is then secreted from the tubular cell and buffered in the lumen by phosphate and ammonium (i.e. forms H2PO3- and NH4+). The remaining bicarbonate is reabsorbed. The end effect is the addition of new bicarbonate to the plasma, which contributes to the alkalinity of the plasma because the hydrogen ion is excreted from the body The nephrons can also reabsorb some of the bicarbonate ion that was filtered, as an additional means of supplying more bicarbonate to the blood when needed to buffer more acid.
alkalosis, a term that is also commonly used in clinical practice. These pH disturbances are often associated with serious pathophysiological deterioration and may be caused by metabolic or respiratory processes (summarised in Table 29.8).
Respiratory acidosis
Respiratory acidosis occurs when the pH is less than 7.35 due to hypoventilation (see Fig. 29.22A). This occurs when
Urinary fluid – 3
HCO
were filtered
–
CO2 + H2O
HPO4
Blood blood CO2
H2CO3 – H+ and HCO3
H+
–
HCO3 combine combine with OR with – filtered HPO42 – HCO3 H2CO3
H3PO4
acidic molecules excreted in urine
Acid–base imbalances
Pathophysiological changes in the concentration of hydrogen ion in the blood lead to acid–base imbalances.18 When the pH of arterial blood is less than 7.35, this is termed acidaemia. A systemic increase in hydrogen ion concentration is termed acidosis, which is the more commonly used term in clinical practice. In alkalaemia, the pH of arterial blood is greater than 7.45. Accordingly, a systemic decrease in hydrogen ion concentration is termed
Blood kidney cells forming the nephron tubule
FIGURE 29.21
In the nephrons, carbon dioxide is converted back to acidic hydrogen, and then it is secreted into the urinary fluid to be removed from the body. At the same time, the nephron cells can return bicarbonate ion to the blood, to buffer more acid as needed.
TABLE 29.8 Summary of changes in acid–base disorders BLOOD DISORDER
PRIMARY ABNORMALITY
PH
PACO2
HCO3–
Metabolic acidosis
HCO3– low
↓
→
↓
_
↓
_
Compensated (respiratory CO2) –
Metabolic alkalosis
HCO3 high
Compensated (respiratory CO2) Respiratory acidosis
CO2 high –
Compensated (renal retention HCO3 ) Respiratory alkalosis Compensated (renal excretion HCO3 )
→
↑
↑
_
↓
↑
→ ↑
_ CO2 low
–
↑ _
↑ _
↓
→ ↓
CHAPTER 29 Fluids and electrolytes, acids and bases
A
↓ ventilation
A
Bicarbonate ↓ e.g. diarrhoea
↓ pH (respiratory)
↓ pH (metabolic) Acid formation ↑ e.g. renal failure
↓ CO2 removal
B
905
↑ ventilation ↑ pH (respiratory)
B
↑ CO2 removal
alveolar ventilation (gas exchange at the alveoli) decreases and there is a build-up of carbon dioxide in the body (hypercapnia). The arterial carbon dioxide pressure (PaCO2) becomes greater than 45 mmHg, which lowers the pH. A decrease in alveolar ventilation in relation to the metabolic production of carbon dioxide produces respiratory acidosis by an increase in the concentration of carbonic acid.19 Respiratory acidosis can be acute or chronic. Common causes include depression of the respiratory centre (from drugs or head injury), respiratory muscle paralysis, disorders of the chest wall (fractured ribs) and disorders of the lung (pneumonia, pulmonary oedema, emphysema, asthma, bronchitis). Compensation to correct the pH abnormality occurs in the kidneys by increasing the elimination of hydrogen ions in the urine and retaining bicarbonate, which causes an increase in pH back to the normal range. The signs and symptoms seen often include headache, blurred vision, breathlessness, restlessness and apprehension followed by lethargy, disorientation, muscle twitching, tremors, convulsions and finally coma. The respiratory rate increases to correct the acidosis. The skin may be warm and flushed as the elevated carbon dioxide causes vasodilation. The restoration of adequate alveolar ventilation removes the excess CO2.
Respiratory alkalosis
Respiratory alkalosis occurs when alveolar hyperventilation (deep, rapid respirations) causes an excessive reduction in plasma carbon dioxide levels (hypocapnia),19 resulting in a carbon dioxide level of less than 35 mmHg and the pH greater than normal (see Fig. 29.22B). Respiratory alkalosis can also be chronic or acute. The most common cause of respiratory alkalosis is anxiety leading to hyperventilation, triggered by a stressful event like a pathophysiology exam! Hypoxaemia (caused by pulmonary disease, congestive heart failure or high altitudes), hypermetabolic states (fever, anaemia), hysteria and sepsis stimulate
↑ pH (metabolic)
Acid e.g. excess vomiting
FIGURE 29.22
Respiratory causes of acid–base disturbances. A Decreased ventilation leads to low pH, or respiratory acidosis. B Increased ventilation leads to high pH, or respiratory alkalosis.
Bicarbonate ↑ e.g. ingestion of antacids
FIGURE 29.23
Metabolic causes of acid–base disturbances. A Metabolic acidosis occurs due to decreased pH, caused by increased levels of acid or decreased bicarbonates. B Metabolic alkalosis occurs when pH is raised by increased bicarbonate or loss of acid.
hyperventilation. The kidneys compensate by decreasing hydrogen excretion and bicarbonate reabsorption in the nephrons. The central and peripheral nervous systems are stimulated by respiratory alkalosis, causing dizziness, confusion, tingling of extremities (paraesthesias), convulsions and coma. Cerebral vasoconstriction reduces cerebral blood flow, which is actually useful in the short term if the patient has raised intracranial pressure. Deep and rapid breathing is the primary symptom that causes respiratory alkalosis. Carpopedal spasm (spasm of muscles in the fingers and toes), tetany, and other symptoms of hypocalcaemia are similar to those of metabolic alkalosis.
Metabolic acidosis
In metabolic acidosis, acids due to sources other than carbonic acid increase. Alternatively, bicarbonate is lost from the extracellular fluid, such as during severe diarrhoea (see Fig. 29.23A). This can occur either quickly, as in lactic acidosis caused by poor perfusion (blood flow) or hypoxaemia, or over an extended period of time, as in renal failure or diabetic ketoacidosis. The buffering systems normally compensate for excess acid and maintain arterial pH within the normal range. When acidosis is severe, buffers become depleted and cannot compensate adequately to correct the decrease in pH.19 Metabolic acidosis is manifested by changes in the function of the neurological, respiratory, gastrointestinal and cardiovascular systems. Early symptoms include headache and lethargy, which progress to coma in severe acidosis. The respiratory system’s efforts to compensate for the increase in metabolic acids result in what is termed Kussmaul respiration — deep, rapid and sustained breaths.
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This represents the body’s attempt to increase pH by exhaling excess carbon dioxide, which decreases carbonic acid. Other symptoms include anorexia, nausea, vomiting, diarrhoea and abdominal discomfort. Death can result in the most severe and prolonged cases, preceded by arrhythmias and hypotension. The underlying condition must be diagnosed to establish effective treatment. Metabolic acidosis is treated with oral sodium bicarbonate supplementation in chronic kidney disease or, in acute metabolic acidosis (e.g. diabetes ketoacidosis), intravenous sodium bicarbonate may be needed.
Metabolic alkalosis
Metabolic alkalosis occurs when there is an excessive loss of metabolic acids or bicarbonate levels increase (Fig. 29.23B).19 When acid loss is caused by vomiting, the kidneys’ compensation is not very effective because the loss of chloride (an anion) in the vomitus in the form of hydrochloric acid (HCl) actually stimulates renal retention of bicarbonate (an anion), known as hypochloraemic metabolic alkalosis. Hyperaldosteronism can also lead to alkalosis as a result of sodium bicarbonate retention and loss of hydrogen and
potassium. Some diuretics (such as frusemide and thiazide) may produce a mild alkalosis because they promote greater excretion of sodium, potassium and chloride than bicarbonate. Metabolic alkalosis can also be seen with excess antacid or bicarbonate ingestion. Some common signs and symptoms of metabolic alkalosis are weakness, muscle cramps, hyperactive reflexes, tetany, shallow slow respirations, confusion, convulsions and atrial tachycardia. Breaths may be shallow and slow as the lungs attempt to compensate by increasing carbon dioxide retention. The manifestations vary with the cause and severity of the alkalosis. The symptoms of hyperactive reflexes and tetany occur because alkalosis increases binding of calcium to plasma proteins, thus decreasing blood calcium levels. The decreased calcium levels cause excitable cells to become hypopolarised (membrane potential moves towards threshold), initiating an action potential more easily and causing muscle contraction. Treatments are related to the underlying cause of the condition. With alkalosis, a sodium chloride solution is required for correction because chloride must be replaced before bicarbonate can be excreted by the kidney.
At birth, total body water represents about 75–80% of body weight; this decreases to about 67% during the first year of life. Physiological loss of body water amounting to 5% of body weight occurs as the infant adjusts to a new environment. Infants are particularly susceptible to significant changes in body fluids because of their high metabolic rate and greater body surface area, as compared with adults. Consequently, they have a greater fluid intake and output in relation to their body size. In addition, the immature kidneys are less able to reabsorb water, so the amount of water excreted is relatively higher than in adults. This can contribute to the infant’s susceptibility for developing dehydration. Renal mechanisms of fluid and electrolyte conservation may not be mature enough to counter abnormal losses related to vomiting or
diarrhoea, thereby allowing dehydration to occur. Symptoms of dehydration include thirst, decreased urine output, decreased body weight, decreased skin elasticity, sunken fontanels, absent tears, dry mucous membranes, increased heart rate and irritability. Dehydration due to fluid loss is a leading cause of death in newborns and children, and therefore restoration of fluids is imperative. Total body water slowly decreases to 60–65% of body weight in adulthood. At adolescence, the body water percentage approaches adult levels and differences in the sexes appear. Males have a greater percentage of body water because of increased muscle mass, and females have more body fat because of the influence of oestrogen and thus have less body water.
PAEDIATRICS
Paediatrics and the distribution of body fluids
Ageing and the distribution of body fluids perception also may decline and loss of cognitive function can influence access to beverages. In the aged population, the total body water is about 50% of the body mass. The further decline in the percentage of total body water in the elderly is in part the result of a decreased free fat mass and decreased muscle, as well as reduced ability to regulate sodium and water balance. As a consequence, water losses or gains have a more pronounced effect on body fluid osmolality.
AGEING
Ageing reduces the renal mass so that an individual aged 30 has 20 to 25% more kidney mass than an individual aged 85. If healthy, the elderly can adequately maintain their hydration status. When disease is present, a decrease in body fluid content and dehydration can become life threatening. As a person ages, the kidneys are less efficient in producing concentrated urine. This is not due to changes in ADH release, rather, in the older adult the sodium-conserving responses are reduced. Thirst
CHAPTER 29 Fluids and electrolytes, acids and bases
In the elderly, there is an increased risk of an extracellular overload, which may be due to an increased response to atrial natriuretic peptide (ANP). ANP increases sodium and water loss in the urine. Exaggerated response to ANP increases plasma concentrations. Ageing also reduces
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renin release and the subsequent aldosterone response which leads to leakage of sodium in the urine. In the aged population, potassium excretion is limited due to a reduction in kidney mass. This increases the risk of the aged population developing hyperkalaemia.
F O CUS O N L E A R N IN G
1 Discuss how acid–base balance is normally regulated in the body. Indicate which system is responsible for the main long-term control of acid–base balance. 2 Explain how alterations in respiration lead to either respiratory acidosis or respiratory alkalosis. 3 Discuss metabolic alterations that lead to acidosis or alkalosis. 4 Describe how fluid balance differs in the infant and in the ageing individual.
chapter SUMMARY Fluid balance • Body fluids are distributed among functional compartments and are classified as intracellular fluid (ICF) and extracellular fluid (ECF). The main divisions of extracellular fluid are the plasma (within blood vessels) and interstitial fluid between cells (outside of the blood). • The sum of all fluids is the total body water, which varies with age and amount of body fat. • Water moves between the intracellular fluid and extracellular fluid compartments principally by osmosis. • Water moves between the plasma and interstitial fluid by osmosis and hydrostatic pressure, which occur across the capillary membrane. Movement across the capillary wall is called net filtration and occurs due to this balance between hydrostatic and osmotic forces (Starling’s law). Fluid in the interstitium is drained by the lymphatic vessels. • Oedema is a problem of fluid distribution that results in the accumulation of fluid within the interstitial spaces. • The pathophysiological process that leads to oedema is related to an increase in forces favouring fluid movement out of capillaries into tissues such as increased capillary hydrostatic pressure, lowered plasma oncotic pressure, increased capillary permeability or blockages of lymphatic channels.
• Oedema is caused by arterial dilation, venous or lymphatic obstruction, increased vascular volume, or increased capillary permeability. • Oedema may be localised or generalised and is usually associated with weight gain, swelling and puffiness, tighter-fitting clothes and shoes and limited movement of the affected area. • The normal distribution of fluid is referred to as first spacing. Increased fluid in the interstitial space results in second spacing, while fluid in areas that are not normal fluid compartments causes third spacing, which can be difficult to treat.
Electrolyte balance • The movement of electrolytes and water is related: sodium is usually followed by water and chloride, while potassium moves in the opposite direction to sodium across cell membranes. • Water balance is regulated by the sensation of thirst and by antidiuretic hormone, which is secreted in response to an increase in plasma osmolality or a decrease in circulating blood volume. • Sodium is the main electrolyte in the extracellular fluid and hence it is a main contributor to fluid volume in this compartment. Sodium is critical for a number of functions, including the normal function of neurons and muscle. Continued
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• Sodium balance is regulated by aldosterone, which increases reabsorption of sodium from the urine into the blood by the distal convoluted tubule of the kidneys. • Atrial natriuretic peptide is involved in decreasing tubular reabsorption and promoting urinary excretion of sodium. • Alterations in water balance may be classified as isotonic, hypertonic or hypotonic. • Isotonic alterations occur when changes in TBW are accompanied by proportional changes in electrolytes. • Hypertonic alterations develop when the osmolality of the ECF is elevated above normal, usually because of an increased concentration of ECF sodium or a deficit of ECF water. • Hypovolaemia is a low blood volume, while hypervolaemia is a high blood volume. Corresponding changes in blood pressure occur with these conditions. • Hypernatraemia (elevated plasma sodium levels) may be caused by an acute increase in sodium or a loss of water. • Hypotonic alterations occur when the osmolality of the ECF is less than normal. • Hyponatraemia (lowered plasma sodium concentration) usually causes movement of water into the cells. • Hyponatraemia may be caused by sodium loss, inadequate sodium intake or dilution of the body’s sodium level with excess water. • Water deficit, or hypertonic dehydration, is rare but can be caused by lack of access to water, pure water losses, hyperventilation, arid climates, and increased renal elimination of water. • Water excess is rare but can be caused by compulsive water drinking, decreased urine formation or the syndrome of inappropriate secretion of antidiuretic hormone. • Hyperchloraemia is caused by an excess of sodium or a deficit of bicarbonate. • Potassium is the predominant intracellular fluid ion; it regulates intracellular fluid osmolality, maintains the resting membrane potential and mediates action potentials in neurons and muscle. • Potassium balance is regulated by the kidneys, mainly by aldosterone. • The mechanism of potassium tolerance or adaptation allows the body to accommodate slowly to increased levels of potassium intake. • Hypokalaemia (low plasma potassium concentration) indicates loss of total body potassium and may be caused by reduced potassium intake, a shift from extracellular fluid to intracellular fluid potassium, increased aldosterone or increased renal excretion. • Hyperkalaemia (elevated plasma potassium levels) may be caused by increased potassium intake, a shift from intracellular fluid to extracellular fluid potassium or decreased renal excretion. • Calcium and phosphate concentrations are rigidly controlled by parathyroid hormone (PTH), vitamin D, and calcitonin. • Calcium is a necessary ion in neuronal signalling and blood clotting and is stored in the bone.
• Calcium is mainly controlled by parathyroid hormone levels. • Hypercalcaemia (high plasma calcium concentration) is usually caused by elevated parathyroid hormone and may cause kidney stones and cardiac arrhythmia. • Hypocalcaemia (low plasma calcium concentration) is usually related to inadequate levels of parathyroid hormone; a serious complication is cardiac arrest. • Phosphate is a main contributor to the energy of all body cells, as it is a component of the molecule ATP. Lack of phosphate, hypophosphataemia, may cause cardiac arrest, convulsions or finally coma. • Hypophosphataemia is usually caused by intestinal malabsorption and increased renal excretion of phosphate. • Hyperphosphataemia develops with acute or chronic kidney failure when there is significant loss of glomerular filtration. • Magnesium is involved in energy metabolism within cells and is involved in the sodium–potassium pump. • Hypomagnesaemia (low plasma magnesium concentrations) is common in hospitalised patients and requires careful magnesium replacement. • Hypomagnesaemia may be caused by malabsorption syndromes. • Hypermagnesaemia is rare and is usually caused by renal failure.
Acid–base balance • Hydrogen ions (acid) must be concentrated within a narrow range if the body is to function normally. Hydrogen ion concentration is expressed as pH and indicates the balance in acid or base. • Hydrogen ion concentration, [H+], is expressed as pH, and indicates the concentration of hydrogen ions in solution. • The normal pH of the blood is 7.35 to 7.45. Acidosis is defined as a pH less than 7.35 and alkalosis as a pH above 7.45. Significant changes in pH are life threatening. • The renal and respiratory systems, together with the body’s protein buffer systems, are the principal regulators of acid–base balance. • Buffers are substances that can absorb excessive acid or base without a significant change in pH. • Proteins, including haemoglobin, are buffers that can bind with acids. • The lungs and kidneys act to compensate for changes in pH by increasing or decreasing ventilation and by producing more acidic or more alkaline urine. • Correction is a process different from compensation; correction occurs when the values for both components of the buffer pair return to normal. • Acid–base imbalances are caused by changes in the concentration of hydrogen ion in the blood; an increase causes acidosis, and a decrease causes alkalosis. • An abnormal increase or decrease in bicarbonate concentration causes metabolic alkalosis or metabolic
•
• • •
CHAPTER 29 Fluids and electrolytes, acids and bases
acidosis; changes in the rate of alveolar ventilation and removal of carbon dioxide produce respiratory acidosis or respiratory alkalosis. Respiratory acidosis occurs with a decrease in alveolar ventilation, which in turn causes hypercapnia (an increase in carbon dioxide) and increases in carbonic acid concentration. Respiratory alkalosis occurs with alveolar hyperventilation and excessive reduction of carbon dioxide or hypocapnia with decreases in carbonic acid. Metabolic acidosis is caused by an increase in noncarbonic acids or loss of bicarbonate from the extracellular fluid. Metabolic alkalosis occurs with an increase in bicarbonate, usually caused by loss of metabolic acids
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from conditions such as vomiting or gastrointestinal drainage or from excessive bicarbonate intake, hyperaldosteronism or diuretic therapy, which increases plasma bicarbonate.
Paediatrics and the distribution of body fluids • Infants are more susceptible to alterations in fluid balance. Their immature kidneys and high body surface area contribute to fluid losses. As a result, dehydration is a serious condition in infants.
Ageing and the distribution of body fluids • The aged may have limited fluid intake if coupled with cognitive changes. In addition, their kidneys are less able to reabsorb water.
CASE STUDY
ADU LT Trevor is 18 years old with type 1 diabetes mellitus. He has been unwell for the last 3 days with flu-like illness. He has been vomiting and not eating very much. Trevor goes to the emergency department complaining of fatigue and weakness. On examination his temperature is 39°C, pulse rate 108 beats per minute, respiratory rate 24 breaths per minute, blood pressure 100/70 mmHg. He is slightly confused. Blood results reveal: Na 152 mmol/L, K 5.8 mmol/L, glucose 28.2 mmol/L. Arterial blood gases were pH 7.25, PO2 95 mmHg, PCO2 30 mmHg, HCO3 15 mmol/L, and O2 sat 98%. Urinalysis showed specific gravity 1030 and positive for glucose and ketone bodies.
1 2 3 4
5
Explain how hyperglycaemia contributes to dehydration and metabolic acidosis. Describe why the respiratory rate has increased. Interpret the blood results and arterial blood gas analysis. (List those which are high, low and normal.) Suggest the type of hydration therapy which is initially used and how it affects sodium, potassium and chloride levels. Would sodium bicarbonate be administered to correct the metabolic acidosis?
CASE STUDY
AGEING Karolina, a patient in her mid-80s, has been admitted to hospital from the nursing home where she has been living for the last 3 years. Over the course of this time, her renal function has deteriorated. She has been prescribed the diuretic drug frusemide, to assist in renal excretion of sodium and water. Karolina presents to the emergency department of the nearby hospital in a dehydrated state due to vomiting and diarrhoea with a decreased serum potassium level (2.6 mmol/L). Aggressive intravenous fluid and potassium replacement therapy over the next 48 hours restore the potassium to the normal range but cause hyponatraemia (130 mmol/L).
1
Define and describe what is meant by hypokalaemia. Explain how diuretic medication may contribute to dehydration and hypokalaemia. 3 Describe why hypokalaemia can be a potentially lifethreatening condition. 4 Suggest how hydration therapies used in hospital may contribute to the development of hyponatraemia. 5 Discuss the potential complications of hyponatraemia, particularly those related to the brain. 2
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REVIEW QUESTIONS 1 Explain how pressure differences promote the movement of water between body compartments. 2 Outline how alterations in pressures lead to the development of oedema. 3 Describe how water balance is normally achieved. 4 Explain the clinical implications of hypovolaemia and hypervolaemia. 5 Explain the factors that contribute to hypernatraemia and why it needs treating.
6 Discuss the effects of hyponatraemia on the neurons. 7 Explain the pathophysiology of hypokalaemia and hyperkalaemia. 8 Outline how alterations in carbon dioxide influence acid– base states. 9 List the factors that may contribute to respiratory alterations in acid–base balance. 10 Explain how metabolic alterations in acid–base balance occur.
Key terms acute cystitis, 918 acute glomerulonephritis, 923 acute kidney injury, 932 calculi, 913 chronic glomerulonephritis, 923 chronic kidney disease, 927 chronic pyelonephritis, 920 cystitis, 918 detrusor hyperreflexia, 915 diabetic nephropathy, 923 end-stage kidney disease, 927 enuresis, 940 glomerulonephritis, 921 hydronephrosis, 912 hydroureter, 912 hypospadias, 937 nephroblastoma, 942 nephritic syndrome, 925 nephrotic syndrome, 924 neurogenic bladder, 915 obstructive uropathy, 912 oliguria, 935 overactive bladder syndrome, 916 prolapsed, 916 prostate enlargement, 916 pyelonephritis, 919 renal colic, 914 renal failure, 933 uraemia (uraemic syndrome), 929 urethral stricture, 916 urinary tract infection, 917 vesicoureteral reflux, 939
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Alterations of renal and urinary tract function across the life span
30
Deanne Hryciw and Ann Bonner Chapter outline Introduction, 912 Urinary tract obstruction, 912 Upper urinary tract obstruction, 912 Lower urinary tract obstruction, 915 Urinary tract infection, 917 Causes of urinary tract infection, 917 Types of urinary tract infection, 918 Glomerular disorders, 921 Glomerulonephritis, 921 Nephrotic syndrome, 924 Chronic kidney disease, 927 Stages of chronic kidney disease, 927 Creatinine and urea clearance, 929 Fluid and electrolyte balance, 929 Calcium, phosphate and bone, 930
Protein, carbohydrate and fat metabolism, 930 Musculoskeletal system, 931 Cardiovascular system, 931 Pulmonary system, 931 Haematological system, 931 Immune system, 931 Neurological system, 931 Digestive system, 932 Endocrine and reproductive systems, 932 Integumentary system, 932 Acute kidney injury, 932 Tumours, 941 Renal tumours, 941 Bladder tumours, 942
911
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Introduction Alterations to the urinary system involve diseases and disorders of the kidneys and urinary structures. Many people will experience a pathophysiological disorder of the urinary system at some point in their life, with infection of the lower urinary structures — a urinary tract infection — being one of the most common disorders. Blockages in the urinary tract, such as kidney stones, are also relatively common. Renal function can be impaired by disorders of the kidneys themselves or by many other systemic diseases. Because the kidneys filter the blood, they are directly linked to every other organ system. Therefore, insult to the kidneys causing injury, whether acute or chronic, can be life threatening. The incidence and type of renal and urinary tract disorders experienced by children varies with age and maturation; newborn disorders may involve congenital malformations. During childhood, the kidney and urinary structures continue to develop, so renal dysfunction may be associated with mechanisms and manifestations that differ from those found in adults.
Urinary tract obstruction Urinary tract obstruction is an interference with the flow of urine at any site along the urinary tract (see Fig. 30.1). An obstruction may be anatomical or functional. It can impede flow proximal (upstream) to the blockage, dilate the urinary system (as it becomes filled with urine that is not being drained), increase the risk for infection and compromise renal function. Anatomical changes in the urinary system caused by obstruction are referred to as obstructive uropathy. The severity of an obstructive uropathy is determined by: 1 the location of the obstructive lesion 2 whether one or both upper urinary tracts are involved 3 the severity (completeness) of the blockage 4 its duration 1,2 5 the nature of the obstructive lesion. Obstructions may be relieved or partially alleviated by correction of the obstruction, although permanent impairments occur if a complete or partial obstruction persists over a period of weeks to months or longer. For the purposes of this discussion, we will consider obstructions in the upper and lower urinary tract: this demarcates an anatomical difference and also treatment differences. We start with the upper urinary structures.
Upper urinary tract obstruction
Common causes of upper urinary tract obstruction include: • stricture (narrowing of tube) • congenital compression (e.g. at the ureterovesical junction where the ureter joins the bladder) • compression from a blood vessel, tumour or abdominal inflammation and scarring
Ureteropelvic valve
Ureteropelvic stricture Fibrous band
Hydronephrosis Polycystic kidney
Dysplasia-agenesis of ureter
Stenosis Ureteral orifice
Urethral sphincter muscle in urogenital diaphragm
Posterior vesicoureteral valve (reflux) Prostate hypertrophy Posterior vesicourethral valve Urethral stenosis
FIGURE 30.1
Major sites of urinary tract obstruction. While obstruction can occur throughout the urinary tract, obstruction at the ureters and urethra are common.
• blockage due to calculi, which are commonly called kidney or renal stones • malignancy of the renal pelvis, ureter, bladder or prostate. Obstruction of the upper urinary tract causes dilation of the ureter, renal pelvis, and calyces proximal to the site of urinary blockage. Dilation of the ureter is referred to as hydroureter (an accumulation of urine in the ureter), and dilation of the renal pelvis and calyces (within the kidneys) proximal to a blockage leads to hydronephrosis (enlargement of the renal pelvis and calyces) or ureterohydronephrosis (dilation of the ureter, the renal pelvis and the renal calyces) (see Figs 30.2 and 30.3). Dilation of the upper urinary tract is an early response to obstruction. It reflects smooth muscle hypertrophy and accumulation of urine above the level of blockage affecting the distal nephron within approximately 7 days. By 14 days, obstruction has adversely affected both distal and proximal aspects of the nephron. Within 28 days, the glomeruli of the kidney have been damaged and the renal cortex and medulla are reduced in size (thinned). Tubular damage (damage to the nephron tubules) initially decreases the kidney’s ability to concentrate urine, causing an increase in urine volume despite a decrease in the glomerular filtration rate (GFR). The affected kidney is unable to
CHAPTER 30 Alterations of renal and urinary tract function across the life span
FIGURE 30.2
Hydronephrosis. Hydronephrosis of the kidney, with marked dilation of the pelvis and calyces and thinning of the renal tissue (arrows).
Nevertheless, even in the face of a complete obstruction, the kidney may recover at least partial homeostatic function, provided the blockage is removed within about 2 months.1 The recovery requires a period of approximately 4 months. Partial obstruction, in the absence of renal infection, leads to more subtle but ultimately permanent impairments including loss of the kidney’s ability to concentrate urine, reabsorb bicarbonate, excrete ammonia or regulate metabolic acid–base balance. This can lead to acute kidney injury or chronic kidney disease, which we discuss later in this chapter. The body is able to partially counteract the negative consequences of unilateral obstruction by a process called compensatory hypertrophy and hyperfunction.3 The other (unobstructed) kidney compensates for the decreased function of the obstructed kidney, by increasing the size of individual glomeruli and tubules, yet not the total number of functioning nephrons. This ability to undergo compensatory hypertrophy and hyperfunction diminishes with age, and the process reverses when relief of obstruction results in recovery of function by the obstructed kidney. Relief of bilateral, partial urinary tract obstruction or complete obstruction of one kidney is usually followed by a brief period of diuresis (commonly called postobstructive diuresis).4 It is a physiological response and is typically mild, representing a restoration of fluid and electrolyte imbalance caused by the obstructive uropathy. Occasionally, relief of obstruction will cause rapid excretion of large volumes of water (polyuria), sodium, or other electrolytes, resulting in a urine output of 10 L/day or more. Rapid postobstructive diuresis causes dehydration and fluid and electrolyte imbalances that must be promptly corrected. Risk factors for severe postobstructive diuresis include chronic, bilateral obstruction, impairment of one or both kidneys’ ability to concentrate urine or reabsorb sodium (nephrogenic diabetes insipidus), hypertension, oedema and weight gain, heart failure, and uraemic encephalopathy. We now turn to some of the common causes of upper urinary tract obstruction.
Kidney stones
FIGURE 30.3
Ureterohydronephrosis. Intravenous contrast dye highlights the dilated ureter (arrow) and renal pelvis (triangle).
reabsorb sodium, bicarbonate and water or to excrete hydrogen or potassium, leading to metabolic acidosis and dehydration (see Chapter 29). The magnitude of this damage, and the kidney’s ability to recover normal homeostatic function, is affected by the severity and duration of the obstruction. With complete obstruction, damage to the renal tubules occurs in a matter of hours and irreversible damage occurs within 4 weeks.
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Calculi, or urinary stones, are masses of crystals, protein or other substances that are a common cause of urinary tract obstruction in adults. The incidence and prevalence of kidney stones in Australia is likely to be underestimated as there is no nationwide collection of statistics.5 However, it has been estimated that about 4–8% of Australians will have kidney stones at some time in their life — the risk of developing a kidney stone is about 1 in 10 for males and 1 in 35 for females.6 The risk of developing kidney stones also increases if there is a family history of stones, the patient has type 2 diabetes mellitus or the patient is older. Most persons develop their first stone before the age of 50 years. Geographic location influences the risk of stone formation because of indirect factors, including average temperature, humidity, and rainfall, and their influence on fluid intake and dietary patterns. Individuals who regularly consume an adequate volume of water and those who are physically active are at reduced risk compared with individuals who
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are inactive or consume lower volumes of fluid. (Note that when we discuss fluid intake in relation to renal function, we mean water and similar fluids; alcoholic and caffeinated drinks do not contribute to the healthy function of the kidneys.) Urinary calculi can be described according to the primary minerals (salts) that make up the stones. The most common stone types include calcium oxalate or phosphate (70–80%), struvite (magnesium, ammonium and phosphate; 15%) and uric acid (7%). PATHOPHYSIOLOGY
Calculus formation is complex and related to factors including supersaturation of salts (presence of more salts than can be dissolved), and hence precipitation of those from a liquid to a solid state, and subsequent growth through crystallisation or agglomeration (sometimes called aggregation). Human urine contains many ions that are capable of precipitating (becoming solid) from solution. These salts form crystals that can grow into stones. Crystallisation is the process by which crystals grow from a small nidus to larger stones in the presence of supersaturated urine. Supersaturation is an important component of kidney stone formation and refers to a solution that contains more dissolved substances than can be dissolved in the water. This can be demonstrated by adding salt to a glass of water until it accumulates and will not dissolve into the solution any more. Although supersaturation is essential for stone formation, the urine need not remain continuously supersaturated for a calculus to grow once its nidus has precipitated from solution. Intermittent periods of supersaturation after the ingestion of a meal or during times of dehydration are sufficient for stone growth in many individuals. In addition, the renal tubules and papillae have many surfaces that may attract a crystalline nidus and add further biologic material to the forming stone.7 This means that under the right conditions (such as insufficient fluid intake), a person may be prone to developing these stones. The pH of urine also influences the risk of precipitation and calculus formation. An alkaline urinary pH (pH >7) significantly increases the risk of calcium phosphate stone formation, whereas acidic urine (pH 25
Female: 3.5–35
Female: > 35
Not CKD unless haematuria, structural or pathological abnormalities present
Combines kidney function stage (stages 1–5) with description of kidney damage (albuminuria) and clinical diagnosis to specify CKD fully (e.g. stage 2 CKD with microalbuminuria, secondary to diabetic kidney disease). ACR = albumin:creatinine ratio Notes: Yellow: Assessment and reduction of cardiovascular risk: • blood pressure, may require ACE inhibitors or angiotensin II receptor blockers • lipids • blood glucose • lifestyle modifications (smoking, weight, physical activity, salt, alcohol). Avoid nephrotoxic drugs (such as the antibiotic gentamicin).
Orange: As for yellow, plus: • monitor every 3–6 months • early detection and management of complications • ensure drug doses are appropriate for level of kidney function • consider indications for referral to renal specialist. Red: As for orange, plus: • monitor every 1–3 months • prepare for dialysis or transplant • prepare for end-of-life decisions.
Different theories have been proposed to account for the adaptation to loss of renal function. The intact nephron hypothesis proposes that loss of nephron mass with progressive kidney damage causes the surviving nephrons to sustain normal kidney function — this means that the remaining nephrons have an increased productivity to compensate for those that no longer contribute to renal function. These nephrons are capable of a compensatory hypertrophy and expansion or hyperfunction in their rates of filtration, reabsorption and secretion and can maintain a constant rate of excretion in the presence of an overall declining GFR. The intact nephron hypothesis explains adaptive changes in solute and water regulation that occur with advancing chronic kidney disease. Although the urine of an individual with chronic kidney disease may contain abnormal amounts of protein and red and white blood cells or casts, the major end products of excretion are similar to those of normally functioning kidneys until the advanced stages of end-stage kidney disease (see below), when there is a significant reduction of functioning nephrons.56,57 The continued loss of functioning nephrons and the adaptive hyperfiltration (more than usual amounts of substances being filtered at the glomerulus) probably results in further nephron injury (glomerulosclerosis and ultimately results in uraemia and end-stage kidney disease.58 This is known as the trade-off hypothesis. Factors involved in the progression of chronic kidney disease are outlined in Table 30.6.
Progression of chronic kidney disease is thought to be associated with common pathophysiological processes regardless of the initial disease (see Fig. 30.9).59 These processes include the following:60 • glomerular hypertension, hyperfiltration, and hypertrophy • glomerulosclerosis (scarring) • tubulointerstitial inflammation and fibrosis. The factors that contribute to the pathogenesis of chronic kidney disease are complex and involve the interaction of many cells, cytokines and structural alterations. Two factors that have consistently been recognised to advance renal disease are proteinuria and angiotensin II.60–63 Glomerular hyperfiltration and increased glomerular capillary permeability lead to proteinuria. Proteinuria contributes to tubule injury by accumulating in the interstitial spaces and activating complement proteins and other mediators and cells, such as macrophages, that promote inflammation and progressive fibrosis. Angiotensin II activity is elevated with progressive nephron injury. Angiotensin II promotes glomerular hypertension and hyperfiltration caused by efferent arteriolar vasoconstriction and also promotes systemic hypertension. The chronically high glomerular pressure increases glomerular capillary permeability, contributing to proteinuria. Angiotensin II may also promote the activity of inflammatory cells and growth factors that participate in the scarring of the tubules.
CHAPTER 30 Alterations of renal and urinary tract function across the life span
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TABLE 30.6 Factors representing progression of chronic kidney failure FACTOR
CHARACTERISTICS
Proteinuria
Glomerular hyperfiltration of protein contributes to tubular interstitial injury by accumulating in interstitial space and promoting inflammation and progressive fibrosis.
Creatinine and urea clearance
In chronic renal failure, the GFR falls and the plasma creatinine concentration increases by a reciprocal amount; because there is no regulatory adjustment for creatinine, plasma levels continue to rise and serve as an index of changing glomerular function. As GFR declines, urea clearance increases. (Note: urea is both filtered and reabsorbed and varies with state of hydration.)
Sodium and water balance
In chronic renal failure, sodium load delivered to nephrons exceeds normal, so excretion must increase; thus less is reabsorbed. Obligatory loss occurs, leading to sodium deficits and volume depletion. As GFR is reduced, ability to concentrate and dilute urine diminishes.
Phosphate and calcium balance
Changes in acid–base balance affect phosphate and calcium balance. Major disorders associated with chronic renal failure are reduced renal phosphate excretion, decreased renal production of 1,25-dihydroxyvitamin D3, and hypocalcaemia. Hypocalcaemia leads to secondary hyperparathyroidism, GFR falls, and progressive hyperphosphataemia, hypocalcaemia, and dissolution of bone result.
Haematocrit
Because of anaemia that accompanies chronic renal failure, lethargy, dizziness, and low haematocrit are common.
Potassium balance
In chronic renal failure, tubular secretion of potassium increases until oliguria develops. Use of potassium-sparing diuretics also may precipitate elevated serum potassium levels. As disease progresses, total body potassium levels can rise to life-threatening levels and dialysis is required.
Acid–base balance
In early renal insufficiency, acid excretion and bicarbonate reabsorption are increased to maintain normal pH. Metabolic acidosis begins when GFR reaches 30% to 40%. Metabolic acidosis and hyperkalaemia may be severe enough to require dialysis when end-stage renal failure develops.
Dyslipidaemia
Chronic hyperlipidaemia may induce glomerular and tubulointerstitial injury, contributing to progression of chronic renal disease.
GFR = glomerular filtration rate.
CLINICAL MANIFESTATIONS
The clinical manifestations of chronic kidney disease are often described using the terms azotaemia and uraemia. Azotaemia is increased levels of serum urea and other nitrogenous compounds related to decreasing kidney function. Uraemia (or uraemic syndrome) presents the systemic symptoms associated with the accumulation of nitrogenous wastes from protein metabolism as well as the systemic symptoms caused by a decline in renal function with the accumulation of toxins in the plasma. Sources of toxins include end products of protein metabolism, alterations in electrolytes, metabolic acidosis and intestinal absorption of toxins produced by gut bacteria. Uraemia represents a pro-inflammatory state with many systemic effects.64 Generally, the symptoms include hypertension, anorexia, nausea, vomiting, diarrhoea, weight loss, pruritus (itching), oedema, anaemia and neurological and skeletal changes. The many systemic manifestations associated with chronic kidney disease are discussed in the following sections and shown in Fig. 30.10.
Creatinine and urea clearance
Creatinine, a breakdown product of creatine phosphate, is constantly released from muscle and excreted by the kidneys through filtration. In chronic kidney disease, with the decline in GFR, the plasma creatinine level increases. The clearance of urea follows a similar pattern, but urea is both filtered and reabsorbed and varies with the state of hydration; therefore urea concentration is not a good index of GFR. However, as the GFR decreases, plasma urea concentration increases.
Fluid and electrolyte balance
Fluid and electrolyte balance is significantly disturbed with chronic kidney disease, especially as the disease progresses. When the GFR decreases to 25%, there is an obligatory loss of 20 to 40 mmol of sodium per day with osmotic loss of water. Dietary intake must be maintained to prevent sodium deficits and volume depletion. As the GFR continues to decline, there is also loss of tubular function
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CONCEPT MAP
Lethargy, seizures, coma
Renal injury causes
Epistaxis
Loss of nephrons
↑ Angiotensin II
results in
results in
Anaemia (mucosal pallor) Sallow pigmentation
Glomerular capillary hypertension
Pruritic excoriations
causes
Bruising
↑ Glomerular permeability and filtration leads to causes further
Proteinuria causes ↑ Tubular protein reabsorption
Amenorrhoea Impotence Infertility
leads to
leads to
results in
Anorexia Nausea Vomiting Hypertension Pericarditis Heart failure Pleurisy Dyspnoea on exercise
Nail changes
Systemic hypertension
Tubulointerstitial inflammation and fibrosis
'Frost' 'Red eye'
results in
Renal scarring
FIGURE 30.9
Myopathy (muscle weakness) Peripheral neuropathy
Bone pain
Oedema
FIGURE 30.10
Common signs and symptoms of kidney failure. Kidney failure can lead to various complications including hypertension, anorexia and nausea, anaemia and coma.
Chronic kidney disease progression, leading to end-stage kidney disease.
to dilute and concentrate the urine and urine-specific gravity becomes fixed at about 1.010 (the specific gravity of distilled water is 1.000). Ultimately, the kidney loses its ability to regulate sodium and water balance. Both sodium and water are retained, contributing to oedema and hypertension. In early stages of chronic kidney disease, tubular secretion of potassium is maintained, with larger amounts of potassium lost via the faeces. With the onset of oliguria, as end-stage kidney disease occurs, total body potassium can increase to life-threatening levels and must be controlled by dialysis. Metabolic acidosis develops when GFR decreases to less than 20% to 25% of normal. The causes of acidosis are primarily related to decreased hydrogen ion elimination and decreased bicarbonate reabsorption. With end-stage kidney disease, metabolic acidosis will be severe enough to require sodium bicarbonate therapy and dialysis.65
Calcium, phosphate, and bone
Bone and skeletal changes develop with alterations in calcium and phosphate metabolism. These changes begin when the GFR decreases to 25% or less. Hypocalcaemia is accelerated
by impaired renal production of 1,25-dihydroxyvitamin D3 (calcitriol) with decreased intestinal absorption of calcium. Renal phosphate excretion also decreases and the increased serum phosphate binds calcium, further contributing to hypocalcaemia. Acidosis also contributes to a negative calcium balance. Decreased serum calcium level stimulates parathyroid hormone secretion with mobilisation of calcium from bone. The combined effect of hyperparathyroidism and vitamin D deficiency can result in renal osteodystrophies (i.e. osteomalacia and osteitis fibrosa) with increased risk for fractures — a term CKD-MBD (chronic kidney disease metabolic bone disorder) is used.66
Protein, carbohydrate, and fat metabolism
Protein, carbohydrate, and fat metabolism are altered in chronic kidney disease. Proteinuria, metabolic acidosis, inflammation, and a catabolic state contribute to a negative nitrogen balance. Levels of serum proteins diminish, including albumin, complement, and transferrin, and there is loss of muscle mass. Insulin resistance and glucose intolerance are common and may be related to proinflammatory cytokines, and alterations in adipokines (high leptin and low adiponectin levels) that interfere with insulin action.67 Hyperparathyroidism also decreases insulin sensitivity and impairs glucose tolerance.56
CHAPTER 30 Alterations of renal and urinary tract function across the life span
Musculoskeletal system
Alterations to the musculoskeletal system occur with chronic kidney disease, due to alterations in calcium and phosphate metabolism. As the GFR decreases, urinary phosphate excretion is impaired and the serum phosphate levels increase. The kidneys fail to activate vitamin D, calcium absorption is impaired and hence serum calcium decreases. Low serum calcium and high serum phosphate levels stimulate the release of PTH, which causes resorption of calcium and phosphate from the bone. This release increases serum calcium as well as serum phosphate levels. The excess phosphate binds with calcium, leading to the formation of insoluble calcifications that are deposited throughout the body, particularly in muscles, lungs, skin and subcutaneous tissue, GI tract, walls of blood vessels and the eyes. Chronic kidney disease can lead to nonspecific symptoms such as pain and stiffness in the joints, predisposition to fracture and muscle weakness. It can cause cardiovascular calcification and calciphylaxis.66 In addition, there is a strong association with accelerated risk of stroke, amputation, disruption of the conduction system and cardiac arrest. The complication of chronic kidney disease contributes significantly to the patient’s increased morbidity and mortality risks. There are three components to alterations to the musculoskeletal system with chronic kidney disease: • Bone turnover describes the skeletal remodelling process that occurs as old bone is replaced with healthy new bone (the balance between bone resorption and formation). It can be classified as low, normal or high. • Bone mineralisation describes the efficiency of collagen calcification during the formation phase of skeletal remodelling and can be classified as either normal or abnormal. • Bone volume is an indication of the amount of bone per unit volume and is classified as normal, low or high. The abnormalities are described in terms of the interactions among these three components and result in four types of renal osteodystrophy: (1) osteomalacia; (2) adynamic bone disease; (3) osteitis fibrosa; and (4) mixed uraemic osteodystrophy.66
Cardiovascular system
Cardiovascular disease is a major cause of morbidity and mortality in chronic kidney disease. Proinflammatory mediators, oxidative stress and metabolic derangements are significant contributors.68,69 Hypertension is the result of excess sodium and fluid volume. Elevated renin also stimulates the secretion of aldosterone, increasing sodium reabsorption. Hyperlipidaemia promotes formation of atherosclerosis. Endothelial cell dysfunction and calcium deposits lead to a loss of vessel elasticity, and vascular calcification. The resulting vascular disease increases the risk for coronary heart disease, left ventricular hypertrophy, heart failure, stroke and peripheral vascular disease in
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individuals with uraemia. Declining erythropoietin production causes anaemia, thereby increasing demands for cardiac output and adding to cardiac workload. Pericarditis can develop from inflammation caused by the presence of uraemic toxins. Accumulation of fluid in the pericardial space can compromise ventricular filling and cardiac output. Dyslipidaemia is common among individuals with chronic kidney disease. There is a high ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL), a high level of triglycerides, and an accumulation of LDL particles with accelerated atherosclerosis and vascular calcification. Uraemia causes a deficiency in lipoprotein lipase and a decreased level of hepatic triglyceride lipase. Decreased lipolytic activity results in a reduction in HDL level. The concentration of apolipoprotein B is also elevated, thereby accelerating atherogenesis.70
Pulmonary system
Pulmonary complications are associated with fluid overload, congestive heart failure and dyspnoea. Pulmonary oedema develops and metabolic acidosis can cause Kussmaul respirations.
Haematological system
Haematological alterations include normochromic-normocytic anaemia, impaired platelet function, and hypercoagulability. Inadequate production of erythropoietin decreases red blood cell production and uraemia decreases red blood cell life span. Lethargy, dizziness and low haematocrit values are common findings. Defective platelet aggregation and altered vascular endothelium promote an increased bleeding tendency, increased risk for bruising, epistaxis, gastrointestinal bleeding, or cerebrovascular haemorrhage. Alterations in thrombin and other clotting factors contribute to hypercoagulability; thus control of coagulation is essential during dialysis.
Immune system
Immune system dysregulation with immune suppression, deficient response to vaccination and increased risk for infection develops with chronic kidney disease. Chemotaxis, phagocytosis, antibody production and cell-mediated immune responses are suppressed. Malnutrition, metabolic acidosis and hyperglycaemia may amplify immunosuppression.
Neurological system
Neurological symptoms are common and progressive with chronic kidney disease. Symptoms may include headache, drowsiness, sleep disorders, impaired concentration, memory loss and impaired judgment. Neuromuscular irritation can cause hiccups, muscle cramps, and muscle twitching. In end-stage kidney disease, symptoms may progress to seizures and coma. Peripheral neuropathies can also develop with impaired sensations particularly in the lower limbs.70
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Digestive system
Gastrointestinal complications are common in individuals with chronic kidney disease. Uraemic gastroenteritis can cause bleeding ulcer and significant blood loss. Nonspecific symptoms include anorexia, nausea and vomiting, constipation, or diarrhoea. Uraemia can cause uraemic fetor (bad breath) caused by the breakdown of urea by salivary enzymes. Malnutrition in these patients is common.
Endocrine and reproductive systems
Endocrine and reproductive alterations develop with progression of chronic kidney disease. Both males and females have a decrease in levels of circulating sex steroids. Males often experience a reduction in testosterone levels and may be impotent. Oligospermia and germinal cell dysplasia can result in infertility. Females have reduced oestrogen levels, amenorrhoea, and difficulty maintaining a pregnancy to term. A decrease in libido occurs in both genders. Insulin resistance is common in uraemia and as chronic kidney disease progresses the ability of the kidney to degrade insulin is reduced and the half-life of insulin is prolonged (which means that insulin’s effects last for longer than usual). Individuals with diabetes mellitus and chronic kidney disease need to carefully manage their insulin dosages. Low-protein diets and renal replacement therapy improve insulin sensitivity.71 Chronic kidney disease also causes alterations in thyroid hormone metabolism, known as nonthyroidal illness syndrome.72 A low-protein, low-phosphorus diet may improve thyroid hormone function.73
Integumentary system
Skin changes are associated with other complications that develop with chronic kidney disease. Anaemia can cause pallor and bleeding into the skin and results in haematomas and ecchymosis (bruises). Retained urochromes manifest as a sallow colour. Hyperparathyroidism and uraemic skin residues (known as uraemic frost) are associated with inflammation, irritation, and pruritus with scratching, excoriation, and increased risk for infection.74 EVALUATION AND TREATMENT
Evaluation of chronic kidney disease is based on risk factors, history and presenting signs and symptoms. Elevated serum creatinine and serum urea concentrations are consistent with chronic kidney disease. Markers of kidney damage include urine protein, particularly albumin, and examination of urine sediment. Ultrasound, CT scan or plain x-ray films will show small kidney size. Renal biopsy confirms the diagnosis. Management of chronic kidney disease is multifactorial and involves a multidisciplinary healthcare team. The mainstay of management (if the kidney disease does not necessitate transplant or dialysis) involves dietary control, including protein restriction, supplementation with vitamin
D, fluid evaluation (with likely restriction), sodium, potassium and phosphate restriction, adequate kilojoule intake, management of dyslipidaemias and erythropoietin replacement therapy as needed. Angiotensin-converting enzyme (ACE) inhibitors or receptor blockers are often used to provide renal protection and to control systemic hypertension.74 End-stage kidney disease related to diabetic nephropathy can often be significantly reduced with control of hyperglycaemia by intense insulin therapy.75 However, when end-stage kidney disease is established, dialysis and kidney transplantation are required to sustain life.76 Fig. 30.11 provides an overview of the management of chronic kidney disease. In Australia in 2014, approximately 22 000 people received kidney replacement therapy (mainly dialysis) for end-stage kidney disease, and about 10 000 had a functioning kidney transplant, with more than 12 000 receiving different forms of dialysis. Each day, six Australians commence dialysis or transplantation to stay alive.6,77,78 Approximately 30% of all dialysis is performed in the home.79 FOCU S ON L EA RN IN G
1 Discuss the different ways that chronic kidney disease can arise. 2 Describe the different stages of chronic kidney disease. 3 Provide a pathophysiological explanation of the progression of chronic kidney disease to end-stage kidney disease.
Acute kidney injury In contrast to chronic kidney disease, acute kidney injury refers to a sudden decline in kidney function occurring over hours to days that inhibits the ability to regulate fluid, electrolyte and acid-base balance.80 Acute kidney injury is associated with a decrease in glomerular filtration and accumulation of nitrogenous waste products in the blood as demonstrated by an elevation in plasma creatinine and blood urea nitrogen levels. Previously, the term acute renal failure was used; however, there were more than 30 different definitions in the literature and this made the finding and diagnosis of acute renal failure difficult to determine, and inconsistent.81 Therefore, the Acute Dialysis Quality Initiative and the Acute Kidney Injury Network collaborated to provide a consensus on the definition, proposing that acute kidney injury more accurately reflects the spectrum of changes that can occur prior to and during failure.81,82 Furthermore, a classification system was devised, which outlined the progressive kidney alterations that lead to failure. This is termed the RIFLE staging system: Risk Injury Failure Loss End-stage kidney disease.
CHAPTER 30 Alterations of renal and urinary tract function across the life span
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Presentation/detection of CKD
Reversible factors
Treatable
Specific diagnosis
Cure/improvement Unexpected decline in function
Monitor BP, albuminuria
Monitor GFR and albuminuria Treatment to:
Slow rate of progression of CKD and cardiovascular disease BP Albuminuria Lipids Diet
Prevent/detect complications CVS Bone Anaemia K , HCO3 GFR 10 mL/min
Prepare for renal Rapidly in uncontrolled replacement therapy diabetes, CHF, BP ↑
Education Available donor? Establish access
End-stage kidney disease Renal replacement therapy FIGURE 30.11
Management of chronic kidney disease. BP = blood pressure; CHF = congestive heart failure; CVS = cardiovascular system; CKD = chronic kidney disease; GFR = glomerular filtration rate
This system more accurately describes the range of stages that may occur (see Table 30.7). Renal injury generally refers to a decline in renal function to about 25% of normal or a GFR of 25 to 30 mL/min. Levels of serum creatinine and urea are mildly elevated. Renal failure refers to significant loss of renal function requiring dialysis. End-stage kidney disease (ESKD) refers to a renal function of less than 10% requiring dialysis or transplant. Acute kidney injury occurs rapidly with a reduction in the GFR and elevation of blood urea and plasma creatinine. It is usually associated with oliguria (urine output of less than 0.5 mL/kg/hr), although in some cases urine output may be normal or increased. Fluid is still filtered at the glomerulus but there is an alteration in tubular secretion or reabsorption. This condition commonly results from
extracellular volume depletion, decreased renal blood flow, or toxic/inflammatory injury to kidney cells resulting in alterations in renal function that may be minimal or severe. Most types of acute kidney injury are reversible if diagnosed and treated early. Acute kidney injury can be classified as prerenal, intrarenal or postrenal (obstructive) (see Fig. 30.12 and Table 30.8).83 PATHOPHYSIOLOGY
Prerenal acute kidney injury is the most common cause of acute kidney injury and is caused by impaired renal blood flow, so the underlying cause is actually prior to the kidney (in terms of direction of blood flow). The GFR declines because of the decrease in filtration pressure. Poor perfusion can result from renal vasoconstriction, hypotension,
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TABLE 30.7 RIFLE classification for acute kidney injury CATEGORY
SERUM CREATININE/GFR
URINE OUTPUT
Risk
Increased creatinine × 1.5
< 0.5 mL/kg/hr ≥ 6 hours
or decrease in GFR > 25% Injury
Increased creatinine × 2 or decrease GFR > 50%
Failure
Increased creatinine × 3 or decrease in GFR > 75%
Loss
Complete loss of kidney function > 4 weeks
End-stage
End-stage kidney disease > 3 months
Prerenal
Intrarenal
TABLE 30.8 Classification of acute kidney injury LOCATION
POSSIBLE CAUSES
Prerenal
Hypovolaemia Haemorrhage leading to significant blood loss (trauma, gastrointestinal bleeding, complications of childbirth)
< 0.5 mL/kg/hr ≥ 12 hours
Loss of plasma volume (burns, peritonitis)
< 0.3 mL/kg/hr ≥ 24 hours
Water and electrolyte losses (severe vomiting or diarrhoea, intestinal obstruction, uncontrolled diabetes mellitus, inappropriate use of diuretics)
or anuria ≥ 12 hours
Hypotension or hypoperfusion Septic shock Cardiac failure or shock Massive pulmonary embolism Stenosis or clamping of renal artery
Postrenal
Intrarenal Acute tubular necrosis (postischaemic or nephrotoxic) Glomerulopathies Acute interstitial necrosis (tumours or toxins) Vascular damage Malignant hypertension Coagulation defects Renal artery/vein occlusion Bilateral acute pyelonephritis Postrenal
Obstructive uropathies (usually bilateral) Ureteral destruction (oedema, tumours, stones, clots) Bladder neck obstruction (enlarged prostate) Neurogenic bladder
FIGURE 30.12
Prerenal, intrarenal and postrenal acute kidney injury.
hypovolaemia, haemorrhage or inadequate cardiac output (such as heart failure). Acute prerenal kidney injury may occur when chronic kidney disease exists if a sudden stress is imposed on already marginally functioning kidneys. Failure to restore blood volume or blood pressure and oxygen delivery causes cell injury. Intrarenal acute kidney injury usually results from acute tubular necrosis related to prerenal acute kidney injury, nephrotoxic acute tubular necrosis (e.g. exposure to radiocontrast media), acute glomerulonephritis, vascular disease (malignant hypertension, disseminated intravascular coagulation, and renal vasculitis), allograft rejection, or interstitial disease (drug allergy, infection, tumour growth).
Acute tubular necrosis caused by ischaemia occurs most often after surgery (40–50% of cases) but is also associated with sepsis, obstetric complications, severe trauma including severe burns, and nephrotoxins (radiocontrast media and some antibiotics). Hypotension associated with hypovolaemia produces ischaemia, generating toxic oxygen-free radicals that cause cell swelling, injury and necrosis.84 Dehydration, advanced age, concurrent chronic kidney disease and diabetes mellitus tend to enhance nephrotoxicity from either antibiotics or radiocontrast media. Certain antibiotics (such as gentamicin and tobramycin) tend to accumulate in the renal cortex and may not cause kidney injury until after treatment is complete. Necrosis caused by nephrotoxins is usually uniform and limited to the proximal tubules. Ischaemic necrosis tends to be patchy and may be distributed along any part of the nephron. Other substances, such as excessive myoglobin (oxygen-carrying substance in muscles), heavy metals (mercury, arsenic), or methoxyflurane anesthetic, and bacterial toxins may promote acute kidney injury.
CHAPTER 30 Alterations of renal and urinary tract function across the life span
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CONCEPT MAP
Ischaemia or nephrotoxins can cause Tubular injury (i.e. acute tubular necrosis)
Possible glomerular injury leads to
Intrarenal vasoconstriction
Decreased permeability and decreased surface area
leads to
leads to
Cellular cast formation causes Obstruction
Tubular back leak
results in
causes
Increased intraluminal pressure
leads to Decreased GFR
leads to
causes
causes Oliguria
FIGURE 30.13
Mechanisms of oliguria in acute kidney injury.
Oliguria can occur in AKI and three mechanisms have been proposed to account for the decrease in urine output in acute tubular necrosis.85,86 All three mechanisms probably contribute to oliguria in varying combinations and degrees throughout the course of the disease (see Fig. 30.13). These theories87 are as follows: 1 Tubular obstruction theory. Necrosis of the tubules causes sloughing of cells, cast formation or ischaemic oedema that results in tubular obstruction, which in turn causes a retrograde increase in pressure and reduces the GFR. Acute kidney injury leading to renal failure can occur within 24 hours. 2 Back-leak theory. Glomerular filtration remains normal, but tubular reabsorption of filtrate is accelerated as a result of permeability caused by the ischaemia (see Fig. 30.14). 3 Alterations in renal blood flow. Efferent arteriolar vasoconstriction may be produced by intrarenal release of angiotensin II or by redistribution of blood flow from the cortex to the medulla. Autoregulation of blood flow may be impaired, resulting in a decreased GFR. Changes in glomerular permeability and a decreased GFR may also result from the ischaemia. Postrenal acute kidney injury is less common than preand intrarenal acute kidney injury and usually occurs with
Glomerulus Vasoconstriction Afferent blood flow
Efferent
Decreased permeability
Tubule backleak Tubule obstruction
FIGURE 30.14
The mechanism of tubular back leak leading to acute kidney injury. Obstruction in the nephron tubules can cause back leak of substances such that they return to the blood unnecessarily.
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TABLE 30.9 Differentiation of acute oliguric kidney failure URINE VOLUME
URINE SPECIFIC GRAVITY*
URINE OSMOLALITY
URINE SODIUM CONCENTRATION
BUN/PLASMA CREATININE
RATIO
FENa*
Prerenal failure
< 400 mL
1.016–1.020
> 500 mOsm
< 10 mEq/L
> 15 : 1
30 mEq/L
< 15 : 1
>1% (also seen in acute urinary tract obstruction and renal disease)
* FENa =
Urine Na plasma plasma Na = ×100 Urine creatinine plasma creatinine
urinary tract obstruction that affects the kidneys bilaterally (e.g. bladder outlet obstruction, prostatic hypertrophy, bilateral ureteral obstruction). A pattern of several hours of oliguria associated with lower urinary symptoms (frequency and hesitancy) or rarely anuria (no urine output) with flank pain followed by polyuria (increased urine output) is a characteristic finding. The obstruction causes an increase in intraluminal pressure upstream from the site of obstruction with a gradual decrease in GFR. This type of acute kidney injury can occur after diagnostic catheterisation of the ureters, a procedure that may cause oedema of the tubular lumen. CLINICAL MANIFESTATIONS
The clinical progression of acute kidney injury with recovery of renal function occurs in three phases: initiation, maintenance, and recovery. The initiation phase is the phase of reduced perfusion or toxicity in which kidney injury is evolving. Prevention of injury is possible during this phase. The maintenance phase is the period of established kidney injury and dysfunction after the initiating event has been resolved and may last from weeks to months. Oliguria may occur, with urine output lowest during this phase and serum creatinine and blood urea nitrogen (BUN) levels both increase. The recovery phase is the interval when kidney injury is repaired and normal renal function is re-established. Increases in urine volume (diuresis) are progressive, with a decline in serum creatinine and urea concentrations and an increase in creatinine clearance. Serial measurements of plasma creatinine provide an index of renal function during the recovery phase. Return to normal status may take from 3 to 12 months although some individuals do not have full recovery of a normal GFR or tubular function.
EVALUATION AND TREATMENT
The diagnosis of acute kidney injury is related to the cause of the disease. A history of surgery, trauma or cardiovascular disorders is common and exposure to nephrotoxins must be considered. Obstructive uropathies (e.g. an enlarged prostate) also need consideration. The diagnostic challenge is to differentiate prerenal from intrarenal acute kidney injury and some evidence is available from urinalysis, plasma creatinine and urea (Table 30.9). Biomarkers are being developed to assess the extent of kidney injury.88 Prevention of acute kidney injury is a major treatment factor and involves maintenance of fluid volume before and after surgery or diagnostic procedures and use of vasoactive drugs (which affect the diameter of the blood vessels) or diuretics.89 The primary goal of therapy is to maintain the individual’s life until renal function has been recovered. Management principles directly related to physiological alterations generally include: • correcting fluid and electrolyte disturbances • treating infections • maintaining nutrition • remembering that drugs or their metabolites are not excreted. Renal replacement therapy in the form of haemodialysis may be indicated. The mortality rate is greater than 30%90 and is associated with the underlying cause of acute kidney injury. FOCU S ON L EA RN IN G
1 Discuss the mechanisms that cause prerenal acute kidney injury. 2 Differentiate between intrarenal and postrenal acute kidney injury.
The incidence and type of renal and urinary tract disorders experienced by children vary with age and maturation. Newborn disorders may involve congenital malformations. During childhood, the kidney and genitourinary structures continue to develop, so renal dysfunction may be associated with mechanisms
and manifestations that differ from those found in adults. Structural abnormalities Variations from the normal anatomical structure of the urinary tract occur in 10–15% of the total population.
PAEDIATRICS
Paediatrics and renal and urinary tract disorders
CHAPTER 30 Alterations of renal and urinary tract function across the life span
These abnormalities range from minor, non-pathological or easily correctable anomalies to those that are incompatible with life. For example, the kidneys may fail to ascend from the pelvis to the abdomen, causing ectopic kidneys — which usually function normally. The kidneys may also fuse as they ascend, causing a single, U-shaped horseshoe kidney. Approximately one-third of individuals with horseshoe kidneys are asymptomatic and the most common problems are hydronephrosis, infection, stone formation and, rarely, renal malignancies. Collectively, structural anomalies of the renal system account for approximately 45% of cases of kidney injury leading to failure in children and many are linked to gene defects. Certain structural anomalies are commonly associated with urinary tract malformations, including: • low-set, malformed ears • chromosomal disorders, especially trisomy 13 (Patau syndrome) and trisomy 18 • absent abdominal muscles (prune-belly syndrome) • anomalies of the spinal cord and lower extremities • imperforate anus or genital deviation • nephroblastoma (Wilms’ tumour) • congenital ascites • cystic disease of the liver • positive family history of renal disease (hereditary nephritis or cystic disease). Hypospadias Hypospadias is a congenital condition in which the urethral meatus is located on the ventral side or undersurface of the penis. The meatus can be located anywhere on the glans, on the penile shaft, at the base of the penis, the penoscrotal junction or the perineum (see Fig. 30.15). This is the most common anomaly of the penis; it occurs in about 1 in 150 infant boys in
FIGURE 30.15
Hypospadias. This image shows the urethral opening in an abnormal position.
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Australia and the incidence appears to be increasing. The cause of this condition is multifactorial and includes genetic, endocrine and environmental factors. Maternal intake of progestin, advanced maternal age and low birthweight also have been implicated. Chordee or penile torsion may accompany cases of hypospadias. In chordee, skin tethering and shortening of subcutaneous tissue cause the penis to bend or ‘bow ventrally’. Penile torsion is rotation of the penile shaft to either the right or the left. Partial absence of the foreskin and cryptorchidism (undescended testes; see Chapter 32) are associated with the anomaly. The goals for corrective surgery on the child with hypospadias are: (1) a straight penis when erect to facilitate intercourse as an adult; (2) a uniform urethra of adequate calibre to prevent spraying during urination; (3) a cosmetic appearance satisfactory to the individual; and (4) repair completed in as few procedures as possible. Surgery is most effective, psychologically as well as physically, when performed between 4 and 8 months of age. Hypoplastic/dysplastic kidneys During embryologic development, the ureteric duct grows into the metanephric tissue, triggering the formation of the kidneys. If this growth does not occur, the kidney is absent — a condition called renal aplasia. A hypoplastic kidney is small with a decreased number of nephrons. These conditions may be unilateral or bilateral; the occurrence may be incidental or familial. Bilateral hypoplastic kidneys are a common cause of chronic kidney disease in children. Segmental hypoplasia may be congenital or secondary to vesicoureteral reflux. Systemic hypertension is a common presentation. Renal dysplasia usually results from abnormal differentiation of the renal tissues; for example, primitive glomeruli and tubules, cysts, and nonrenal tissue (such as cartilage) are found in the dysplastic kidney. Dysplasia may be secondary to antenatal obstruction of the urinary tract from ureteroceles, posterior urethral valves, or prune-belly syndrome (congenital absence of abdominal muscles). Polycystic kidneys Polycystic kidney disease (PKD) is an autosomal dominant (PKD1 or PKD2 gene) and an autosomal recessive inherited disorder (PKHD1 gene). It occurs in about 1 in 1000 live births. The affected kidney has large fluidfilled cysts that include the tubules and collecting ducts (see Fig. 30.16). Defects in the formation of epithelial cells and their cilia result in cyst formation in all parts of the nephron. Other organs also may have cysts, including the liver, pancreas and ovaries. Hypertension, heart valve defects and cerebral and aortic aneurysms may develop. Symptoms may not develop until adulthood. Autosomal recessive PKD is often first suspected on a Continued
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A
B
FIGURE 30.16
Polycystic kidneys. A This kidney was substantially enlarged and weighed 3 kg with large cysts. B The cysts (red diamond shapes on CT scan) are not present at birth but develop slowly over time. Chronic kidney disease occurs later in life, approximately at 50 years of age.
prenatal ultrasound. Cyst formation is related to tubular cell proliferation, basement membrane remodelling and fluid accumulation with obstruction. Hepatic disease and hypertension typically accompany autosomal recessive PKD. No treatment is available. Renal agenesis Renal agenesis (the absence of one or both kidneys) may be unilateral or bilateral and randomly occurring or clearly be hereditary. The kidney is usually polycystic and dysplastic (abnormal cells). The condition may occur as an isolated entity or as a problem associated with other urological disorders. Unilateral renal agenesis occurs in approximately 1 in 1000 live births. Males are more often affected and it is usually the left kidney that is absent. The single remaining kidney is often completely normal so that the child can expect a normal, healthy life. By the time the child is several years old, the volume of this kidney may approach twice the normal size. In some instances, however, the single kidney is abnormally formed and associated with abnormalities of its collecting system. Extrarenal congenital abnormalities of the urogenital, skeletal, cardiac and other systems may co-exist. Bilateral renal agenesis is a rare disorder incompatible with extrauterine life. Approximately 75% of affected children are males. Oligohydramnios (low amount of amniotic fluid) leads to underdeveloped lungs and Potter syndrome (wide-set eyes, parrot-beak nose, low-set ears
and receding chin). Approximately 40% of affected infants are stillborn. Infants with this condition rarely live more than 24 hours because of pulmonary insufficiency. Renal agenesis can be detected prenatally by ultrasound. Bladder disorders Epispadias and exstrophy of the bladder Epispadias and exstrophy of the bladder are the same congenital defect expressed to differing degrees. In male epispadias, the urethral opening is on the dorsal surface of the penis. In females, a cleft along the ventral urethra usually extends to the bladder neck. The incidence of epispadias is 1 in 1 117 000 in boys and 1 in 484 000 in girls at birth. More boys than girls present with this defect. In boys, the urethral opening may be small and situated behind the glans (anterior epispadias), or a fissure may extend the entire length of the penis and into the bladder neck (posterior epispadias). Children with anterior epispadias may only have stress incontinence, but those with posterior epispadias will experience constant dribbling of urine. Treatment is surgical reconstruction. Exstrophy of the bladder is a rare extensive congenital anomaly of herniation of the bladder through the abdominal wall. The bony part of the pelvis remains open, and the posterior portion of the bladder mucosa is exposed through the abdominal opening and appears bright red. The incidence of bladder exstrophy is approximately 2 per 100 000 live births and occurs equally in males and females.
CHAPTER 30 Alterations of renal and urinary tract function across the life span
Exstrophy of the bladder is caused by intrauterine failure of the abdominal wall and the mesoderm of the anterior bladder to fuse. The rectus muscles below the umbilicus are separated, and the pubic rami (bony projections of the pubic bone) are not joined. This causes a waddling gait when the child first learns to walk, but most children quickly learn to compensate. The clitoris in girls is divided into two parts with the urethra between each half. The penis in boys is epispadiac. Urine seeps onto the abdominal wall from the ureters, causing a constant odour of urine and excoriation of the surrounding skin. Because the exposed bladder mucosa becomes hyperaemic and oedematous, it bleeds easily and is painful. The unrepaired exstrophic bladder is prone to cancerous changes as soon as 1 year after birth. Ideally, the bladder and pubic defect should be closed before the infant is 72 hours old. Surgical reconstruction is usually performed within the first year either as a complete primary repair or as staged procedures. Staged procedures may include bladder augmentation, bladder neck reconstruction, and epispadias repair. Objectives of management include preservation of renal function, attainment of urinary control, prevention of infection, and improvement of sexual function. Diagnosis is often made by prenatal ultrasound. Cloacal exstrophy is the most rare and severe form of bladder exstrophy. The intestine and spine may be involved, and reconstruction with restored urine and faecal control is difficult. Bladder outlet obstruction Congenital causes of bladder outlet obstruction are rare and include urethral valves and polyps. A urethral valve is a thin membrane of tissue that occludes the urethral lumen and obstructs urinary outflow in males. Most valves occur in the posterior urethra, although a few arise from the embryologically distinct anterior urethra. Urethral polyps arising from the prostatic urethra are rare. They often cause relatively severe obstruction and may impair renal embryogenesis and lead to renal failure. Urethral valves or polyps are resected as soon as they are diagnosed. Ureteropelvic junction obstruction Ureteropelvic junction (UPJ) obstruction is a blockage of the tapered point where the renal pelvis transitions into the ureter. UPJ obstruction is the most common cause of hydronephrosis in neonates. An intrinsic malformation of smooth muscle or urothelial development produces obstruction in 90% of cases, and approximately 10% are caused by extrinsic compression. During infancy or childhood, secondary ureteropelvic junction obstruction is caused by kinking or secondary scarring in the presence of high-grade vesicoureteral reflux (see below). There is an increased risk of vesicoureteral reflux in children with UPJ obstruction in the obstructed or
939
contralateral kidney, or both; whether this represents a sequela of the embryonic defect leading to the UPJ defect is not known. Diagnosis can be made by ultrasound. Obstruction of the distal ureter (ureterovesical junction obstruction) causes dilation of the entire ureter, renal pelvis, and caliceal system. An ureterocele is a cystic dilation of the intravesical ureter. Open or endoscopic surgery to relieve an obstruction occurs if there is decline of renal drainage or function. Vesicoureteral reflux Vesicoureteral reflux is the retrograde flow of urine from the bladder into the kidney or ureters, or both. Reflux allows infected urine from the bladder to be repeatedly swept up into the kidneys. The reflux perpetuates infection by preventing complete emptying of the bladder and allows the maximal intravesical pressure to be transmitted to the renal calyces and pyramids. The combination of reflux and infection is an important cause of pyelonephritis, especially in children younger than 5 years. Vesicoureteral reflux occurs more often in girls by a ratio of 10 : 1. Its incidence is approximately 1 in 1000 children. Siblings of those affected have a 25–33% chance of having reflux, but children with parents who had childhood reflux have almost a 70% chance of reflux. Although reflux is considered abnormal at any age, the shortness of the submucosal segment of the ureter during infancy and childhood renders the anti-reflux mechanism relatively inefficient and delicate. Thus reflux is seen commonly in association with infections during early childhood but rarely in older children and adults. PATHOPHYSIOLOGY
The normal distal ureter enters the bladder through the detrusor muscle and passes through a submucosal tunnel before opening into the bladder lumen via the ureteral orifice. As the bladder fills with urine the ureter is compressed within the bladder wall preventing reflux. Primary reflux results from a congenitally abnormal or ectopic insertion of the ureter into the bladder. It develops in association with infection, malformations of the ureterovesical junction (see Fig. 30.17), increased intravesical pressures or surgery on the ureterovesical junction. Urine sweeps up into the ureter and then flows back into the empty bladder. The reflux perpetuates infection by preventing complete emptying of the bladder and providing a reservoir for infection. With the next bladder filling, the maximal intravesical pressure can be transmitted up the ureter to the renal pelvis and calyces. The combination of reflux and infection is an important cause of pyelonephritis. Renal tissue injury, scarring, hypertension, and chronic kidney disease can occur many years later making early diagnosis and treatment important. Secondary reflux develops in association with acquired conditions (e.g. neurogenic bladder Continued
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FIGURE 30.17
Normal and abnormal configuration of the ureterovesical junction. Shown from left to right, progressive lateral displacement of the ureteral orifices and shortening of the intramural tunnels. (Top) Endoscopic appearance. (Bottom) Sagittal view through the intramural ureter.
dysfunction, ureteral obstruction, voiding disorders, or surgery on the UV junction). Reflux may be unilateral or bilateral. CLINICAL MANIFESTATIONS
Children with reflux have recurrent UTIs or unexplained fever, poor growth and development, irritability and feeding problems. The family history reveals reflux or UTIs, pain with voiding and signs of urinary obstruction or nephropathy.
TABLE 30.10 Classification of incontinence TYPE
DEFINITION
Daytime voiding frequency
Decreased: 3 or fewer voids per day Increased: 8 or more voids per day
Dysfunctional voiding
Habitual contraction of urethral sphincter during voiding; observed by uroflow measurements
Enuresis
Incontinence of urine while sleeping
Incontinence, continuous
Continuous leakage, not in discrete portions
Incontinence, stress
Leakage with raised intraabdominal pressure
Urgency
Sudden, unexpected, immediate need to void
Overactive bladder
Child with urgency; increased voiding frequency and/or incontinence may or may not be present
Underactive bladder
Decreased voiding frequency with use of raised intraabdominal pressure to void
Urge incontinence
Incontinence in children with urgency
EVALUATION AND TREATMENT
In addition to the history of recurrent UTIs and other symptoms, a voiding cystourethrogram is the primary diagnostic procedure. Most children with vesicoureteral reflux respond to non-operative management aimed at prevention and treatment of infection. Spontaneous remission of grades I and II reflux may occur in 30–60% of children younger than 5 years. Children with grades III and IV reflux need careful monitoring. Recurrent infection requires surgical intervention or endoscopic injection of a synthetic ureteral orifice valve. In cases of grade V reflux, early surgical intervention may be indicated to prevent renal scarring. Urinary incontinence Urinary incontinence (enuresis) refers to the involuntary passage of urine by a child who is beyond the age when voluntary bladder control should have been acquired. Bladder control is usually accomplished by most children before the age of 4 or 5 years. However, toilet training is largely determined by cultural beliefs and the practices of parents. In 80% of children, enuresis occurs at night only, in which case it is called nocturnal enuresis. Wetness during the day is called diurnal enuresis. (Types of incontinence are defined in Table 30.10.)
CHAPTER 30 Alterations of renal and urinary tract function across the life span
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In primary enuresis, the child has never been continent. In secondary enuresis or acquired enuresis, the child has experienced a period of dryness of at least 3–6 months after toilet training and then becomes incontinent. Secondary enuresis may be diurnal or nocturnal, or a combination of both. The incidence of enuresis is difficult to determine because it is not a problem that parents readily share with others and because definitions vary according to cultural norms and family practices. Some families start toilet training before 1 year of age and expect continence by the age of 1 to 1 1 2 years, whereas other families do not expect dryness earlier than 5 years. The incidence of enuresis in children older than 5 years ranges from 10% to 20%. Boys represent more cases of enuresis than girls by a ratio of 3 : 2. Teenage and adult enuresis is rare and usually is a continuation of childhood bed-wetting.
or surgery, and occult spinal dysraphism. Difficult sleep arousal and obstructive sleep apnoea may be associated with enuresis. Stressful psychological situations, such as a new sibling, may cause incontinence or enuresis to develop. Genetic factors as a cause of enuresis are likely and the condition shows a familial tendency. Bed-wetting occurs with high frequency among parents, siblings and other near relatives of symptomatic children. Other problems may be associated with enuresis, such as perinatal anoxia, central nervous system trauma, seizures, developmental delay, UTI and bladder trauma or surgery. Difficult sleep arousal, prolonged rapid eye movement (REM) sleep intervals and the presence of obstructive sleep apnoea syndrome (see Chapter 25) are also associated with nocturnal enuresis.
PATHOGENESIS
Diagnostic evaluation of childhood incontinence includes a thorough history, voiding diary, physical examination, and urinalysis. Urodynamic flow studies or imaging may be required based on the history and physical findings. Therapeutic management of incontinence or enuresis begins with education. If the child and family understand the probable aetiology of the child’s condition, they are better able to choose and participate in therapies that are most likely to succeed. Therapeutic management of enuresis can also include fluid management, diet therapy, drugs (desmopressin, an antidiuretic), treatment of obstructive sleep apnoea and behavioural modification therapy. The main goals of therapy should be to have the child awaken and get up to use the toilet during the night to preserve self-esteem and to relieve psychological stress.
A combination of factors is likely to be responsible for enuresis. Organic causes account for 2–10% of cases and include UTI; neurological disturbances; congenital defects of the meatus, urethra and bladder neck; and allergies. Disorders that increase the normal output of urine, such as diabetes mellitus and diabetes insipidus, or disorders that impair the concentrating ability of the kidneys, such as chronic kidney disease or sickle cell disease, must be considered in the evaluation of enuresis. Some incontinence or enuresis, in which no structural or neurological abnormality is identified, is common in children. Other conditions that may be associated with incontinence include perinatal anoxia, CNS trauma, seizures, attention-deficit hyperactivity disorder, developmental delay, imperforate anus, bladder trauma
F O CUS O N L E A R N IN G
1 Describe hypospadias. 2 Describe the pathogenesis of vesicoureteral reflux. 3 Discuss the different causes for enuresis.
Tumours Renal tumours
Kidney cancers are diagnosed in almost 3100 Australians each year and account for 962 deaths each year,90 with projections that the rate will increase slightly in the future. The rate in males is almost double that in females. Although the cause of these tumours is unknown, almost one-fifth of kidney cancers can be attributed to smoking, obesity, hypertension and excess alcohol consumption.91,92 There are a number of different types of kidney tumours. Renal adenomas (benign tumours) are uncommon but
TREATMENT
are increasing in number. The tumours are encapsulated and are usually located near the cortex of the kidney. Because they can become malignant, they need to be surgically removed. Renal cell carcinoma is the most common renal neoplasm (90% of all renal neoplasms).90 The 5-year survival is less than 50% and less than 2% with metastasis.93 PATHOGENESIS
Renal cell carcinomas are adenocarcinomas (see Chapter 37) that usually arise from tubular epithelium (lining cells) commonly in the renal cortex (see Fig. 30.18). They are classified according to cell type and extent of metastasis. Clear cell tumours, the most common, present a better prognosis than granular cell or spindle tumours. Confinement within the renal capsule, together with treatment, is associated with a better survival rate. The tumours usually occur unilaterally. About 25% of individuals with renal cell carcinoma present with metastasis — this means that the cancer has already spread to other organs, prior to it being diagnosed.94
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males in Australia and New Zealand. Approximately 2400 people develop bladder cancer each year and 1038 die from the cancer.96 There is a projected increase in bladder cancer in the future, with more males developing the disease than females. Bladder cancer is most common in males over the age of 60 years, and transitional cell carcinoma is the most common bladder malignancy. PATHOGENESIS
FIGURE 30.18
Renal cell carcinoma. The carcinoma is located on the pole of the kidney and is large but defined. It contains cysts (arrows) and has grown over a number of years.
CLINICAL MANIFESTATIONS
The classical clinical manifestations of renal tumours are haematuria, flank pain, palpable flank mass and weight loss. However, it should be noted that these symptoms occur in fewer than 10% of cases. Furthermore, they represent an advanced stage of disease, whereas earlier stages are often silent. The most common sites of metastasis are the lungs, lymph nodes, liver, bone, thyroid and central nervous system.95 EVALUATION AND TREATMENT
Diagnosis is based on the clinical symptoms, plain x-ray films of the abdomen, intravenous pyelography (whereby contrast dye is intravenously injected to show the urinary structures), renal angiography and CT scan. Treatment for localised disease is surgical removal of the affected kidney (called a radical nephrectomy) with combined use of chemotherapeutic agents. Radiation therapy may also be used.
Bladder tumours
Urinary bladder cancer accounts for 2.3% of all cancers in Australia and is the eighth most common malignancy for
The risk of primary bladder cancer is greater among people who smoke.97 Bladder cancer can result from genetic alterations in normal bladder epithelium.98 Metastasis is usually to lymph nodes, liver, bones or lungs. Staging for bladder carcinoma follows the TNM system described in Chapter 37. Secondary bladder cancer develops by invasion of cancer from bordering organs, such as cervical carcinoma in women or prostatic carcinoma in men. CLINICAL MANIFESTATIONS
Gross painless haematuria is the classical clinical manifestation of bladder cancer. Episodes of haematuria tend to recur and they are often accompanied by bothersome lower urinary tract symptoms including daytime voiding frequency, nocturia, urgency and urge urinary incontinence. Flank pain may occur if tumour growth obstructs the ureters connecting to the bladder. Bothersome lower urinary tract symptoms are particularly intense in individuals with carcinoma in situ (remaining confined to the area). EVALUATION AND TREATMENT
Urinalysis for evidence of haematuria in the absence of infection provides a useful screening tool for high-risk patients. Several bladder tumour antigen-testing systems have been developed for screening, but they have proved more useful in monitoring patients with known cancer as compared to being used for primary screening. Urine cytology (pathological analysis of sloughed cells within the urine) is completed in individuals with evidence of haematuria from unknown causes; cystoscopy (direct inspection of the bladder) with tissue biopsy confirms the diagnosis. Transurethral resection or laser ablation, combined with intrabladder chemotherapy, is effective for superficial tumours, but radical cystectomy (surgical removal of the entire bladder) with urinary diversion and adjuvant chemotherapy is required for locally invasive tumours.
Nephroblastoma (also referred to as Wilms’ tumour) is an embryonal tumour of the kidney (see Fig. 30.19). The tumour is the fifth most common childhood cancer and the most common solid tumour occurring in children. It accounts for about 7% of all childhood cancers. The peak incidence occurs between 2 and 3 years of age. Maternal preconception toxin exposure (e.g. pesticides) may be associated with increased risk in offspring.
PATHOGENESIS
Nephroblastoma has both sporadic (not inherited) and inherited origins. The sporadic form occurs in children with no known genetic predisposition. Inherited cases, which are relatively rare, are transmitted in an autosomal dominant fashion (see Chapter 37). Nephroblastoma has been linked to mutation of tumour-suppressor genes such as WT1 mutations.
PAEDIATRICS
Paediatrics and renal cancer
CHAPTER 30 Alterations of renal and urinary tract function across the life span
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CLINICAL MANIFESTATIONS
Most children with nephroblastomas usually present with enlarging asymptomatic abdominal masses before the age of 5 years. Many tumours are actually discovered by the child’s parent, who feels or notices an abdominal swelling, usually while dressing or bathing the child. The child appears healthy and thriving. Other presenting complaints include vague abdominal pain (37%), haematuria — blood in the urine — (18%) and fever (22%). Hypertension may be present, often as a result of excessive renin secretion by the tumour. Nephroblastoma may occur in any part of the kidney and varies greatly in size at the time of diagnosis. The tumour generally appears as a solitary mass surrounded by a smooth, fibrous external capsule and may contain cystic or haemorrhagic areas. A pseudocapsule generally separates the tumour from the renal tissue. EVALUATION AND TREATMENT
FIGURE 30.19
Nephroblastoma. The tumour is clearly visible and is a large circumscribed mass.
Of children who have nephroblastoma, 18% also have a number of congenital anomalies, including aniridia (lack of an iris in the eye), hemihypertrophy (an asymmetry of the body) and genitourinary malformations (such as horseshoe kidneys, hypospadias, ureteral duplication or polycystic kidneys).
F O CUS O N L E A R N IN G
1 Describe the difference between adult and childhood renal tumours. 2 Discuss the implications of bladder carcinoma on normal urinary function.
On physical examination, the tumour feels firm, nontender and smooth and is generally confined to one side of the abdomen. If the tumour is palpable past the midline of the abdomen, it may be large or may be arising from a horseshoe or ectopic kidney. Once an abdominal mass is detected, diagnostic imaging demonstrates a solid intrarenal mass. Diagnosis is based on surgical biopsy. Abdominal CT or MRI scans and laboratory studies are used to evaluate the presence or absence of metastasis. The most common sites of metastasis are regional lymph nodes and the lungs. Metastases also occur in the liver, brain and bone. Primary treatment is usually surgical exploration and resection or chemotherapy and then surgical resection. Survival approaches 90% for localised disease and 70% for metastatic disease.
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chapter SUMMARY Urinary tract obstruction • Obstruction can occur anywhere in the urinary tract and it may be anatomic or functional, including renal stones, an enlarged prostate gland or urethral strictures. The most serious complications are hydronephrosis, hydroureter, ureterohydronephrosis and infection caused by the accumulation of urine behind the obstruction. • Persistent obstruction of the bladder outlet leads to residual urine volumes, low bladder wall compliance and risk for vesicoureteral reflux and infection. • Kidney stones are caused by supersaturation of the urine with precipitation of stone-forming substances, changes in urine pH or urinary tract infection. • Obstructions of the bladder are a consequence of a neurogenic bladder or anatomical alterations, or both. • A neurogenic bladder is caused by a neural lesion that interrupts innervation of the bladder. • Partial obstruction of the bladder can result in overactive bladder contractions with urgency. There is deposition of collagen in the bladder wall over time, resulting in decreased bladder wall compliance and ineffective detrusor muscle contraction.
Urinary tract infection • Urinary tract infection (UTI) is commonly caused by the retrograde movement of bacteria into the urethra and bladder. UTI is uncomplicated when the urinary system is normal or complicated when there is an abnormality. • Cystitis is an inflammation of the bladder commonly caused by bacteria and may be acute or chronic. • Pyelonephritis is an acute or chronic inflammation of the renal pelvis often related to obstructive uropathies and may cause abscess formation and scarring with an alteration in renal function.
Glomerular disorders • Glomerular disorders are a group of related diseases of the glomerulus that can be caused by immune responses, toxins or drugs, vascular disorders and other systemic diseases. • Acute glomerulonephritis commonly results from inflammatory damage to the glomerulus as a consequence of immune reactions after a streptococcal infection. • Chronic glomerulonephritis is related to a variety of diseases that cause deterioration of the glomerulus and a progressive loss of renal function. • Immune mechanisms in glomerulonephritis are the deposition of antigen–antibody complexes, often with complement components, and the formation of
antibodies specific for the glomerular basement membrane. • Nephrotic syndrome is the excretion of at least 3.5 g protein (primarily albumin) in the urine per day because of glomerular injury with increased capillary permeability and loss of membrane negative charge. Its principal signs are hypoproteinuria, hyperlipidaemia and oedema. The liver cannot produce enough protein to adequately compensate for urinary loss. • Glomerulonephritis in children may follow infections, especially those of the upper respiratory tract caused by strains of group A β-haemolytic streptococcus. Increases in glomerular capillary permeability lead to haematuria and proteinuria.
Chronic kidney disease • Chronic kidney disease represents a progressive loss of renal function. Plasma creatinine levels gradually become elevated as the GFR declines; sodium is lost in the urine; potassium is retained; acidosis develops; calcium metabolism and phosphate metabolism are altered and erythropoietin production is diminished. All organ systems are affected by chronic kidney disease. • Approximately 1 in 3 adults have an increased risk of developing chronic kidney disease. • The factors that contribute to the pathogenesis of chronic kidney disease are complex and involve the interaction of many cells, cytokines and structural alterations. Two factors that have consistently been recognised to advance renal disease are proteinuria and angiotensin II. • One in three Australians are at risk of developing chronic kidney disease. • Diabetes mellitus (mostly type 2), glomerulonephritis and hypertension are the three leading causes of chronic and end-stage kidney disease in Australia
Acute kidney injury • Acute kidney injury refers to the range of changes that can be associated with a rapid decline in renal function. Acute kidney injury is classified as prerenal, intrarenal or postrenal and is usually accompanied by oliguria with elevated blood urea and plasma creatinine levels. • Prerenal acute kidney injury is caused by decreased renal perfusion with a decreased GFR, ischaemia and tubular necrosis. • Intrarenal acute kidney injury is associated with several systemic diseases but is commonly related to acute tubular necrosis. • Postrenal acute kidney injury is associated with diseases that obstruct the flow of urine from the kidneys.
CHAPTER 30 Alterations of renal and urinary tract function across the life span
Structural abnormalities • Congenital renal disorders affect 10–15% of the population. These disorders range in severity from minor, easily correctable anomalies to those incompatible with life. • Hypospadias is a congenital condition in which the urethral meatus can be located anywhere on the ventral surface of the glans, the penile shaft, the midline of the scrotum or the perineum. • Ureteropelvic junction obstruction causes urethral obstruction by a malformation of junctional smooth muscle. • Polycystic kidneys is an inherited disorder that results in large, fluid-filled cysts within the kidneys. • Renal agenesis is the failure of a kidney to grow or develop. The condition may be unilateral or bilateral and may occur as an isolated entity or in association with other disorders. • Vesicoureteral reflux is the retrograde flow of bladder urine into the ureters providing a mechanism for
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pyelonephritis in children, whose ureters are shorter than those of adults. • Enuresis refers to the involuntary passage of urine. Enuresis may occur during the day (diurnally) or during the night (nocturnally). The disorder tends to occur during non-REM sleep and can have a variety of organic and psychological causes.
Tumours • Renal cell carcinoma is the most common renal neoplasm. The larger neoplasms tend to metastasise to the lungs, liver and bone. • Nephroblastoma (Wilms’ tumour) is an embryonal tumour of the kidney that usually presents between birth and 5 years of age. The tumour can be successfully treated by surgery, a combination of drugs and, sometimes, radiation therapy. • Bladder tumours are commonly composed of transitional cells with a papillary appearance and a high rate of recurrence.
CASE STUDY
A DU LT Simon is a 57-year-old Aboriginal man who works as an electrician. Simon has been a smoker since he was 14 years old and consumes about three cans of beer most nights. He was diagnosed with hypertension 15 years ago and his medication dosage has increased over that time. More recently, he has been short of breath, has periods of nausea and vomiting, and has been generally tired. At a checkup with his general practitioner, it is found that Simon has large concentrations of protein in his urine, his creatinine level is 297 mmol/L, his estimated GFR is 19 mL/min and his blood glucose level is 16.2 mmol/L. He is immediately referred to the specialist renal service where he is reviewed by a multidisciplinary renal healthcare team. The nephrologist
advises Simon that he may need to commence dialysis within 6 months. 1 Provide a rationale for the strong link between cardiovascular disease, diabetes and chronic kidney disease. 2 Discuss the lifestyle choices that Simon has taken that have contributed to the development and progression of chronic kidney disease. 3 Explain the connection between the GFR and progression of chronic kidney disease. 4 Describe why Simon’s symptoms (nausea, vomiting, tiredness) have arisen now. 5 Explain what treatment is needed to slow the progression of chronic kidney disease.
CASE STUDY
A GEING Joan is an 84-year-old lady who was found collapsed at home by her daughter; an ambulance was called and she was transferred to the emergency department of a nearby hospital. On arrival, her vital signs are: temperature 39.3°C, pulse 102 bpm, respiratory rate 26 breaths/minute, and BP 94/55 mmHg. Joan is conscious but confused to time and place. She has a past medical history of heart failure and type 2 diabetes. She requests to go to the toilet and you assist her onto a bedpan; she voids 75 mL of dark concentrated and
highly offensive smelling urine. A urinalysis reveals: +blood, ++protein, +++nitrites, +leucocytes, ++glucose, +ketones, and specific gravity 1.025. 1 Provide a rationale for the link between urinary tract infections and acute kidney injury. 2 Explain the connection between urinary tract infection and confusion in the elderly. 3 Describe why Joan’s symptoms (febrile, hypotension, concentrated urine) have arisen now. 4 What immediate treatment is needed for Joan?
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REVIEW QUESTIONS 1 Describe the various types of bladder obstruction. 2 Explain why urinary tract infections are prevalent in the young and elderly populations. 3 Outline differences between acute and chronic glomerulonephritis. 4 Describe the link between chronic kidney disease and cardiovascular disease. 5 Outline the pathophysiological changes that lead to end-stage kidney disease.
6 Describe the 3 proposed theories associated with acute kidney injury. 7 Outline the differences between pre-, intra- and postrenal acute kidney injury. 8 Describe the anatomical changes that occur with hypospadias. 9 Provide an overview of the pathogenesis of enuresis. 10 Discuss reasons for renal carcinoma.
Key terms acini, 957 amniotic fluid, 973 areola, 958 bulbourethral glands (Cowper’s glands), 953 cervix, 955 ductus arteriosus, 977 ductus deferens, 951 ductus venosus, 977 ejaculatory duct, 953 epididymis, 951 fertilisation, 950 fetus, 950 foramen ovale, 977 glands of Montgomery, 958 human chorionic gonadotrophin (hCG), 967 meiosis, 961 menarche, 959 menopause, 958 mitosis, 961 nipple, 958 ovarian cycle, 965 ovaries, 956 penis, 951 prostate gland, 953 semen, 953 seminal vesicles, 953 seminiferous tubules, 950 thelarche, 958 uterine (menstrual) cycle, 965 uterine tubes, 956 uterus, 955 vagina, 955 vulva, 954
CHAPTER
The structure and function of the reproductive systems
31
Karole Hogarth Chapter outline Introduction, 950 The structure and function of the male reproductive system, 950 External structures, 950 Internal structures, 951 The structure and function of the female reproductive system, 954 External structures, 954 Internal structures, 955 Breast structure, 957 Puberty in males and females, 958 The effects of testosterone in males, 959 The effects of oestrogen and progesterone in females, 959 Gametogenesis, 961 General principles, 961 Meiosis, 961 Spermatogenesis, 961 Oogenesis, 964
The ovarian cycle, 965 The uterine menstrual cycle, 965 Ovarian and uterine cycle timing, 968 Male and female sexual responses, 968 The female sexual response, 968 The male sexual response, 969 Conception, gestation and parturition, 969 Fertilisation, 970 Implantation, 971 The development and function of the placenta, 971 The embryonic sac, 973 The origin, composition and significance of amniotic fluid, 973 The mother’s adaptations to pregnancy, 974 Fetal development, 976 The neonate, 977 Ageing and the reproductive systems, 979
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Introduction Human beings are sexually reproductive organisms; parts of the genetic material from the mother and father combine to produce offspring, each of which has a unique and distinguishing set of DNA. With the exception of identical (monozygotic) twins (and other multiple births), which are derived from the same fertilised egg, each individual human being has a one-of-a-kind combination of DNA. The production of this exclusive DNA code is made possible by the process of sexual reproduction — only half of the mother’s DNA goes into each egg (ovum = singular, ova = plural) and only half of the father’s DNA goes into each sperm, and for each egg or sperm, a different mix of chromosomes makes the DNA. This explains our incredible diversity of appearance, ability and genetic susceptibility to some diseases. Sexual reproduction involves two fundamental processes: 1 production of reproductive cells or gametes (gametogenesis) 2 fusion of these gametes (fertilisation). The sex cells (sperm and ova), collectively known as gametes, are special cells in the body which have only half the number of chromosomes than all other types of body cells (somatic cells) have. When two gametes fuse during fertilisation, the normal chromosome number is reached. The cell that is created by the fusion of the male and female gametes is initially known as a zygote and goes on to develop into an embryo, then a fetus and finally the newborn from the time of birth. The primary reproductive organs that create the gametes are known as the gonads (i.e. gametogenic organs): the testes in the male and the ovaries in the female. These have two functions: 1 production of gametes: spermatozoa (sperm) in the male and ova (eggs) in the female 2 secretion of steroid sex hormones: testosterone in the male and oestrogen and progesterone in the female, as well as other hormones. Although the gonads are the primary reproductive organs, the reproductive system requires other organs and tissues to deliver sperm to the female and to transport and support the growing fertilised embryo. In both males and females there are ducts (tubes) for the transport of gametes. In males there are glands for the secretion of fluids (collectively semen) essential for fertilisation; and in females there is the uterus to support, protect and nurture the embryo until birth, and breasts to feed the newborn infant. The genitalia of both males and females are comprised of internal and external structures; while most people are familiar with the names and shapes of the external genitalia, the internal genitalia are less well known to the layperson. In this chapter we introduce the anatomical and functional aspects of the adult male and female reproductive systems and explore the role of hormones in the control of reproductive development in the early embryo, children and adults. We also consider how gametes are formed in
both males and females and outline the stages of the sexual process that brings the gametes together. Finally, we focus on stages of conception, gestation and parturition. We begin by looking at the anatomy and physiology of the male and female reproductive organs.
The structure and function of the male reproductive system In males, the external organs that are visible are the scrotum (containing the testes) and the penis. The external genitalia perform the major functions of reproduction (see Fig. 31.1). Sperm (spermatozoa) are produced in the testes (plural; singular = testis) and are delivered by the penis. The internal male genitalia consist of tubes to transport the sperm, and fluid-producing glands to aid in the transport of sperm from the testes to the urethral opening of the penis.
External structures Testes
The testes (see Fig. 31.2) are the source of sperm and the androgen, testosterone. There are usually two testes, oval in shape and approximately 4–5 cm long, located outside the body cavity in the scrotum (a pouch of skin). The cremaster muscles in the scrotum can raise the testes closer to the body (in a cold environment) or lower them further from the body (in a hot environment). The temperature in the scrotum is approximately 3°C lower than normal core body temperature (see Fig. 31.3) — this is essential for the survival of sperm. During fetal development, the testes develop in the upper body cavity and from 7 months gestation they begin to move through the inguinal canal to the scrotum together with the spermatic cord, although 4% of full-term infants have one or both testes that remain undescended. Each testis is divided into about 250 internal compartments called lobules, each of which contains 1 to 3 long, thin tightly coiled hollow tubes called seminiferous tubules. The seminiferous tubules are the sites of sperm production and contain two major types of cells: (1) spermatogonia, which are germ cells that line the walls and develop into spermatozoa; and (2) sustentacular (Sertoli) cells, which support this process. Adjacent sustentacular cells form tight junctions in which the walls of two adjacent cells are ‘stuck’ together very firmly. These tightly joined cells create a blood–testis barrier, which prevents immune blood cells from entering the seminiferous tubules. This barrier is required because the developing sperm have surface antigens that could be recognised as foreign by the immune system; in the absence of the barrier, an immune attack would be mounted against the sperm, causing inflammation and possible male sterility. Located between the tightly packed seminiferous tubules are cells called interstitial (Leydig) cells. These cells secrete testosterone when stimulated by luteinising hormone (LH).
CHAPTER 31 The structure and function of the reproductive systems
951
Ureter Seminal vesicle Urinary bladder
Ejaculatory duct
Pubic symphysis Prostate gland
Vas (ductus) deferens
Rectum
Pelvic floor muscles Urethra
Bulbourethral (Cowper’s) gland
Penis
Anus Epididymis Testis
Foreskin (prepuce)
S
Scrotum P
A I
FIGURE 31.1
The male reproductive system. Main structures include the testes, ductus deferens, seminal vesicles, prostate gland, and penis. Note the close location of the urinary bladder to reproductive structures.
Penis
The human male penis (see Fig. 31.4) performs two major functions: (1) the elimination of urine; and (2) the delivery of mature spermatozoa and associated fluids to the female reproductive tract. The structure of the penis is such that it is a small soft organ for the majority of the time, but becomes greatly enlarged and stiffened for the purpose of reproduction. The penis contains three cylindrical columns of erectile tissue — that is, ‘spongy’ tissue that becomes rigid when filled with blood (supplied to the penis from the internal iliac artery via the internal pudendal or penile artery). On each side of the penis there is an erectile corpus cavernosum and medially there is the corpus spongiosum, the tip of which is enlarged to form the glans penis. The urethra in males comprises three segments with distinct names: prostatic (in the prostate), membranous (in the pelvic floor) and penile (in the penis). The penile urethra runs through the corpus spongiosum and the glans is covered by a double fold of skin, the prepuce (foreskin). The nerve supply to the penis is from the second, third and fourth sacral spinal nerves, through the pelvic plexuses
and the internal pudendal nerve. These are the nerves that are involved in the different stages of the male sexual response. These nerves can be damaged through trauma (often car or motorcycle accidents) and can result in altered sexual function.
Internal structures Spermatic ducts
Sperm cells must travel from the testis to the tip of the penis in order to be delivered into the female reproductive system. This is achieved by a series of dedicated tubes (see Figs 31.2 and 31.4) through which the sperm move. Sperm leave the seminiferous tubules, travel through the efferent ducts (coiled tubules) and reach the epididymis. The epididymis is attached to the posterior side of the testis. It consists of a head, body and tail region, the tail continuing into the ductus deferens. Within the epididymis there is a highly coiled tube called the ductus epididymis, which is the site of sperm maturation and storage. Mature sperm move from the epididymis into the pelvic cavity through the ductus deferens (previously
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A
B
FIGURE 31.2
The testes. A The scrotum. B The tubules of the testis and epididymis.
FIGURE 31.3
The heat exchanger of the testis. As blood descends from the body through the testicular artery, heat is transferred into nearby venous blood, so the arterial blood cools as it descends. The blood that reaches the testes is approximately 3°C cooler than blood in the rest of the body.
FIGURE 31.4
A cross-section of the penis. This image shows the penis, including the erectile tissues which are the corpus cavernosum and corpus spongiosum. The urethra carries ejaculate or urine through the penis (at different times).
CHAPTER 31 The structure and function of the reproductive systems
known as the vas deferens), which passes upwards behind the testis and epididymis, through the inguinal canal and into the pelvic cavity. Here it turns back over the ureter and tunnels through the urinary bladder (although the contents of the ductus deferens do not mix with the bladder; refer to Fig. 31.1). The last section of the ductus deferens is dilated to form the ampulla. Mature sperm are stored here, awaiting ejaculation. The ductus deferens together with blood vessels, lymphatics, autonomic nerves and cremaster muscle make up the spermatic cord. The cremaster muscle elevates the testes during sexual arousal or during exposure to cold and lowers the testes when body temperature rises. Located at the distal end of the ampulla is the ejaculatory duct. This short tube (2 cm) enters the posterior of the prostate gland (without mixing with prostate tissue) projecting anteriorly to join the prostatic urethra. Note that it is within the prostate gland at the prostatic urethra that the tubules that contain reproductive contents (including sperm) become shared with the tubules that contain urine (urethra). The urethra transports these fluids to exit the penis at different times such that they do not mix.
Accessory glands
The male reproductive system includes three accessory glands (see Fig. 31.5). These glands produce the fluids that are added to the sperm to produce the final mixture known as semen. • Seminal vesicles. These two pouches behind the bladder, alongside the ampullae, secrete and store the seminal fluid. The seminal fluid is viscous and alkaline, and it
Urinary bladder
Prostate gland Utricle
helps to neutralise the acid environment of the female vagina. The fluid also contains fructose (a sugar energy source for sperm) and fibrinogen (to clot the semen and attach it to the wall of the vagina). The fluid is emptied into the ejaculatory ducts to join the sperm from the ductus deferens and forms a major part of the ejaculate (60% of semen volume). • Prostate gland. This gland is located at the base of the bladder, surrounding the first part of the urethra. It may be palpated through the rectum in a prostate examination. The prostate is often enlarged in old age (obstructing the flow of urine from the bladder). The prostate gland secretes a milky, slightly acidic fluid that contains acid phosphatase, clotting enzymes and fibrinolysin (which breaks the clot of sperm to allow sperm to move into the uterus). This contributes to sperm motility and viability and makes up about 30% of semen volume. Many small ducts within the prostate deliver this fluid to the urethra. It is important to note the spelling of the word prostate, as it is sometimes confused with the word prostrate, which means lying face-down. • Bulbourethral glands (Cowper’s glands). These glands are the size of peas and lie immediately below the prostate. The ducts empty into the penile urethra below the prostate. The fluid produced by these glands is clear, mucous and alkaline and makes up 5% of the semen. This small volume of secretion is released shortly before ejaculation, serving to neutralise the acidic pH of the penile urethra. The remaining 5% of semen volume consists of the sperm.
Urinary bladder Seminal vesicle
Ejaculatory orifice
Prostate gland
Bulbourethral glands
Opening of Bulbourethral glands ducts
953
Urethra
Ejaculatory duct
FIGURE 31.5
Anatomy of the prostate gland and seminal vesicles. Secretions from the seminal vesicle mix with the sperm entering from the ductus deferens, and together these travel down the ejaculatory duct towards the urethra. Secretions from the prostate gland then join with the secretions from the ejaculatory duct, and together this forms the ejaculate that travels down the urethra. Secretions from the bulbourethral gland enter the urethra just prior to the main ejaculate.
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F OC US O N L E ARN IN G
1 Describe the structure of the testes and penis. 2 Describe the progression of sperm from the testes through the spermatic ducts and penis. 3 Outline the roles of the male accessory glands. 4 List the components of semen.
The structure and function of the female reproductive system In females the major sexual functions of gametogenesis and gestation are carried out by the internal structures.1–3 A general overview of the female reproductive system is shown in Fig. 31.6.
External structures
The vulva is the collective name for the external female genitalia comprising the mons pubis, clitoris, vestibule,
introitus (entrance), Bartholin’s glands and the labia (lips) majora and minora (see Fig. 31.7). The mons pubis is a pad of fat that covers and protects the pubic symphysis. The clitoris is erectile tissue and it is the female equivalent of the male penis, in that it arises from the same embryonic tissue, has a similar (but much smaller) structure and becomes engorged with blood during arousal. It consists of a spongy tissue that becomes rigid when congested with blood (during arousal) and is highly innervated, being the major site of female sexual stimulation and orgasm. The vestibule contains the openings of the urethra, vagina and Bartholin’s glands (which produce lubricating secretion).The introitus is the vaginal orifice itself, and is covered by a thin membrane (hymen) prior to the first sexual encounter. The labia majora (plural; singular = labium majorum) are two folds of skin that extend from the mons pubis to the fourchette. They are highly sensitive to temperature, touch, pressure and pain and are homologous to the male scrotum. Sebaceous glands on the medial (inner) surfaces secrete lubricants and the labia protect the structures of the vulva. The labia minora (plural; singular = labium minorum) are two smaller and thinner folds of skin within the labia majora. They form the prepuce (foreskin) of the clitoris, are hairless and secrete a bactericidal lubricant.
Uterus Ovary
Uterine tube
External iliac vessels Ovarian ligament
Ureter
Corpus of uterus Round ligament
Sacrouterine ligament
Fundus of uterus Posterior cul-de-sac
Anterior cul-de-sac Bladder
Cervix
Symphysis pubis
Levator ani muscle
Clitoris Urethra
Fornix of vagina
Labium minus External anal sphincter
Anus
Urogenital diaphragm
Vagina
Labium majus
FIGURE 31.6
Internal female genitalia and other pelvic organs. Main structures include the ovaries, uterine tubes, uterus, cervix and vagina. Note the close location of the urinary bladder to reproductive structures.
CHAPTER 31 The structure and function of the reproductive systems
955
Mons pubis (Veneris)
Clitoris Prepuce of clitoris
Urethral or urinary orifice Vestibule
Labium minus
Labium majus Vaginal orifice Hymen
Vestibule Fourchette Anus Perineum FIGURE 31.7
External female genitalia. This image shows the vaginal orifice (opening), labia (labium majorum and minorum), and the urethral opening.
When aroused, the labia become flushed with blood and enlarge slightly. The labia minora are also highly innervated and provide stimulation during coitus (sexual intercourse). Posterior to the vestibule are the perineum and anus, the perineum being the area of skin lying between the vaginal orifice and the anus — it has very little subcutaneous fat, little hair and sebaceous glands.
Internal structures
The internal structures of the female reproductive system (see Fig. 31.6) are the vagina, cervix, uterus, uterine (fallopian) tubes and ovaries.
Vagina
The vagina is an elastic, fibromuscular canal that is 9–10 cm in length. It extends up and back from the introitus to the lower portion of the uterus. As Fig. 31.6 shows, the vagina lies between the urethra (and part of the bladder) and the rectum. Mucosal secretions from the upper genital organs, menstrual fluids and products of conception leave the body through the vagina, which also receives the penis during coitus. During sexual excitement, the clitoris and labia minora become engorged with blood, and the vaginal and clitoral length and diameter increase. The vaginal wall consists of a mucous membrane lining of squamous epithelial cells that allows the vagina to stretch during coitus and childbirth. There is also a thick layer of smooth muscle that assists with these functions.
The upper part of the vagina surrounds the cervix, the lower end of the uterus (see Fig. 31.8). The recessed space around the cervix is called the fornix of the vagina. The posterior fornix is deeper than the anterior fornix because of the angle at which the cervix meets the vaginal canal, which is usually about 90°. A pouch called the cul-de-sac separates the posterior fornix and the rectum. The vagina’s elasticity and relatively sparse nerve supply enhance its function as the birth canal. During sexual arousal, however, the vaginal wall becomes engorged with blood, like the labia minora and clitoris. Engorgement pushes some fluid to the surface of the mucosa, enhancing lubrication. The vaginal wall does not contain mucus-secreting glands; rather, secretions drain into the vagina from the endocervical glands or enter from the vestibule from the Bartholin’s glands.
Uterus, cervix and uterine tubes
The uterus is a hollow, pear-shaped organ with thick muscular walls and a small central cavity (see Fig. 31.8). Its major function is the anchorage and protection of a developing embryo, as well as the expulsion of the baby at birth. The uterus of a non-pregnant female is about 7–9 cm long and 6.5 cm at its widest part. It is held loosely in place by ligaments, folds of the peritoneum and the pressure of surrounding organs (bladder, sigmoid colon and rectum) while the blood supply is from the uterine artery. In most women the uterus is tipped forwards,
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Interstitial portion of uterine tube Perimetrium Fundus of uterus Body of uterus
Isthmus of uterine tube
Ampulla of uterine tube
Ovarian ligament
Infundibulum of uterine tube
Corpus of uterus Endometrium Myometrium
Cervix of uterus
Internal os of cervix Endocervical canal External os of cervix Vagina
Suspensory ligament
Fimbriae Ovary Broad ligament Uterine artery and vein Reflection of peritoneum Isthmus of uterus Fornix of vagina
FIGURE 31.8
A cross-section of the uterus, uterine tube and ovary. The ova travels from the ovary, down the uterine tube, and enters the uterus. The layers of the uterus include the endometrium (which is shed to form the menstrual fluid), and the myometrium. The cervix is located between the uterus and the vagina.
resting on the urinary bladder (anteverted), but it may be in various positions from anteverted to retroverted (tipped backwards). There are two principal parts of the uterus: the corpus (or body) and the cervix. The cervix is the lowest part of the uterus and projects into the vagina. A continuous channel of the cervix connects the uterine cavity from the internal (uterine) cervical opening (internal os) to the external (vaginal) cervical opening (external os). The uterus is a three-layered organ (see Fig. 31.8): 1 Innermost is the endometrium, a mucous membrane that varies in thickness according to the phase of the uterine (menstrual) cycle. It contains glands and spiral arteries; these enlarge in pregnancy, especially in the region of the placenta. 2 The middle layer is the myometrium, which consists of smooth muscle. The muscle fibres enlarge greatly in pregnancy and contract during parturition (childbirth) and menstruation. 3 The outer layer is the peritoneum (serosa). Two uterine tubes (also known as fallopian tubes or oviducts) extend from the superior region of the uterus and end by curving around the ovaries. The lumen of each tube connects the uterine cavity to the peritoneal cavity. The lumen is straight and narrow as it leaves the uterus, but expands and becomes funnel-shaped towards the ovary. The ovarian end is fringed with fimbriae (small, finger-like projections), which waft the egg into the tube.
Each uterine tube has three sections: (1) the uterine end is the isthmus; (2) the middle section is the ampulla; and (3) the ovarian end is the infundibulum. The uterine tubes are lined with beating cilia, which beat rhythmically towards the uterine cavity. The combined action of smooth muscle peristalsis and the beating cilia serve to convey the ovulated ova to the uterine cavity for either implantation or expulsion (via the vagina). Fertilisation usually occurs closer to the ovarian end of the tube in the ampulla, whereby the fertilised ovum, now known as a zygote, is conveyed to the uterine cavity. If the tube is dysfunctional, a zygote may implant in the uterine tube; this is a life-threatening outcome called ectopic or tubal pregnancy.
Ovaries
The ovaries (see Fig. 31.9) are the female gonads responsible for the production and maturation of the gametes, as well as the production of the major female sex hormones, oestrogen and progesterone plus other hormones (activin, inhibin) which have important roles in the stimulation or inhibition of the anterior pituitary gland, respectively. There are two small, oval-shaped ovaries, one on each side of the uterus. In women of reproductive age, each ovary is 3–5 cm long, 2.5 cm wide and 2 cm thick and weighs 4–8 g. Size and weight vary somewhat from phase to phase of the uterine (menstrual) cycle. Each ovary is secured by ligaments, including the mesovarian, ovarian and suspensory ligaments, while the blood supply comes from the ovarian artery.
CHAPTER 31 The structure and function of the reproductive systems
Corpus luteum
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Blood vessels
Ovulation Degenerating corpus luteum Mature follicle (Graafian follicle) Antrum Granulosa Oocyte cells
Secondary follicle
Granulosa Primary cells follicles
FIGURE 31.9
A cross-section of an ovary during the reproductive years. Oocytes in various stages of development are shown. The follicle bursts at ovulation, and the oocyte is released.
Clavicle Intercostal muscle Pectoralis major muscle Acinus Ductule Duct Lactiferous duct Lactiferous sinus Nipple pore Suspensory ligaments of Cooper
FIGURE 31.10
The female breast. The acini are the site of milk production. Note the muscles and ribs posterior (behind) the breast tissue.
Breast structure
The female breast is composed of 15–20 pyramid-shaped lobes that are separated and supported by Cooper’s ligaments (see Fig. 31.10). Each lobe contains 20–40 lobules, which subdivide into many functional units called acini (plural;
singular = acinus). Each of these is lined with epithelial cells capable of secreting milk and subepithelial cells that contract to squeeze milk from the acinus. The acini empty into a network of ducts that reach the skin surface through openings (pores) in the nipple. The lobes and lobules are
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surrounded by muscle strands and fatty connective tissue. The amount of fatty connective tissue varies from individual to individual, depending on weight, genetic and endocrine factors. An extensive capillary network surrounds the acini, with supply from the internal and lateral thoracic arteries and intercostal arteries, while venous return follows the arterial supply and empties into the superior vena cava. Lymphatic drainage of the breast occurs largely through axillary nodes, but approximately 25% occurs through transpectoral and internal mammary routes. The breasts receive sensory innervation from branches of the second to sixth intercostal nerves and the cervical plexus. This accounts for the fact that breast pain may be referred to the chest, back, scapula, medial arm and neck. The nipple is a pigmented, cylindrical structure, which has multiple openings, one from each lobe. The areola is the pigmented, circular area around the nipple. A number of sebaceous glands, the glands of Montgomery, are located within the areola and aid in lubrication of the nipple during lactation (milk production). The nipple and areola contain smooth muscles, which receive motor innervation from the sympathetic nervous system. Sexual stimulation, breastfeeding and exposure to cold cause the nipple to become erect. At the onset of puberty in the female, oestrogen secretion stimulates mammary growth. Breast development, or thelarche, is usually the first sign of puberty. During the reproductive years, the breast undergoes cyclic changes in response to changes in the levels of oestrogen and progesterone associated with the uterine (menstrual) cycle. Oestrogen promotes development of the lobular ducts; progesterone stimulates development of cells lining the acini. Lactation occurs after childbirth in response to increased levels of prolactin. Prolactin secretion increases by continued breastfeeding. Oxytocin, another hormone released after delivery, controls milk ejection (let down) from acini cells. During the proliferative phase of the uterine cycle, high oestrogen levels increase the vascularity of breast tissue and stimulate proliferation of ductal and acinar tissue. This effect is sustained into the luteal phase of the cycle. During this phase, progesterone levels increase and contribute to the breast changes induced by oestrogen. Specific effects of progesterone include dilation of the ducts and conversion of the acinar cells into secretory cells. Most women experience some degree of premenstrual breast fullness, tenderness and increased breast nodularity. Breast volume may increase as much as 10–30 mL. Because the length of the uterine cycle does not allow for complete regression of new cell growth, breast growth continues at a slow rate until approximately 35 years of age. Because of the cyclic changes that occur in breast tissue, breast examination should be conducted at the conclusion of or a few days after the menstrual flow, when hormonal effects are minimal and breasts are at their smallest. The function of the female breast is primarily to provide a source of nourishment for the newborn. Physiologically,
breast milk is the most appropriate nourishment for newborns. Not only does its composition change over time to meet the changing digestive capabilities and nutritional requirements of the infant, but it also contains specific immunoglobulins, especially IgA, and nonspecific antimicrobial factors, such as lysosomes and lactoferrin, that protect the infant against infection. During lactation, high prolactin levels interfere with hypothalamic-pituitary hormones that stimulate ovulation. This mechanism suppresses the uterine cycle and may prevent ovulation.4 In underdeveloped countries, breastfeeding is the major means of contraception, although this method alone doesn’t provide contraception as effective as other options available in Australia and New Zealand. FOCU S ON L EA RN IN G
1 Discuss how the uterus is structured to facilitate its functions. 2 Describe the role of the ovaries in female maturation and reproductive function. 3 Explain the internal anatomy of the breasts.
Puberty in males and females In both males and females the sexually mature period begins with the onset of puberty.1 Puberty is the name given to the process of development and growth that leads to a reproductively capable adult. The end of the reproductive years (particularly for females) is called the climacteric and is commonly known as the menopause. Males do not reach such an obvious end to their reproductive years, although there is a general decline in function with ageing (see ‘Ageing and the reproductive systems’ below). The process of sexual maturation usually begins earlier in females than in males, but in both it begins between the ages of 8 and 12 years and continues during the early ‘teens’. Sexual maturation begins with the secretion of gonadotrophin-releasing hormone (GnRH) from the hypothalamus and the process of maturation is completed in males with the first complete ejaculation and in females with the first ovulation. Puberty involves dramatic changes in the male and female body shape, as well as the beginning of the activity of the gonads to produce gametes. Puberty and continued reproductive function are coordinated by the hypothalamus, the endocrine system (the anterior pituitary) and the gonads (refer to Chapter 10). This is called the hypothalamic– pituitary–gonadal axis. Males and females commence puberty in response to the same set of hormones released from the hypothalamus and anterior pituitary gland. The hypothalamus releases gonadotrophin-releasing hormone (GnRH).1,3,5,6 This name is descriptive, in that gonado- refers to the gonads, while trophin means growth-stimulating
CHAPTER 31 The structure and function of the reproductive systems
— hence this hormone causes the release of hormones that will ultimately result in growth of the gonads. In response to GnRH, the anterior pituitary releases follicle-stimulating hormone (FSH) and luteinising hormone (LH), as seen in Fig. 31.11. These hormones target the gonads. In both males and females, puberty follows the same pattern but with differences according to sex. In males, spermatogenesis starts and testosterone production in the testes increases dramatically. Puberty leads to the adolescent growth spurt, which requires testosterone and growth hormone from the anterior pituitary. Differences in the growth rate of different regions of the body lead to the male build (wide shoulders, narrow pelvis). In females, oogenesis starts due to a release of FSH from the anterior pituitary, oestrogen levels rise and the ovarian and uterine (menstrual) cycles start — the first uterine cycle is known as menarche. The ovarian and uterine cycles work together to produce (at least) one mature oocyte and to prepare the uterus for the potential implantation of a fertilised embryo every 28 days, until the reproductive years cease. In both sexes, there is a corresponding development of secondary sex characteristics.
Hypothalamus releases Gonadotrophin-releasing hormone (GnRH) stimulates
releases Gonadotrophins FSH and LH stimulates Gonads stimulates production of Gametes
negative feedback
Anterior pituitary
release Sex hormones
FIGURE 31.11
The hypothalamic–pituitary–gonadal axis. The hypothalamus releases GnRH, which travels down the hypothalamo-pituitary portal system (two capillary beds connected in series by venules) to the anterior pituitary. The anterior pituitary releases the gonadotropic hormones follicle-stimulating hormone (FSH) and luteinising hormone (LH) into the systemic blood flow. When the gonadotrophins are detected by receptors in the gonads, they respond by producing sex hormones and these influence the production of gametes. Since this is a pathway that relies on each step working, a dysfunction in any part (hypothalamus, anterior pituitary or the gonads) can result in failure of the gonads to produce sex hormones and/or gametes.
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Testosterone and oestrogen cause huge changes throughout the male and female bodies. These hormones also cause changes in the brain (such as moodiness), which may be particularly evident during puberty. The exact cause of the rise in GnRH levels is not entirely understood but it has been linked to the presence of the hormone leptin. Leptin is secreted by adipose tissue (refer to Chapter 35), and precocious (early) puberty is associated with increased body mass index (BMI) and height. This implies that the body becomes reproductively active when it is ‘large’ enough, but this is not necessarily the only trigger.
The effects of testosterone in males
Testosterone is a very powerful hormone causing major changes in the male body. Testosterone is essential for spermatogenesis and the changes seen in the young male when puberty commences. After puberty, it is necessary to maintain the function and size of the reproductive organs. The effects of castration (removal of the testes, also known as orchidectomy) include both depression of sexual function and a reduction in the size of the accessory organs; this is evidence of the necessity for the continued production of testosterone throughout adult life. Testosterone stimulates the development and maintenance of the male secondary sex characteristics of hair growth (facial, pubic and axillary or underarm), growth of the larynx resulting in a deepening of the voice, secretion of skin oil glands, the male pattern of fat distribution and the male libido (sex drive). In individuals with a genetic predisposition, higher levels of testosterone are thought to be associated with baldness. Higher levels of testosterone also cause negative feedback to the hypothalamus and anterior pituitary (to lower the secretion of GnRH, FSH and LH). The main functions of sex hormones are summarised in Table 31.1. A major function of testosterone is to drive anabolism — namely, increased muscle and bone growth. These effects have been exploited by athletes who use anabolic steroids (similar to testosterone) to gain muscle mass and hence sports controlling bodies commonly test for anabolic steroids. An increased level of aggression is often associated with testosterone; however, this is a hotly debated topic and there is no clear evidence to show that high levels of testosterone lead to violent tendencies. Note that androgens are the male sex hormones, the main ones being testosterone and dihydrotestosterone. Dihydrotestosterone is converted from testosterone by 5α-reductase and is more potent than testosterone with three times greater affinity to the androgen receptor. Approximately 5% of testosterone is converted into dihydrotestosterone which has its major function in the prostate gland, skin and hair.
The effects of oestrogen and progesterone in females
Oestrogen and progesterone are powerful hormones that cause major changes in the female body. Unlike testosterone,
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TABLE 31.1 Steroid hormones and reproductive function Steroid hormones are found in both males and females and have multiple systemic effects. This table is a summary of the effects of the main steroid hormones and their effect on the reproductive function of males and females. HORMONE
FUNCTION IN FEMALES
FUNCTION IN MALES
Luteinising hormone (LH)
Produced by the anterior pituitary gland. Target tissue is the ovaries, stimulating ovarian production of oestrogen and progesterone
Produced by the anterior pituitary gland. Target tissue is the testes, stimulating testosterone production
Follicle-stimulating hormone (FSH)
Target tissue is the ovaries, stimulates ovarian follicle maturation and oestrogen production
Target tissue is the testes, stimulating spermatogenesis
Progesterone
Produced by the ovary. During adult years it promotes the cyclic changes in the uterus (with oestrogen). Prepares uterus for the fertilised egg (zygote) and maintains uterus during pregnancy
Produced by the testes and adrenal gland. Effects spermiogenesis, sperm capacitation and acrosome reaction and testosterone production in the interstitial cells of the testes
Oestradiol
Produced by the ovary. In puberty initiates the maturation of the reproductive organs and secondary sex characteristics including breast development. During adult years it promotes the cyclic changes in the uterus (with progesterone). Feminises the brain
Produced by the interstitial cells of the testes and the sustentacular cells of immature males. It prevents apoptosis of sperm cells
Testosterone
Produced by the ovary and adrenal gland. Associated with the maintenance of bone and muscle mass and sex drive
Produced by the testes. During puberty initiates the maturation of male reproductive organs, sex drive and secondary sex characteristics. In adult males it is essential for sperm production and to maintain the reproductive organs in their mature functional state
Dihydrotestosterone
Converted from testosterone. Maintenance of libido. Excess amounts can promote the growth of unwanted body hair
Converted from testosterone. Maintenance of differentiation of male tissues. Essential for prostate and other male reproductive functions; also indicated in male-pattern baldness and benign prostatic hyperplasia
Androstenedione
Released by thecal cells as a precursor for oestrogen production in granulosa cells. Influences sexual and aggressive behaviour
Is the immediate precursor of testosterone and is converted to testosterone. Influences sexual and aggressive behaviour
they are not required to be produced in the fetus to develop a female reproductive anatomy, so the absence of testosterone in a fetus results in female development. Remember that the sex of the fetus is determined at conception by the combination of chromosomes from the mother and father, and the hormones are produced to match this sex. There are three oestrogen subtypes, each of which is dominant at different times in the female reproductive life. Oestrone (E1) is the dominant oestrogen in menopause, oestradiol (E2) is the dominant oestrogen during the normal uterine cycle in the reproductive years and oestriol (E3) is dominant during pregnancy. Oestrogen is analogous with testosterone in that it stimulates the growth of the ovaries and primordial follicles (germ cells that become oocytes, the immature eggs). In addition, it stimulates the growth of smooth muscle and the proliferation of the epithelial
linings of the reproductive tract, growth of the external genitalia and breast growth (particularly the lactiferous ducts and fat deposition). Oestrogen promotes development of the female body configuration (narrow shoulders, broad hips), the female fat distribution pattern and the development of pubic, axillary and body hair. Another effect is on bone growth, and oestrogen is protective against osteoporosis. Progesterone is predominantly a sexual cycle hormone, as it stimulates the endometrial glands of the uterus during the uterine cycle, induces the production of thick sticky cervical mucus, stimulates breast growth (particularly glandular tissue) and has feedback effects on the hypothalamus and anterior pituitary to maintain control of the sexual cycles. It is also essential for the maintenance of a healthy pregnancy, as it decreases contractions of the uterine tubes and myometrium and hence prevents miscarriage.
CHAPTER 31 The structure and function of the reproductive systems
F O CUS O N L E A R N IN G
1 Outline the changes that occur in both sexes at the onset of puberty. 2 Discuss the specific roles of testosterone in males and oestrogen and progesterone in females after puberty.
Gametogenesis General principles
Adult males and females produce a set of specialised reproductive cells called gametes. Cells that give rise to gametes undergo a different type of cell division in which the amount of genetic material received by each daughter cell is halved. This type of division is called meiosis and it occurs solely in the gonads (see Fig. 31.12). Thus gametes contain one half of the genetic material of somatic cells: one copy of each type of chromosome. The total number of chromosomes in all other body cells is 46, comprising 22 pairs of autosomes and 2 sex chromosomes: XX in females (homologous) and XY in males. Mitosis Diploid parent cell (46 chromosomes)
Primary sex cells (DNA replicated before division)
Secondary sex cells (DNA not replicated before division)
Meiosis I
In the gametes, the egg (ovum) and sperm cells each contain half of the genetic material of all other body (somatic) cells, as they have only 23 chromosomes instead of 23 pairs of chromosomes. When an ovum (from the mother) and sperm (from the father) combine to undergo fertilisation, a new cell with the full human genetic complement is produced (that is, with 23 pairs of chromosomes). This cell is called a zygote and it then undergoes many cycles of cell division to give rise to a new individual. At each cycle, genetic material is precisely copied for transmission to the new daughter cells. Products of any one cell division are genetically identical to each other, to their parent cell and to the original fertilised egg (zygote). This type of cell division is known as mitosis and it continues throughout life in growth, turnover and repair (see Chapter 5).
Meiosis
Meiosis can essentially be thought of as two rounds of mitosis in which the production (synthesis) phase (namely, replication of the chromosomes) is skipped in the second round, resulting in a halving of the genetic material. The steps of meiosis are shown in Fig. 31.12 and you can see that the second round of division (meiosis II) begins immediately after telophase I without the duplication of chromosomes so that the daughter cells each receive only half the chromosome number. A fundamental law of genetics is the process of individual assortment which occurs due to crossing over of genetic material between the chromosomes; this process accounts for the variation seen between siblings. In males this process of meiosis is called spermatogenesis and in females it is called oogenesis. Gamete formation in both males and females is controlled by the sex hormones. In both sexes the same set of hormones triggers the process and the end result is the production of sperm and testosterone in the male, and the production of ova, oestrogen and progesterone in the female. In addition, in females the hormones that trigger oogenesis are also responsible for the changes of uterine thickness during the uterine cycle.
Spermatogenesis
Meiosis II Haploid gametes (23 chromosomes)
FIGURE 31.12
Meiosis. The replication of the sex cells involves a cycle of mitosis first, in which the cell is completely replicated and hence has 46 chromosomes. In this way, one copy of the complete sex cell remains available for future replication, and the other copy undergoes meiosis into mature sex cells. Meiosis then commences with the primary sex cells, and progresses through meiosis I and II, resulting in sex cells (ova or sperm) which have only 23 chromosomes, being half of the number from the original ‘parent’ cell.
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Spermatogenesis is the formation of spermatids and it takes place in the seminiferous tubules of the testes under the influence of testosterone (see Figs 31.13 and 31.14). Spermatogonia (plural; singular = spermatogonium) are primitive germ cells that line the walls of the seminiferous tubules. They progress through several developmental stages to become more developed spermatocytes; each spermatocyte then undergoes meiosis to give rise to four spermatids that reach the lumen of the seminiferous tubules. These four spermatids are immature sperm cells and are not free-swimming. They need to mature in a process called spermiogenesis to ultimately give rise to four mature free-swimming spermatozoa (commonly abbreviated to sperm). It takes approximately 64 days for spermatogonia to become mature sperm and a healthy adult male will produce several million mature sperm each day; these mature sperm are stored in the ductus deferens (including the ampulla) awaiting ejaculation.
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Basement membrane Sertoli cell
Spermatogonia (germ cells)
Tight junction between Sertoli cells
46 Mitotic division
46 46
Daughter cell
Primary spermatocyte 46 Sertoli cell nucleus
1st meiotic division Secondary spermatocytes
Tight junction
2nd meiotic division 23
Spermatids
Spermatids becoming sperm cells
Lumen of seminiferous tubule 23
Sperm cells
23
23
23
23
23
23
23
23
23
23
23
23
Sperm cells
FIGURE 31.13
Seminiferous tubule. The process of meiosis and sperm cell formation. Sperm production occurs in the outer parts of the seminiferous tubules, and progresses towards the lumen.
Mature sperm have named parts each with a specific function (see Fig. 31.15): the head contains the genetic material, the midpiece contains mitochondria, which provide energy for sperm movement; and the tail or flagellum provides locomotion. The pathway of sperm from the testes to the tip of the penis is shown in Fig. 31.16. The transport of sperm from the epididymis to the ductus deferens is due to peristalsis of smooth muscle in the epididymis and ductus deferens,
rather than the sperm’s own motility. Mature sperm, together with other components of semen, are ejaculated by contraction of smooth muscle in the epididymis, ductus deferens, ejaculatory ducts, prostate and seminal vesicles (sympathetic stimulation). Each ejaculate is a volume of about 3 mL containing on average 300 million sperm. The complete process, from hormonal roles through to spermatogenesis, is shown in Fig. 31.17.
CHAPTER 31 The structure and function of the reproductive systems
Nuclear vacuoles Acrosome Neck
Anterior head cap
Nucleus
Posterior head cap
End piece of tail
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Mitochondrial sheath of middle piece
Body
Fibrous sheath of principal piece
FIGURE 31.15
Anatomy of a mature sperm cell. Note the acrosome in the sperm head, which is important for penetrating the outer layer of the ova for fertilisation.
5 Seminal vesicle
4 Ductus (vas) deferens
FIGURE 31.14
Hormonal control of spermatogenesis in a sexually mature male. The hypothalamus releases GnRH, which stimulates the anterior pituitary to release LH and FSH, both of which act on the testes. LH stimulates the interstitial cells of the testes to produce testosterone, some of which remains in the testes to promote spermatogenesis, and some of which enters the bloodstream and leads to the other body-wide functions of testosterone. FSH stimulates the sustentacular cells in the testis to produce ABP, which keeps testosterone concentrated locally and promotes spermatogenesis. In controlling these processes, adequately high levels of testosterone in the blood signals to inhibit further release of GnRH, LH and FSH. Inhibin is also produced by the sustentacular cells, and assists with inhibiting the release of GnRH, LH and FSH when sperm count is adequately high. ABP = androgen-binding protein; FSH = follicle-stimulating hormone; GnRH = gonadotrophin-releasing hormone; LH = luteinising hormone.
3 Epididymis
2 Rete of testis
1 Testes (seminiferous tubules)
6 Ejaculatory duct
7 Prostate gland
8 Bulbourethral gland
9 Urethra
10 Penis F O CUS O N L E A R N IN G
1 Explain the process of somatic (normal body) cell division in mitosis, and how gametes are formed in meiosis. 2
Describe the process of spermatogenesis (sperm production), in terms of the cells and hormones involved.
3 Explain how GnRH, FSH, LH and testosterone control male reproductive function.
FIGURE 31.16
The pathway of sperm from the seminiferous tubules to the tip of the penis. Sperm are produced in the testes, and pass through structures including the epididymis and ductus deferens. Secretions from the seminal vesicle combine with sperm in the ejaculatory duct, and further secretions from the prostate gland also combine with this fluid as it travels down the urethra. Bulbourethral secretions usually travel through the urethra prior the main ejaculate.
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CONCEPT MAP
Hypothalamus produces GnRH stimulates Anterior pituitary produces FSH and LH stimulates produce
Secondary sexual characteristics
Testes
stimulates and maintains enable
Testosterone required for
Spermatogenesis produces Spermatozoa
RESEARCH IN F CUS The quest for male contraception Safe, reliable hormonal contraception for women has changed the face of human reproduction over the last 50 years with 64% of women of reproductive age worldwide using contraception. The goal to also provide this choice to men has been a long time coming. Inhibition of spermatogenesis without affecting normal sexual function, secondary sexual characteristics or inducing adverse effects has been the main barrier. In a recent intensive multi-centre clinical study, the efficacy of an injection which inhibits the feedback mechanism to the pituitary gland and hypothalamus reducing the production of GnRH and consequently LH and FSH was investigated. The study was designed to test the contraceptive efficacy and safety in men, using a regimen of intramuscular injections of a long-acting progestogen, norethisterone enanthate, when administered with replacement doses of a long-acting androgen, testosterone undecanoate. The study population was healthy men 18–45 years in stable monogamous relationships and their partners. The men received 8 weekly injections over 18 months with regular sperm counts undertaken. In the later weeks of the study couples were exposed to the risk of pregnancy. The couples reported high satisfaction with this method of contraception with 94% of men returning to normal sperm counts within 1 year of discontinuing injections. While there is still more trialling necessary the implications for human health and population growth are significant if this method proves reliable and there is uptake by men.
travel via Epididymus and urethra passes via Prostate ejaculated from Penis
FIGURE 31.17
Hormonal changes and sperm production. In response to signals from the hypothalamus, follicle stimulating hormone (FSH) and luteinising hormone (LH) are released, which in turn stimulate the testes to produce testosterone necessary for sexual maturation, as well as spermatogenesis. Following spermatogenesis, the spermatozoa travel through the ducts to exit via the penis. GnRH = gonadotrophin-releasing hormone.
Oogenesis
The same hormones that control male sexual development control female sexual development and uterine and ovarian cycling (see Fig. 31.18). At birth, a female has all of the oocytes she will ever have — approximately 2 million. No new oocytes are subsequently produced, so a female is born with all her immature gametes already present — a situation that is in contrast to male gamete production. Most of these will degenerate so that at puberty she has 200 000–400 000 left. Over a woman’s reproductive lifetime of about 30–40 years, approximately 450 oocytes will completely differentiate and be released from the ovary (ovulation). The gametes are all present in each of the ovaries in the form of primordial follicles. The actual gamete is surrounded by a layer of cells called the granulosa cells in the cortex of the ovary. The oocyte and the granulosa cells together comprise the follicle. During a woman’s reproductive years, every 28 days 1 follicle develops to maturity and is ovulated. In 1–2% of cycles more than 1 oocyte develops to this stage, potentially resulting in multiple births. The oocyte degenerates within a few days if it is not fertilised by sperm.
CHAPTER 31 The structure and function of the reproductive systems
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2
1 3 4 FIGURE 31.19
Hormonal control of ovulation. As the follicle matures, more and more oestrogen is produced from the larger number of granulosa cells surrounding the ovum. When the concentration of oestrogen in the blood reaches a certain level it has a positive feedback action on the hypothalamus 1 triggering a ‘surge’ in production of GnRH 2 and a consequent rapid increase in LH concentration. This rise in LH concentration is essential for the wall of the follicle to burst 3 and release the oocyte 4.
The ovarian cycle
FSH = follicle-stimulating hormone GnRH = gonadotrophin-releasing hormone LH = luteinising hormone Stimulation Inhibition FIGURE 31.18
Hormonal control of female reproductive development. The hypothalamus releases GnRH, which stimulates the anterior pituitary to release LH and FSH, both of which act on the ovaries. FSH stimulates the development of follicles, and promotes the secretion of oestrogen, some of which remains in the ovaries to promote the secretion of progesterone, and some of which enters the bloodstream and leads to the other body-wide functions of oestrogen. LH, in conjunction with rising oestrogen, promotes endometrial growth, whilst the surge in LH leads to ovulation. In controlling these processes, rising levels of oestrogen in the blood early in the cycle promotes further release of GnRH, LH and FSH. However, high levels of progesterone signals to inhibit further release of GnRH, LH and FSH.
The ovarian cycle is the series of changes in the ovarian follicles that include oocyte development and ovulation. The follicles respond to FSH which is initiated by the secretion of activin from the ovary. Follicles grow and mature, with one follicle emerging as dominant. It is this follicle that undergoes full maturation, developing receptors for LH on its granulosa cells. The granulosa cells within this follicle proliferate and a zona pellucida (clear area or zone) forms between the oocyte in the middle and the surrounding granulosa cells, while a fluid-filled antrum appears. The granulosa cells increase in number and produce increasing amounts of oestrogen until the follicle bursts and the oocyte is released. The oocyte is surrounded by a layer of granulosa cells (corona radiata) at ovulation and the remains of the follicle stay in the ovary and become the corpus luteum. Oestrogen and progesterone are secreted from the corpus luteum for about 10 days if a pregnancy does not occur. Ovulation is stimulated by the surge in LH (see Fig. 31.19). Following the LH surge, meiosis I is completed in the oocyte and meiosis II begins and is then arrested at metaphase where it remains until fertilisation.
The uterine (menstrual) cycle
The uterine (or menstrual) cycle lasts for approximately 28 days and is controlled by oestrogen and progesterone secreted by the ovaries (see Fig. 31.20).1,7,8 The ovarian and uterine cycles occur in concert with each other as the developing follicle produces oestrogen, which stimulates
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Hypothalamus GnRH
Pituitary gland
HYPOTHALAMICPITUITARY CYCLE
Posterior
Anterior Follicle-stimulating hormone (FSH)
Pituitary hormones
Luteinising hormone (LH)
Follicular phase
Luteal phase
LH FSH Ovulation
OVARIAN CYCLE Primary follicle Graafian follicle
Egg
Corpus luteum
Degenerating corpus luteum Ovarian hormones
Progesterone Some oestrogen
Oestrogen
Oestrogen Progesterone Menstruation
Proliferative phase
Secretory phase
Ischaemic phase Menstruation
ENDOMETRIAL CYCLE
Functional layer Basal layer Day
1
5
10
14
28 1
5
FIGURE 31.20
The uterine cycle. Rising FSH promotes the ovaries to release rising levels of oestrogen, which promotes growth of the endometrium. Rising oestrogen causes a surge in LH, which triggers ovulation. Rising progesterone promotes further growth of the endometrium. However, near the end of the cycle, the decline in both progesterone and oestrogen lead to shedding of the endometrium, forming the menstrual bleed. GnRH = gonadotrophin-releasing hormone.
CHAPTER 31 The structure and function of the reproductive systems
Hypothalamus
CONCEPT MAP
the uterine endometrium to proliferate. This is necessary to prepare the uterus to receive a zygote (fertilised egg). The uterine cycle is divided into three stages: 1 Menstrual stage: days 1–5. Levels of oestrogen and progesterone are relatively low and the thick endometrial lining of the uterus is sloughed off. As this layer breaks down it is accompanied by bleeding (the menstrual flow). 2 Proliferative (or follicular) stage: days 6–14. Under the influence of oestrogen produced by the growing follicle in the ovary, the endometrium thickens and glands and blood vessels proliferate. Spiral arteries grow into the thickened endometrium. Ovulation occurs at the end of this stage, typically at day 14. During both the menstrual and the proliferative stages, the follicle is developing under the influence of FSH and oestrogen levels are rising as the number of granulosa cells in the follicle increases. The levels of oestrogen rise until a positive feedback loop between oestrogen and the anterior pituitary results in a large ‘spike’ in LH concentration. This spike causes the follicle to rupture and the oocyte to be released. Hence, these stages are started by FSH, which causes a rise in oestrogen (progesterone remains low), and this rise in oestrogen causes an LH spike and the mature egg is ovulated. 3 Luteal (or secretory) stage, days 15–28. Under the influence of progesterone from the corpus luteum, the blood supply to the endometrium continues to increase and the glands increase in size and begin to secrete nutrients (e.g. glycogen — stores of glucose) in readiness for implantation of an embryo. If implantation occurs, embryonic tissues will secrete the hormone human chorionic gonadotrophin (hCG), which maintains the function of the corpus luteum. If implantation does not occur — either because the oocyte has not been fertilised or there is a physical problem with the uterine tube or endometrium — the corpus luteum deteriorates after 10 days and the withdrawal of its endocrine support reduces blood supply to the endometrium. Without implantation, menstruation begins 14 days after ovulation, as the endometrium is sloughed off. The luteal stage is controlled by the corpus luteum and is under the influence of LH. The corpus luteum produces more progesterone than oestrogen, so this phase is dominated by progesterone. Progesterone causes the endometrial glands to fill with glycogen, the endometrial blood vessels to grow and it inhibits smooth muscle activity in the myometrium. Changes in hormone levels are quite dramatic throughout the cycle (Fig. 31.20) and can be measured to monitor the cycle and potential pregnancy. The complete process, from hormonal roles through to ovulation, is shown in Fig. 31.21. Cervical mucus plays a role in contraception (to some extent) and the sexual act itself. In the menstrual and proliferative stages, which are under the influence of oestrogen, the mucus is abundant, clear and non-viscous. This is most pronounced at the time of ovulation and the freely flowing liquid allows sperm easy access from
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produces GnRH stimulates Anterior pituitary produces FSH and LH stimulates Ovaries
produce Oestrogen Progesterone
undergo Ovarian cycle oogenesis
stimulate and maintain
produces Oocyte
Secondary sexual characteristics
descends down Uterine tube
Fertilisation may occur
through Uterus leads to Cervix leads to Vagina
FIGURE 31.21
Hormonal changes and oocyte production. In response to signals from the hypothalamus, FSH and LH are released, which in turn stimulate the ovaries to produce oestrogen and progesterone necessary for sexual maturation, as well as oogenesis. Following ovulation, the oocyte travels through the uterine tube and exits the body via the vagina. The corpus luteum, which remains in the ovary, continues producing hormones for several days before degenerating.
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the vagina, through the uterus and to the uterine tubes. During the luteal phase under the influence of progesterone the cervical mucus is thick and sticky. This can form a barrier to sperm movement and create a plug to seal off the uterus (and embryo if implantation occurs) from infection.
Ovarian and uterine cycle timing
The ovarian and uterine cycles occur in concert with each other, as the ovarian cycle drives the uterine cycle. The developing primordial germ cells in the ovary begin releasing oestrogen in increasing amounts as their development proceeds. The granulosa cells, which produce oestrogen, increase in number throughout the development process and the endometrial layer of the uterus responds to the increasing levels of oestrogen in the blood. When a follicle is fully matured and ready to ovulate, it is producing a higher amount of oestrogen, which causes positive feedback on the hypothalamus (see Fig. 31.19). The hypothalamus responds by increasing the GnRH pulses and, in turn, the anterior pituitary produces large quantities of LH. This sharp rise in LH blood concentration is the trigger necessary for the oocyte to burst out of the ovary (ovulate). In assisted reproductive technology this increase in LH must be artificially created (by LH injections) to stimulate maturation of ova for egg collection (refer to Chapter 32). After ovulation has occurred, oestrogen levels drop and the remains of the follicle in the ovary (the corpus luteum) produce a relatively higher concentration of progesterone. One important effect that progesterone has is to prevent muscular contraction of the myometrium (the middle layer of smooth muscle of the uterus). This is essential for the uterus to hold and carry a baby to full term; if the uterine myometrium contracts, then the zygote or more developed embryo could be expelled and the pregnancy fail. The corpus luteum will persist in the ovary and secrete progesterone for about 10 days before it degenerates. If an egg is fertilised soon after ovulation (within hours) it will take the zygote about 5–6 days to reach the uterus and another day to become embedded in the endometrium (implantation) and produce sufficient hCG to establish the pregnancy. The hCG produced maintains the corpus luteum for a longer period until the placenta is established, at which time the placenta produces the progesterone necessary to maintain the quiet state of the myometrium. So the corpus luteum produces progesterone long enough for a possible pregnancy to establish and then degenerates into the corpus albicans (which does not produce progesterone). After 10 days, if no implantation is established, the levels of progesterone fall and the myometrium begins to contract to expel the excess endometrium, which is not needed. This is the menstrual flow. Human chorionic gonadotrophic (hCG) will continue to be produced by an implanted embryo and this is the basis of a pregnancy test: hCG detection in the urine (or blood, for greater sensitivity) is positive 2 weeks after fertilisation.
The interplay of the ovarian and uterine cycles may at first seem very complex, but when you focus on the reasons for the events you will see that this elegant system brings about maturation of an oocyte and prepares the uterus to receive the oocyte if it is fertilised. The hormonal interplay also seems complex, but essentially the pre-ovulation phase is dominated by oestrogen (preparing the uterus) while the post-ovulation phase is dominated by progesterone (holding the prepared uterus ready) in case fertilisation and implantation occur. If there is no fertilisation, both hormone levels are relatively low and the thickened uterus, which is not needed, is expelled. FOCU S ON L EA RN IN G
1 Describe the phases of the ovarian and uterine cycles. 2 Describe the process of oogenesis (egg production), in terms of the cells and hormones involved. 3 Explain how GnRH, FSH, LH, oestrogen and progesterone control female reproductive function.
Male and female sexual responses The most widely discussed reference on the sexual responses of men and women is the four-stage model: (1) excitement, (2) plateau, (3) orgasm and (4) resolution.9 There are no really clear distinctions between the stages or time points at which one phase ends and the next begins. Although biologically accurate, this model does not account for the psychological aspects of the sexual response. In both males and females, initiation of the sexual response may include visual, mental and physical stimuli. The sexual responses of males and females have many similarities. Two basic physiological responses to sexual stimulation are vasocongestion and myotonia. Vasocongestion occurs when body tissues fill with blood and swell in size. This is responsible for the erection of the penis and also causes a woman’s breasts to increase in size and the vagina to lubricate. Other body parts that may be affected are the labia, testicles, clitoris and nipples. Myotonia is the increased muscle tension that happens during sexual arousal. This includes both flexing (which is voluntary) and contractions (which are involuntary). The most obvious examples of this are the muscle contractions that occur during both male and female orgasm.
The female sexual response
When not sexually aroused, the uterus lies in its normal anteverted position over the bladder, the vagina is relatively narrow and the labia minora are retracted (see Fig. 31.22). In the excitement phase, sexual stimulation from a combination of physical, neuronal, hormonal and psychological inputs results in the uterus standing more vertically and the
CHAPTER 31 The structure and function of the reproductive systems
1
Excitement phase
2
Plateau phase
3
Orgasm phase
4
Resolution phase
FIGURE 31.22
The female sexual response. The main phases are excitement, plateau, orgasm, and resolution.
inner end of the vagina dilating. The labia minora become vasocongested and may extend beyond the labia majora. A vaginal transudate moistens the vagina and vestibule. The plateau phase is a continuation of the excitement phase up to the moment of orgasm and resolution. In this phase the uterus is vertical and the cervix is withdrawn from the vagina. The clitoris is engorged and the labia are bright red and flushed with blood, and the lower third of the vagina constricts the penis. This phase can continue for a long or short time depending on the couple and the circumstances of the sexual activity. During the orgasm phase, the vagina contracts rhythmically and the uterus has peristaltic contractions. Finally, at resolution the uterus returns to its original anteverted position and the cervix protrudes into the top of the vagina; it may contact a pool of sperm as it does so, thereby allowing the sperm to gain access to the uterus and uterine tubes.
The male sexual response
The physiological response of the male can also be thought of in terms of four stages. Fig. 31.23 details both the nerve impulses responsible and the actions they bring about in males. As with the female sexual response males are also stimulated by physical stimulation as well as psychological, hormonal and neuronal inputs that result in the initiation
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of the excitement phase. Signals are transmitted via the internal pudendal nerve to the sacral level of the spinal column, which in turn sends efferent parasympathetic signals to the internal pudendal artery of the penis and the trabecular muscles of the erectile tissue. The trabecular muscles relax, allowing blood to flow into the erectile tissue, with the result that the penis becomes erect. A second consequence of this is the release of a small amount of fluid from the bulbourethral glands. During the plateau phase this heightened state of arousal, accompanied by widespread muscle myotonia, is maintained and built up further. The male orgasm phase is divided into two parts: the orgasm-emission phase and the orgasm-expulsion phase. During the orgasm-emission phase sympathetic nerve signals arising in the L1–L2 level of the spinal cord induce peristaltic movement of the ductus deferens, which moves sperm from the epididymis to the ampulla and from there into the prostatic urethra. In addition, these nerve signals induce release of seminal and prostatic fluids from the seminal vesicles and prostate gland, respectively. The orgasm-expulsion phase is triggered by the presence of semen in the urethra, which is detected by sensory receptors and signalled to the central nervous system; nervous signals are integrated in the L1–S4 level of the spinal cord. Efferent sympathetic and efferent somatic signals arise from this integration of sensory input. The sympathetic signals cause further release of seminal and prostatic fluid and close the internal urethral sphincter, preventing the release of urine. The somatic signals innervate the bulbocavernosus and ischiocavernosus muscles, which contract rhythmically around the bulb and root of the penis. This rhythmical compression of the penis forces the semen out through the penile urethra (ejaculation). Finally, during the resolution phase, efferent sympathetic signals arising from the L1–L2 level of the spinal cord cause the internal pudendal artery to contract; this reduces blood flow to the erectile tissue. At the same time the trabecular muscles contract and the remaining blood is squeezed out of the penis as it returns to its flaccid state. FOCU S ON L EA RN IN G
1 Outline the physiological changes that occur in males and females during sexual intercourse.
Conception, gestation and parturition During intercourse increased blood flow to the vagina causes transudation of fluid through the walls, providing lubrication. Mucous lubricant is secreted by the Bartholin’s glands (at the vaginal entrance). Sperm are deposited in the vagina near the cervix and from there must travel through the uterus to the uterine tubes. The cervical mucus is non-viscous at the time of ovulation, as the production of progesterone is relatively low — this aids the free movement of sperm. Sperm move due to the motility of the sperm tail and
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FIGURE 31.23
The male sexual response. The main phases are excitement, orgasm-emission, orgasm-expulsion, and resolution.
peristaltic activity in the uterus. There are millions of sperm in each ejaculate, but very few reach the uterine tubes; however, those few do not take long to get there.
Fertilisation
The oocyte is ‘fertilisable’ for only a few hours after ovulation and entering the uterine tube; however, sperm can live for
2–3 days after ejaculation into the vagina. The sperm meet the oocyte at fertilisation in the ampulla of the uterine tube (at the ovarian end), and the zygote implants in the uterus (see Fig. 31.24). At ovulation, an oocyte completes its first meiotic division. As it is released from the ovary, it is surrounded by the zona pellucida and granulosa cells (corona radiata), both of which are a barrier to the sperm. The sperm undergo capacitation in the female tract, which
CHAPTER 31 The structure and function of the reproductive systems
Oocyte travels down
travel through Epididymis urethra passes through Prostate ejaculated from
Uterine tube sperm meets ovulated oocyte in
joins to Uterus
leads to
Corpus luteum remains in ovary Zygote moves to uterus and implants Placenta develops 38 weeks
produces sex hormones for 10 days then degenerates Corpus albicans
Gestation
CONCEPT MAP
Spermatozoa
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Penis Cervix
Parturition
leads to Vagina
FIGURE 31.24
Fertilisation, gestation and parturition. After sperm fertilise the oocyte within the uterine tube, the zygote continues travelling until it reaches the uterus. Here, it implants and grows, while the placenta also develops, until parturition (labour). The fetus is expelled from the uterus through the cervix and vagina.
‘primes’ them for the meeting with the oocyte. It actually takes many sperm to bind to the zona pellucida to release the acrosome that gradually breaks down this barrier. When one sperm finally penetrates the zona pellucida and reaches the oocyte cell membrane, the membrane alters immediately to prevent any more sperm binding to it. This is termed the fast block and is essential to prevent the entry of more than one sperm ‘head’. The fertilised ovum completes meiosis II and now contains the oocyte nucleus (with 23 chromosomes) and the sperm nucleus (with 23 chromosomes) and these fuse together to form one cell nucleus containing the full complement of 46 chromosomes. At this stage the fertilised egg is called a zygote. The zygote travels along the uterine tube to the uterus (this takes 3–4 days) and as it does so, it undergoes a series of rapid mitotic divisions to become an embryo. The embryo reaches the uterine cavity as a tiny hollow ball of 64 cells termed a blastocyst. After several more days, this implants in the uterine wall. At this stage the uterus is primed by progesterone and oestrogen (from the corpus luteum) such that the endometrium is thickened and rich in nutrients and blood flow. As discussed above, oestrogen and progesterone are vital for the maintenance of a pregnancy. When fertilisation occurs, the corpus luteum is stimulated by hCG secreted from the developing embryo to secrete oestrogen and progesterone for 2–3 months.
Implantation
Implantation is the process whereby the blastocyst adheres to and then invades the endometrium. Implantation is completed early in the second week (after fertilisation) and normally occurs in the upper part of the uterus; if the blastocyst implants lower, near to the cervix, there may be complications during birth (parturition). The outer cell layers of the blastocyst proliferate and ‘invade’ the endometrium. These cells produce enzymes that break down the endometrial cells, allowing the blastocyst to ‘sink’ into the endometrium until it becomes completely embedded. The blastocyst initially derives its nutrition from the endometrial cells that are broken down — the blastocyst literally ‘eats’ its way into the thickened endometrium and digests the released products to continue growing. As the blastocyst develops into an embryo, it eventually forms the placenta and obtains its nutrition from maternal blood, via the placenta.
The development and function of the placenta
The placenta is a complex organ that acts as an interface between the mother and the fetus. It is derived from the outer cells of the blastocyst which form the chorion of
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RESEARCH IN F CUS Assistive reproductive technologies Since the birth of Louise Brown in 1978, approximately 5 million children worldwide have been born using assistive reproductive technologies (ART). This is a highly successful treatment for couples with infertility. Adverse effects related to ART have been reported, with most of these focusing on the perinatal period such as birth defects, and also the implications of multiple births on mother and infants. The potential for adverse effects is a concern as ART procedures coincide with epigenetic programming events. A new study has shown through epidemiological evidence that in children born through ART, there are detectable differences in blood pressure, body composition and glucose homeostasis. The implications for this may include early onset hypertensive and cardiac disorders, diabetes and other comorbidities. If there are known potential pathologies in this population that have long-term effects on health, this information could be of use in surveillance and planning of care for this adult population to improve health outcomes.
the developing embryo and is attached to the maternal endometrium. The mature placenta secretes hCG, oestrogen and progesterone. The oestrogen has negative feedback on the hypothalamus, which reduces the production of GnRH, thus reducing the production of FSH and LH. In this way, with very little FSH, there is no stimulation of the primordial germ follicles in the ovaries and the ovarian and uterine cycles stop. By 12 days following implantation, the embryo is completely embedded in the endometrium. The continued invasion of the endometrium results in eroded spaces that become filled with maternal blood over time; these spaces are termed sinuses or lacunae (literally, empty spaces). Lacunae receive blood from the uterine arteries and drain into the uterine veins. Nutrients, gases and wastes thus diffuse to and from the embryo and maternal blood across a layer of blastocyst cells (now termed chorionic cells), but without direct connection between the two circulations — at this and all subsequent stages of development, maternal blood is separated from embryonic and fetal tissues, including embryonic blood, by a layer of chorion. By the end of the second week after fertilisation, chorionic villi (projections of the chorion) have grown over the entire surface of the embedded embryo and the menstrual period is missed. During the third week, embryonic blood vessels begin to appear in the chorionic villi and soon establish connections with the blood vessels developing in the embryo itself via the umbilical blood vessels (in the umbilical cord). By the end of the third week, when the embryo’s heart begins to beat, blood begins to circulate from the embryo, through the umbilical arteries to capillaries in the chorionic villi. Up to the eighth week of gestation, chorionic villi cover the entire surface of the embryonic sac. After this time,
they begin to disappear, eventually remaining only where they form the fetal part of the mature placenta; the rest of the chorion becomes smooth as the villi disappear. As the embryo and its sac grow, they begin to bulge from the uterine wall into the uterine cavity, and by the end of the tenth week the fetus completely obliterates the uterine cavity. Formation of the placenta is completed by the end of the first trimester. The fetal side of the placenta is that part of the chorion that retained its villi — these branch as they continue to grow, providing a large surface area for diffusional exchange between fetal and maternal blood (see Fig. 31.25). The maternal surface to which the placenta is attached is the endometrium. Over the second and third trimesters, the placenta increases in size, in the degree of branching of the villi and in the volume of the intervillous space (i.e. the continuous space between the villi, filled with maternal blood). At term, the placenta weighs 500–600 g and is 18–20 cm in diameter.
Fetal placental circulation
Blood from the fetus, low in oxygen and high in carbon dioxide and other wastes, passes through the two umbilical arteries to the placenta. Here the arteries branch to enter the villi. In the villi, blood flows in the capillaries. The villi are surrounded by a ‘lake’ of maternal blood and the capillaries in the villi bring fetal blood close to maternal blood; exchange of gases, wastes and nutrients can thus be effected across the placental (chorionic) membrane, which at all times separates the fetal and maternal circulations. Fetal blood, now rich in oxygen and nutrients and low in carbon dioxide, leaves the villi and returns to the fetus in the single umbilical vein, which feeds directly into the fetal right atrium via the inferior vena cava. (Refer to ‘Paediatrics and fetal circulation’ in Chapter 22 and Fig. 22.11 for additional details of fetal circulation.)
Maternal placental circulation
Maternal blood enters the intervillous space through spiral arteries in the decidua basalis, and it leaves through endometrial veins. Maternal blood pressure is low in the placenta and the flow of blood is correspondingly slow: this aids diffusional exchange between maternal and fetal blood.
Transfer (exchange) across the placenta
The welfare of the fetus depends above all else on adequate bathing of its chorionic villi by maternal blood. If maternal placental circulation is reduced, fetal hypoxia, growth retardation or fetal death may ensue. Most blood-borne substances can cross the placental ‘barrier’ between the fetal and maternal bloodstreams. Many large molecules, such as immunoglobulin G (IgG), pass the barrier readily, but a few such as heparin and immunoglobulin M are excluded. Transfer of the following occurs readily by a variety of mechanisms: • water • oxygen
CHAPTER 31 The structure and function of the reproductive systems
A
Umbilical arteries Umbilical vein
Maternal venule
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B
Umbilical cord
Maternal arteriole Endometrium Fetal arteriole Fetal venule
Placenta Maternal Chorionic villi blood
FIGURE 31.25
Structural features of the placenta. The close placement of the fetal blood supply and maternal blood supply permits diffusion of nutrients and other substances. It also forms a thin barrier to prevent diffusion of most harmful substances. No mixing of fetal and maternal blood occurs. A Diagram showing a cross-section of the placental structure. B Photograph of a normal, full-term placenta (fetal side) showing the branching of the placental blood vessels.
carbon dioxide nutrients (e.g. glucose) wastes (e.g. urea) electrolytes hormones some antibodies such as IgG, which serve to confer passive immunity to a variety of pathogens on the newborn (but which can also harm the baby in the case of Rhesus incompatibility) • alcohol • most drugs, including those used for the management of labour • many infectious agents — bacterial, viral and protozoal. From the perspective of the fetus, the placenta acts as a lung (gas exchange), gut, liver (nutrient absorption and metabolism) and kidney (excretion, water and electrolyte homeostasis) — the main limiting factor for the efficiency of all these functions being the maternal placental circulation.
The middle layer is the chorion, termed the chorion laeve. 3 The outermost layer is the decidua capsularis which degenerates by 12 weeks gestation. These membranes constitute a barrier to infection of the fetus through the vagina and cervix. Within the sac, the fetus floats freely in amniotic fluid, anchored through the umbilical cord. Note that all the cells derived from the fertilised egg, which includes the fetus itself, the fetal components of the placenta and the fetal membranes other than the decidua capsularis, are genetically identical to each other, but genetically different from the mother. Thus, if a biopsy sample of the chorionic villi is taken, we can look at the karyotype and genetic composition of the baby, enabling prenatal testing for genetic diseases.
The embryonic sac
Amniotic fluid is derived in part as a filtrate of maternal blood and in part from fetal urine. At term, about 1 L of amniotic fluid is present in the sac. The composition of amniotic fluid is similar to that of extracellular fluid, with the addition of: • hormones, enzymes and other fetal metabolites — many of these metabolites can be measured in a sample of amniotic fluid derived by amniocentesis to give a prognosis of the health of the baby (e.g. alpha
• • • • • •
From the time the embryonic (amniotic) sac begins to bulge into the uterine cavity until the time it completely occupies the cavity some 10 weeks after fertilisation, it has the following three layers: 1 The innermost layer of the sac is the amnion. Extensions of the amnion cover the fetal surface of the placenta and the umbilical cord. The amnion is continuous with the skin of the fetus at the umbilicus.
2
The origin, composition and significance of amniotic fluid
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(α)-fetoprotein as an indicator of neural tube disorder, bilirubin as an indicator of haemolysis) • cells shed from the fetus — some of these are viable and can be cultured for genetic and biochemical analysis. The functions of the amniotic fluid are of significance in terms of the normal development of the fetus. The fluid mechanically cushions the fetus from external shock and the mother’s physical activity (e.g. walking, exercise), and it also helps maintain a constant temperature of 37°C. But perhaps one of its most important functions involves allowing the external growth of the fetal limbs and the free movement essential for musculoskeletal development. As the fetal central nervous system develops, reflex actions of swallowing and urination begin and the amniotic fluid circulates through the fetus as well as surrounding it. Circulation of the amniotic fluid involves exchange between three fluid compartments: the amniotic cavity, the fetus (gastrointestinal tract, blood, urinary tract) and the mother (blood). This circulation is essential to the normal development of the fetus, and the level of amniotic fluid (checked by ultrasound) can be diagnostic for the development of the fetus.
Endocrine changes
Many of the anatomical and physiological changes of pregnancy are driven by maternal hormonal changes. The principal changes are the high levels of oestrogen and progesterone produced by the placenta and corpus luteum; other hormonal changes are summarised in Table 31.3. In the first 2 months, the corpus luteum, under the influence of chorionic gonadotrophin, is almost entirely responsible for the secretion of these hormones; thereafter, they are produced by the placenta. Among the many effects of oestrogen on the woman in pregnancy are growth of the uterus and breasts, fluid retention and widespread vasodilation, which assists in preventing blood pressure from increasing as blood volume increases in pregnancy. The effects of progesterone include reduced smooth muscle activity in the uterus, gastrointestinal
TABLE 31.2 Typical weight gains during pregnancy Maternal body
Uterus
1 kg
The mother’s adaptations to pregnancy
Breasts
0.5–1 kg
Extra fat and protein
3 kg
Weight gain
Blood and intracellular fluids
2 kg
Fetus
3.5 kg
Placenta
1 kg
Amniotic fluid
0.5 kg
During pregnancy a woman usually gains 10–12 kg, mainly during the second and third trimesters. The usual components of this weight gain are shown in Table 31.2, but of course this is different for each pregnancy, so the values given are merely examples.
Uterine contents
TABLE 31.3 Hormonal changes other than oestrogen and progesterone during pregnancy SITE OF PRODUCTION
HORMONE
EFFECTS
Anterior pituitary
Prolactin
Breast development Lactation
Posterior pituitary
Adrenocorticotrophic hormone (ACTH)
Stimulates the adrenal cortex
Melanocyte-stimulating hormone
Causes some skin darkening, especially around the nipple
Oxytocin
Uterine contractions during labour Letdown of milk post parturition
Thyroid
Antidiuretic hormone (ADH)
Fluid retention by kidneys
Thyroid hormones (T3 and T4)
Increases basal metabolic rate Increases pulse rate Increases CO2 production (due also to increased metabolism)
Adrenal cortex
Aldosterone
Sodium retention by kidney
Kidney
Erythropoietin (EPO)
Increased erythrocyte production
Corpus luteum and placenta
Relaxin
Increased arterial compliance Relaxes ligaments including pubic symphysis
CHAPTER 31 The structure and function of the reproductive systems
tract, airways and arterioles; growth of the breasts; an increase in the basal metabolic rate; and stimulation of the respiratory centre in the medulla of the brain.
Changes in reproductive and other organs during gestation
The uterus and breasts increase in size in the pregnant female, but the degree of increase depends on a variety of factors. For example, a small baby will not expand the uterus quite as much as a larger baby. UTERUS
The uterus expands to contain the ever-growing fetus. At 12 weeks the height of the fundus of the uterus is at the level of the pubic symphysis, by 20 weeks it is at the level of the umbilicus and between 36 and 40 weeks it is at the level of the xiphoid process of the sternum. The uterus enlarges mainly by hypertrophy (enlargement) of existing cells. In late pregnancy, stretching leads to thinning of the uterine wall. Irregular contractions of the uterine muscle occur throughout pregnancy; these are known as Braxton-Hicks contractions. CERVIX
The cervix enlarges and softens, and the cervical canal is filled by a mucous plug (operculum). The operculum not only helps to hold the fetus and placenta within the uterus, but it also acts as a physical barrier to infection. At the onset of labour the operculum is expelled as a ‘show’ and is a clear indication of impending parturition. BREASTS
There is hyperproliferation of breast tissue, increasing the size of the breasts. This is physiologically normal growth, not to be confused with the rapid growth of breast tissue experienced in breast cancer (see Chapter 32). This growth may be accompanied by a feeling of fullness and tenderness. There will also be dilation of the veins, a deepening in colour of the nipples and areola, and the appearance of Montgomery follicles (enlarged sebaceous glands) in the areola. RESPIRATORY CHANGES
In pregnancy, there is an increase in the depth of breathing (at rest), without an increase in the rate of breathing. This change leads to better clearance of carbon dioxide and improved oxygenation of maternal blood; this is clearly favourable for fetal gas exchange in the placenta. Progesterone acts on the respiratory centre in the medulla of the brain to increase its sensitivity to carbon dioxide: the result is an increase in tidal volume, thereby increasing the depth of breathing. Thus ventilation increases, without an increase in respiratory rate. This is aided by the relaxing effect of progesterone on the smooth muscle of the airways (reducing airway resistance). Late in pregnancy, the growing uterus pushes up the diaphragm, leading to more effective ‘emptying’ of the lungs
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(lower lung residual volume), improving clearance of carbon dioxide from the maternal blood. In addition to increased concentrations of oxygen (and reduced concentrations of carbon dioxide), oxygen carriage by maternal blood is increased because the blood volume and the total number of erythrocytes (oxygen-carrying red blood cells) are increased in pregnancy. CARDIOVASCULAR CHANGES
The cardiovascular changes of pregnancy ensure increased blood flow to the placenta and uterus. The fundamental change is a large increase in blood volume. Plasma volume increases (by 45%) to a greater extent than does the number of erythrocytes (by 25%); thus there are apparent falls in values for red blood cells and haemoglobin (haemodilution), with an actual increase in oxygen-carrying capacity. Haemodilution is beneficial in that it results in better circulation of the blood. One of the effects of this improved circulation is more efficient loss of heat, from both the fetus and the mother, through the woman’s skin. The increased blood volume automatically causes increased cardiac output, as both stroke volume (blood ejected from each ventricle at each contraction) and heart rate increase. While increased blood flow to the placenta and the uterus is affected in this way, it is achieved without corresponding increases in blood pressure, as the relaxing effect of progesterone on the smooth muscle of the arterioles leads to reduced peripheral resistance. Thus blood pressure does not in general change with pregnancy and may in fact fall slightly due to the vasodilative effect of progesterone. Fetal blood has a higher concentration of haemoglobin than maternal blood, and fetal haemoglobin has a greater affinity for oxygen than adult haemoglobin: these differences favour the transfer of oxygen from maternal blood to fetal blood in the placenta. WATER AND ELECTROLYTES
In pregnancy there are increases in both body water content and urine output. The increase in body water comprises increases in plasma volume and increased extracellular fluid (i.e. widespread oedema). With the increased blood volume, there is increased renal blood flow and thus the glomerular filtration rate increases. This leads to increased urine output, even though aldosterone causes reabsorption of sodium and antidiuretic hormone causes reabsorption of water at markedly high levels during pregnancy. Increased urine output, of course, leads to a greater frequency of micturition. Another contributor to this effect is the increasing pressure of the growing uterus on the bladder. Increased thirst and drinking in pregnancy maintain the supply of water for these processes. NUTRITION AND METABOLISM
In pregnancy food intake and anabolism increases, and there is some increase in the basal metabolic rate. In early pregnancy the mother may experience nausea, but appetite and thirst subsequently increase to high levels and these
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are maintained throughout pregnancy. The increase in food intake supplies the required nutrients for: • growth of the fetus • the increase in the mother’s basal metabolic rate • laying down of fat stores in the mother, to be drawn upon for lactation • laying down of fat and glycogen stores in the fetus, late in pregnancy — at the beginning of independent life glycogen stores are used as metabolic fuels and the fat as insulation. There may also be some problems associated with nutrition in pregnancy: • If the increased requirements for special nutrients (e.g. calcium, iron, folic acid) are not met, these may be reflected in abnormal development, such as congenital defects of the spinal cord. • A reduction in gut motility, caused by the relaxing effect of progesterone on smooth muscle, can lead to constipation. • Stomach reflux and heartburn may be frequent as the lower oesophageal sphincter has reduced tone (an effect of progesterone) and the stomach is ‘crowded’ by the uterus. • Unusual food cravings and food aversions may develop — these are highly individual and do not occur in all women. • Blood glucose may rise, as insulin is antagonised by placental lactogen, and glycosuria may occur, due to increased blood glucose and an increased glomerular filtration rate (hence tubular reabsorption of filtered glucose may be incomplete).
Fetal development
The fetus’ organ systems are established by the end of the eighth week after fertilisation. In the following 30 weeks the fetus changes in proportion, as growth of the body ‘catches up’ to the relatively large head. In addition the fetus also grows in size — the increase in length is especially marked from 9 to 16 weeks and the increase in weight is especially marked in the last few weeks of pregnancy. In the first half of pregnancy, all babies grow at the same rate, so measurement of size, by ultrasound, gives accurate dating of the pregnancy within this period. However, in the second half of pregnancy, individual differences in the sizes of different fetuses appear. Some features of the fetal period: • 9–12 weeks • Body length (measured as ‘crown–rump’ length) increases faster than head size; thus, at the end of the period, the head is proportionally smaller than at its beginning. • Ossification centres appear in many bones. • External genitalia, which are not obviously differentiated at the beginning of the period, achieve their mature forms in the twelfth week.
• Urine begins to form, making its contribution to amniotic fluid. • 17–20 weeks • Overall growth slows, as final proportions are reached. • Fetal movements are felt by the mother although they are evident on ultrasound well before this time. • The skin is covered in vernix caseosa (a cheese-like fatty secretion that acts as a ‘barrier cream’ or moisturiser) and lanugo (fine hair). • Brown fat is deposited around the neck and shoulders: these deposits are used for heat production in the newborn. • From 20 weeks onwards • The fetus is considered (legally) viable: birth before this time is recorded as miscarriage or abortion, but after 20 weeks it is recorded as birth or stillbirth. Medically, the baby is considered potentially viable from 22 weeks gestation or from 400 g in weight. • 21–25 weeks • The fetus is lean, with little subcutaneous fat; skin is red and wrinkled. • Surfactant begins to be secreted in the fetal lungs, but babies born at this age usually die because of respiratory immaturity. • 26–29 weeks • If born at this age, the baby moves energetically and cries; the lungs are not mature, but are capable of breathing air and the baby can survive with intensive care. • The central nervous system has matured such that temperature homeostasis and rhythmic breathing are possible. • 30–38 weeks • Weight doubles; subcutaneous fat is laid down in quantity such that at birth fat constitutes 16% of body weight. • The newborn also has extensive glycogen reserves; it will utilise both fat and glycogen reserves in the first few days after birth and lose weight. The average pregnancy is 266 days (38 weeks) after conception or 40 weeks after the last menstrual period. Pregnancy may be prolonged up to 2 weeks; a baby born this late will have thin, dry skin (‘postmature’).
Development of the reproductive systems in utero
The structure and function of both the male and the female reproductive systems depend on the sex hormones. Hormonal effects on the reproductive systems begin during embryonic development and continue in varying degrees throughout life. The development of reproductive organs begins during the fifth week of gestation with the formation of the gonadal ridge behind the membranes lining the abdominal cavity. By the sixth week the primary sex cords form within the
CHAPTER 31 The structure and function of the reproductive systems
gonadal ridge. The primary sex cords in the male will mature in to the seminiferous tubules and in the female they become the ovarian follicles. In the male embryo, each testis connects to the mesonephric duct which develops into the seminiferous tubules, epididymis, ductus deferens, ejaculatory duct, and the seminal vesicle. In the male the paramesonephric duct degenerates without contributing any functional structures to the reproductive system. In the female embryo, the mesonephric duct degenerates, and the paramesonephric ducts fuse to form the vagina and uterus and the unfused portions become the uterine tubes. By the sixth week the genital tubercle is visible in the perineum of the embryo. The mesonephric (males) or paramesonephric (females) ducts open to the outside through the genital tubercle. The genital tubercle consists of a glans, a urethral groove, paired urethral folds, and paired labioscrotal swellings. The glans of the genital tubercle enlarges to become the phallus. The testes of the male embryo will begin to produce testosterone and the ovaries of the female embryo produce oestrogen. Between the 10th and 12th week of gestation sexual differentiation of the external genitalia is obvious. In the male, the phallus enlarges into the glans of the penis; urethral folds fuse around the urethra and become the erectile tissue that forms the body of the penis. The labioscrotal swellings fuse to form the scrotum, into which the testes will descend. In the female, the phallus gives rise to the clitoris, the urethral folds remain separated as the labia minora, and the urethral groove is retained as the vestibule. By 9 months of gestation, the internal and external genital structures are all present for both sexes and the testes have descended into the scrotum.
The immune system of the fetus
The structural components of the immune system (the thymus, spleen and lymphatic system) appear early in the embryo and become functional in the fetus in the second trimester. Maturation of the embryonic immune system starts early in fetal life. By nine weeks gestation B lymphocytes are present in the blood and in the spleen by 12 weeks. T lymphocytes start to leave the thymus from about then and are found in the spleen along with T suppressor and T helper cells from 14 weeks gestation. Recent evidence shows that fetuses produce a different type of T cells to adults. The fetal T cell is highly tolerant of foreign substances which it can recognise but do not attack. This is thought to be as a protective mechanism of the maternal cells and own developing organs. This converts to the adult T cell form by the third trimester in preparation for extrauterine life. Production of antibodies does not reach effective levels until several months after birth. Thus in the first few months after birth, the baby relies for immune protection on passive immunity from IgG, transferred across the placenta in fetal life. In addition, IgA in colostrum and milk provides protection in the lumen of the baby’s digestive tract (but is not taken up into the baby’s bloodstream).
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Note that during pregnancy, the mother may produce antibodies to some fetal cells (e.g. fetal erythrocytes that have escaped into the maternal circulation), but she does not produce antibodies to the fetal part of the placenta.
The neonate Changes in the cardiovascular system at birth
Profound changes in the pattern of circulation must occur rapidly at birth. The fundamental causes of these changes are the cessation of circulation in the placenta and the inflation of the baby’s lungs with air. Cessation of placental circulation occurs as the umbilical arteries constrict at birth, so there is no loss of the newborn’s blood to the placenta. The remnants of the umbilical arteries are recognisable throughout life as the umbilical ligaments. The umbilical vein continues to carry fetal blood from the placenta to the newborn for a minute or so after birth; it is eventually transformed into the ligamentum teres, running from the umbilicus to the liver. The ductus venosus (liver bypass) ceases to carry blood after birth and is transformed into the ligamentum venosus, running from the portal vein to the inferior vena cava, through the liver (see Fig. 22.12). As the newborn’s lungs fill with air, resistance to blood flow through the lungs falls. Thus pulmonary blood flow increases and the volume of blood that returns from the lungs to the left atrium increases. Pressure in the left atrium increases and rises to exceed pressure in the right atrium, a reversal of the situation before birth. As left atrial pressure rises above right atrial pressure, the valve-like foramen ovale in the interatrial septum closes so that blood can no longer move directly from the right atrium to the left atrium. The closure is at first ‘functional’ — that is, a valve-like closure. It eventually becomes ‘anatomical’ by the growth of fibrous tissue, the site of the foramen ovale becoming part of the interatrial septum. The ductus arteriosus in the fetus is a bypass from the pulmonary trunk (high right ventricular pressure) to the aorta (low pressure). At birth with inflation of the lungs, the ductus arteriosus constricts (at the same time as the foramen ovale closes); thus all of the blood pumped by the right ventricle now travels to the lungs. There is subsequently no vascular connection between the pulmonary trunk and the aorta and the ductus arteriosus is transformed into the ligamentum arteriosus, running from the left pulmonary artery to the aorta. In some individuals, the foramen ovale may remain partly open after birth, allowing movement of some deoxygenated blood from the right atrium to the left atrium. In premature babies, especially those experiencing respiratory difficulties (and in those whose mother had rubella), the ductus arteriosus may remain patent for some time after the birth; the flow of blood in this bypass will, however, now be reversed as blood flows from high pressure (aorta, after birth) to low (pulmonary trunk). In the fetus, the right side of the heart is at higher pressure than the left, because relatively little blood flows
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from the lungs to the left atrium. The right ventricle of the fetus works harder than the left and the muscle of the right ventricular wall is correspondingly thicker. Relative pressures are reversed at birth and the left ventricular wall becomes thicker than the right ventricular wall by the end of the first month.
Changes in the respiratory system at birth
In the fetus, the lungs are not collapsed, but are filled and expanded by a fluid (mainly sodium chloride solution) secreted by the lungs themselves. Breathing movements occur before birth and are apparently required in order for the fetal lungs to be maintained in their expanded, fluid-filled state. At birth, the fluid in the lungs is cleared by pressure on the thorax during delivery, the fluid draining through the nose and mouth; absorption into the blood of the pulmonary capillaries; and absorption into the pulmonary lymphatics. Breathing normally commences within 1 minute of birth as the amniotic fluid in the lungs is squeezed out or absorbed. Respiration is initiated by multiple stimuli as the baby suddenly moves from a warm quiet dark environment (inside the mother) to a colder brighter and noisier outside world. The trigger to breathe comes from: (1) chemoreceptors responding to low blood oxygen, high carbon dioxide and low pH as the blood flow from the placenta stops; (2) thermoreceptors responding to reduced ambient temperature; and (3) other receptors responding to movement, pain, handling, light, noise and gravity. It is not necessary to hold the baby upside down and smack its backside as is commonly depicted, although this will not actually harm the baby and can be used to assist lung fluid drainage and stimulation of breathing. These stimuli act through the respiratory centre in the brain to trigger breathing. Diaphragm activity usually becomes settled within a few hours, with a breathing rate of about 40/min — before settling, it may be irregular for some time, with higher rates such as 60/min. Aeration and expansion of the lungs with air immediately lead to a reduced resistance to blood flow through the lungs (hence the increase in pulmonary blood flow). This gives rise to an increase in left atrial pressure (higher than the right atrial pressure) and closure of the foramen ovale and ductus arteriosus, as discussed above. Fully mature alveoli do not appear until some time after birth and most of the alveoli that will eventually be present in the adult develop within the child’s first 8 years. However, the alveoli present at birth, although fewer and different in structure from those of the adult, are adequate for gas exchange. Functioning of the alveoli, of whatever age,
depends on surfactant, and this does not reach adequate levels for efficient lung function until shortly before the end of pregnancy.
Changes in liver function at birth
The liver of the newborn is relatively large. One of its major functions is the storage of iron: if the mother’s iron intake has been adequate during pregnancy, considerable iron stores are present in the baby’s liver at birth. These stores are drawn upon until solid feedings with high iron content commence. The newborn’s liver also has a store of glycogen, which provides energy in the first few days after birth, until abundant carbohydrate becomes available from milk. The glycogen store is especially rapidly depleted if the newborn is hypoxic or hypothermic. In addition, the liver of the newborn must metabolise bilirubin, a waste produce of red blood cell breakdown. This is extensive after birth, as fetal red blood cells are replaced with new adult red blood cells. This substance must be metabolised in the liver and then excreted in the bile. If, as is frequently the case, the liver is not yet proficient at metabolising bilirubin at birth, a mild jaundice may be evident. Persistently high levels of bilirubin in the blood of the newborn may pass into the brain and cause permanent damage (kernicterus). Potentially damaging high levels of bilirubin can be reduced by phototherapy in which the infant is exposed to bright light, which modifies bilirubin as it flows through the skin into a form that can be excreted by the kidneys (discussed further in Chapter 27). Production of blood-clotting factors by the liver requires vitamin K. In later life, this vitamin is produced by intestinal bacteria, but these are not present at birth. As a result, it is recommended that vitamin K is administered prophylactically to all newborns to avoid the possibility of spontaneous bleeding.
FOCU S ON L EA RN IN G
1 Describe the developmental events of gestation from implantation to parturition. 2 Outline the maternal physiological adaptations to pregnancy. 3 Draw the circulatory system of the fetus and describe the changes that occur following parturition.
CHAPTER 31 The structure and function of the reproductive systems
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Ageing and the reproductive systems
Females In females, the regular monthly cycling of hormones continues until some time in the fourth or fifth decade,
when the uterine (menstrual) cycle becomes irregular.7 In Australia 110 000–150 000 women every year pass into menopause, which is defined as the cessation of menses for 12 consecutive months.15 This process occurs due to the reduction in the amount of oestrogen being secreted by follicle cells, which is not sufficient to cause a surge of LH, so ovulation may fail to occur (climacteric). Finally, the ovarian and uterine cycles cease at menopause due to the decreasing number of follicles and the reduced responsiveness of the follicles to FSH. The loss of oestrogen can have profound effects on many body tissues. The sex organs atrophy — for example, the breasts lose much of the fat and milk-producing ducts. Bone density decreases (because oestrogen is required for the maintenance of bone). Loss of bone density can lead to brittleness of the bones, which may break easily in older women. Increased risk of cardiovascular disease, hypertension and myocardial infarction also occur, due to loss of the protective effect that oestrogen has on the maintenance of arterial endothelium. Interference in normal brain function may occur, as neurotransmitters and enzymes activated by oestrogen begin to undergo change. There is also evidence that oestrogen reduces damage in the brain, including protection from formation of substances that contribute to neurofibrillary tangles and senile plaques seen in Alzheimer’s disease (discussed in Chapter 9). Hormone replacement therapy has received a lot of negative publicity over the last decade, but there is increasing evidence of the benefits of hormone replacement to reduce both the physiological effects of menopause and to reduce the changes on other body systems. Only 11% of Australian women in menopause use hormone replacement therapy while 27% say their symptoms are significant.16 Oestrogen can be given to protect the reproductive tissues of the vagina and vulva and also the brain, heart and bones; it can also improve overall feeling of wellbeing. The most benefit from hormone replacement comes from its initiation as a treatment in the peri-menopausal period, though treatment within 2 years of menopause can also provide some benefit and reduction of symptoms and risk.15 There are a number of different methods of delivering these replacement hormones: transdermal patches, vaginal therapies, hormone implants, oral therapy including troches and tablet form. The adverse effects of hormone replacement are similar to those seen with the contraceptive pill and include weight gain, breakthrough bleeding, and breast tenderness.15
AGEING
Males Changes in the male reproductive system occur slowly over time and are more subtle than those seen in the female reproductive system; this change is referred to as andropause. Changes occur primarily in the testes as testicular tissue mass decreases. Testosterone levels peak at 20 years of age and then slowly decline as the number and function of the interstitial and sustentacular cells decrease. A reduction in testosterone (and inhibin) results in a rise in FSH and LH levels as the negative feedback by testosterone is reduced, resulting in higher levels of FSH and LH being released from the anterior pituitary. The ductus deferens become less elastic and become sclerotic. Although spermatogenesis continues, the rate of sperm cell production slows. The epididymis, seminal vesicles, and prostate gland lose some of their surface cells but continue to produce seminal fluids. Fertility varies between individuals so age may not be an accurate predictor of fertility. The volume of seminal fluid may not alter, though the number of living spermatozoa may be decreased and the cells may not be as motile as those of a younger man and can take significantly longer to traverse the female reproductive tract: 45 minutes to the ova in a 20-year-old man and up to 24 hours to the ova in a man of 70 years. Changes to the urinary system are closely linked to those in the reproductive system — the prostate gland enlarges with age although all men will experience prostatic hyperplasia if they live long enough. This condition results in fibrosis within the gland and stricture (physical compression) of the prostatic urethra, and can cause problems with urination and ejaculation. It does not, however, impair fertility and men who have had prostatectomy may still be able to father children. Reduction in testosterone and increases in FSH and LH causes a male climacteric (mood changes and hot flushes), which is much less well-defined and less physically apparent than menopause in women. Impotence (inability to maintain an erection sufficient for intercourse) becomes more common with increasing age. Decreases in libido may occur in some men and sexual responses may become slower and less intense. This may be related to decreased testosterone level, but it may also result from psychological or social changes related to ageing, illness, chronic conditions or medications.10–14
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chapter SUMMARY The structure and function of the male reproductive system • The scrotum is a pouch of skin that contains the testes and epididymis. It is maintained at a cooler temperature than that of the body core. • The testes are the male gonads; they are filled with seminiferous tubules, which contain primordial germ cells for sperm production. The sustentacular (Sertoli) cells support sperm production, while the interstitial cells produce testosterone. • The penis is an erectile organ for sexual intercourse, delivering semen into the vagina. • The epididymis is the site for sperm maturation and storage. Sperm then move through the ductus deferens (vas deferens), the ejaculatory duct, prostate gland and urethra. • The prostate gland, at the base of the bladder, surrounds the first part of the urethra and secretes fluid that makes up about 25% of the volume of semen. • The bulbourethral glands lie immediately below the prostate. They produce an alkaline fluid that makes up 5% of the semen and which neutralises the penile urethra before sperm pass through.
The structure and function of the female reproductive system • The vulva is the collective name for the external female genitalia. It includes the clitoris, which is an erectile tissue that is important in sexual stimulation. • The vagina is an elastic fibromuscular canal that receives the penis and ejaculate during sexual intercourse, as well as being the route for parturition of the fetus. • The uterus has thick muscular walls that consist of the endometrium, the myometrium and the serosa. Its function is for gestation of the fetus. • The uterine (or fallopian) tubes each extend from the uterus and end by curving around the ovary. They transport the oocyte or zygote to the uterus. • The ovaries are the female gonads. They are the site of oogenesis and the production of the sex hormones oestrogen and progesterone. • The cervix is the lowest part of the uterus and it projects into the vagina. It has a major role during gestation of retaining the fetus and preventing the entry of infectious organisms. • The female breast is composed of lobes separated and supported by Cooper’s ligaments. Their main role is the production of milk for the postpartum feeding of the newborn.
Puberty in males and females • Puberty commences when the hypothalamus produces gonadotrophin-releasing hormone, which stimulates the anterior pituitary to produce the gonadotrophins folliclestimulating hormone (FSH) and luteinising hormone (LH). • The gonadotrophins are released into the general circulation; the ovaries or testes (gonads) respond by producing sex hormones (oestrogen, progesterone and testosterone) and gametes (oocytes and spermatozoa). • Testosterone causes spermatogenesis (production of sperm). It is also responsible for other functions, including bone and muscle mass, and the development of male secondary sex characteristics. • Oestrogen causes the development of ova (oogenesis). Progesterone contributes to the uterine cycle, which ensures that the uterus is prepared for implantation of the zygote after fertilisation. Oestrogen and progesterone also stimulate the development of the female secondary sex characteristics.
Gametogenesis • Most body cells contain 23 pairs of (or 46) chromosomes. The ova and sperm each contain 23 chromosomes. • Spermatogenesis is the process by which the germ cells within the seminiferous tubules undergo development into spermatids. Spermiogenesis allows them to mature into spermatozoa (sperm). • Sperm consist of a head (which contains chromosomes), a midpiece (which contains mitochondria to produce energy) and a tail (for propulsion). • Sperm travel through the epididymis, ductus deferens, ejaculatory ducts and urethra to exit the male body. • The ovarian cycle occurs in response to FSH and LH. FSH causes the development of the follicle, and a surge in LH causes ovulation. • The uterine (menstrual) cycle occurs in response to oestrogen and progesterone, and consists of the menstrual stage (days 1–5), the proliferative stage (days 6–14) and the luteal stage (days 15–28). This cycle allows the uterus to be prepared for implantation (in the event of fertilisation), or for the endometrium to be shed (in the event of no fertilisation). • The corpus luteum produces progesterone to maintain the environment necessary in the first few days after fertilisation. Human chorionic gonadotrophin continues with hormone production until the placenta develops and secretes progesterone.
CHAPTER 31 The structure and function of the reproductive systems
Male and female sexual responses • The general features of the sexual response in both sexes are similar, including vasocongestion and myotonia. • In the female, orgasm is characterised by contractions of both the vagina and the uterus. • In the male, orgasm is characterised by peristalsis to propel semen through the ducts and urethra.
Conception, gestation and parturition • Capacitation of sperm allows them to be physically ready to meet the oocyte. Sperm break down the zona pellucida until one sperm penetrates it and reaches the oocyte cell membrane. • Fusion of the 23 chromosomes from the sperm with the 23 chromosomes from the oocyte results in the fertilised egg, referred to as the zygote. • The zygote undergoes cell divisions to enlarge and eventually implants in the endometrium as the embryo. • The placenta develops to supply the essential blood vessel network between mother and fetus. • Umbilical arteries transport nutrient-rich oxygenated blood from the placenta to the fetus, while the umbilical vein transports deoxygenated blood from the fetus to the placenta.
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• The fetal membranes contain amniotic fluid, which allows the fetus to float and provides it with physical protection. • Major changes occur to the mother’s body during pregnancy. These include changes in her reproductive organs, as well as increases in both respiratory and cardiovascular system functions. The mother’s needs for adequate nutrition, fluids and electrolytes all increase with pregnancy. • After birth, the newborn’s circulation changes to allow blood to travel through the lungs and liver, which did not receive rich blood supply as a fetus, as the function of those organs was performed by the placenta. • Respiratory changes after birth include inflation of the alveoli and secretion of surfactant in the newborn.
Ageing and the reproductive systems • In males, decreased testosterone leads to increased FSH and LH, which may lead to symptoms such as mood changes and hot flushes. • In the female, menopause occurs as a result of decreased oestrogen and increased FSH and LH; it can produce mood changes, hot flushes and other physical effects. • Hormone replacement therapy may be an alternative for women and can help reduce the physiological and psychological symptoms of menopause.
CASE STUDY
ADU LT Anthea is 28 years old. When she missed her last uterine cycle, she thought she might be pregnant for the first time, and a home pregnancy test confirmed her suspicions. After seeing her doctor she was given further tests, which confirmed her pregnancy, and scheduled for ultrasound examination. As the pregnancy developed she was given further tests (blood tests, glucose tolerance test, urine and vaginal swabs) to determine how well her body was coping and how the baby was progressing. A friend told her that she should begin to feel the baby moving by 14 weeks and she was worried when she felt nothing. However, at her regular ultrasound examination she was assured that all was progressing well. At term, Anthea’s waters broke and she began to experience regular contractions which became stronger and more frequent, so she immediately attended the maternity hospital. The staff examined her: her cervix had dilated to 10 cm, so she was taken to a delivery room and told she can have some medication (epidural pethidine) for the pain if she wanted.
The frequency of contractions was timed and the fetal heart rate was monitored at 120 bpm. She was told that she should deliver soon. The baby was delivered without complication and started breathing almost immediately; after a minute, the umbilical cord was cut. Some 20 minutes later the placenta was delivered and examined. Anthea had a healthy baby girl and was left to bond with her. 1 Explain which hormone is the basis of the home pregnancy test, and what produces the hormone at this early stage. 2 Outline, with reasons, the changes you would expect in blood pressure over the course of Anthea’s pregnancy. 3 Explain what might interfere with airflow in the newborn’s respiratory system. 4 Discuss why the umbilical cord is left intact with the baby for a short time after delivery. 5 Outline how the intactness of the placenta is checked after birth and why this is important. Continued
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CASE STUDY
AG EING Marie is 68 years old and has gone through menopause. She did not use hormone replacement therapy during menopause, as she had heard news reports that it was not good for you. She and her husband enjoyed an intimate relationship when they were younger but she has lost all interest in sex in recent months and says that it can be painful. Her husband David (72) has noticed that he has been having difficulty in maintaining an erection; these changes in both of them are having an impact on their relationship. They visit their doctor who prescribes hormone replacement therapy for Marie and sends David for further investigation for his erectile dysfunction.
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2 3 4 5
Outline the changes to hormonal and ovarian function as a woman ages and the impact this has on reproductive tissues. Explain the likely cause of Marie’s discomfort during sexual intercourse. Describe the changes to male reproductive function that may be contributing to David’s erectile dysfunction. Discuss how David’s testosterone level would be influencing his reproductive function. Marie had heard negative things about hormone replacement therapy in the news. Outline the benefits and risks of this treatment.
REVIEW QUESTIONS 1 Outline the sequence of events that result in the maturation and ovulation of the female gamete. 2 Explain how sperm are produced in the male gonads; include the sites of production and the hormones responsible. 3 Upon fertilisation of the egg, describe the sequence of events leading to the implantation of the blastocyst. 4 Describe the changes in cervical mucus that occur over the 28-day cycle and the hormones responsible for each of these changes. 5 The placenta develops from both maternal and fetal tissue to house the fetus in amniotic fluid. Name the layers of the placenta and from which tissues of the embryo or mother these develop. 6 Describe the origin, composition, functions and circulation of the amniotic fluid, and discuss the diagnostic possibilities arising from observed alterations to normal levels of fluid.
7 Discuss what is different about the blood circulation of the fetus compared to the newborn and describe how this circulation must change on birth of the baby. 8 Discuss briefly the major adaptations that occur in the mother when she becomes pregnant. 9 In early development, both genetically male (XY sex chromosomes) and genetically female (XX sex chromosomes) embryos have the same immature reproductive structures. Describe how and why these structures develop into the mature male and female reproductive systems, respectively.
Key terms acute bacterial prostatitis, 1015 adenomyosis, 997 amenorrhoea, 1000 anorgasmia (orgasmic dysfunction), 1006 assisted reproductive technology, 1020 bartholinitis, 1005 benign prostatic hyperplasia, 1014 bladder outflow obstruction, 1014 cervical intraepithelial neoplasia (CIN), 990 cervicitis, 1004 Chlamydia trachomatis, 1025 chronic bacterial prostatitis, 1015 circumcision, 1009 corpus luteum cysts, 997 cryptorchidism, 1012 cystocele, 1005 dysfunctional uterine bleeding, 1001 dyspareunia (painful intercourse), 1006 endometrial polyps, 997 endometriosis, 998 enterocele, 1005 epididymitis, 1013 Essure, 1018 follicular cysts, 996 functional cysts, 996 galactorrhoea, 1017 gonorrhoea, 1021 gynaecomastia, 1017 herpes simplex virus (HSV), 1025 human immunodeficiency virus (HIV), 1026 human papillomavirus (HPV), 1025 hydrocoele, 1011 infertility, 1019 leiomyomas, 997 mucopurulent cervicitis, 1004 non-bacterial prostatitis, 1016 oophoritis, 1003 orchitis, 1013 paraphimosis, 1009 pelvic inflammatory disease (PID), 1003 pessary, 1005 Peyronie’s disease, 1010 phimosis, 1009 polycystic ovary syndrome, 998 premenstrual dysphoric disorder, 1001 premenstrual syndrome (PMS), 1001 priapism, 1011 primary amenorrhoea, 1000 primary dysmenorrhoea, 999 prostatitis, 1014 rectocele, 1005 salpingitis, 1003 secondary amenorrhoea, 1000 secondary dysmenorrhoea, 1000 spermatocele, 1011 syphilis, 1024 torsion of the testis, 1012 tubal ligation, 1017
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Alterations of the reproductive systems across the life span
32
Karole Hogarth Chapter outline Introduction, 984 Classification of reproductive system alterations, 984 Growths, 984 The endocrine system, 984 The reproductive system, 984 Cancer, 985 Cancers of the female reproductive system, 985 Cancers of the male reproductive system, 992 Disorders of the female reproductive system, 996 Benign growths and proliferative conditions, 996 Hormonal and menstrual alterations, 999 Premenstrual syndrome, 1001 Infection and inflammation, 1002 Pelvic relaxation disorders, 1005 Reproductive and sexual dysfunction, 1005 Disorders of the male reproductive system, 1007 Disorders of the urethra, 1007
Disorders of the penis, 1009 Disorders of the scrotum, testis and epididymis, 1011 Disorders of the prostate gland, 1014 Sexual dysfunction, 1016 Disorders of the breast, 1017 Disorders of the female breast, 1017 Disorders of the male breast, 1017 Fertility, 1017 Control of fertility, 1017 Impaired fertility, 1019 Assisted reproductive technologies, 1020 Major sexually transmitted infections, 1021 Gonorrhoea, 1021 Syphilis, 1024 Chlamydia trachomatis, 1025 Herpes simplex virus, 1025 Human papillomavirus, 1025 Human immunodeficiency virus, 1026 Other infections, 1026
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Key terms continued urethral stricture, 1008 urethritis, 1007 urethrocele, 1005 uterine prolapse, 1005 vaginismus, 1006 vaginitis, 1004 varicocele, 1011 vasectomy, 1017 vulvitis, 1004
Introduction Alterations of the reproductive systems span a wide range of concerns, from delayed sexual development and suboptimal sexual performance to structural and functional abnormalities. Many common reproductive disorders carry potentially serious physiological and psychological consequences. For example, sexual dysfunction such as impotence can dramatically affect self-confidence, relationships and overall quality of life. Other factors such as psychosocial problems, alcoholism, depression, chronic illness and medications, can affect ovulation and menstruation, sexual performance and fertility. In addition, these alterations may be risk factors for the development of some types of reproductive tract cancers. Cancers of the reproductive system in both sexes can cause considerable alteration to homeostasis and are potentially life threatening. In Australia and New Zealand, breast cancer is one of the leading causes of cancer deaths in women, and prostate cancer is one of the most common cancers in men. Therefore, a thorough understanding of the pathogenesis of these cancers is fundamental when caring for the individuals affected by them. In this chapter we consider problems in both male and female reproductive structure and function. We briefly explore the likely causes of these problems and outline some of the symptoms and treatments. The reproductive systems and sexual function are often taboo subjects outside of the healthcare professions. Many people find it difficult to talk about reproductive problems with their health professional — let alone their partner. Diagnosis and treatment of reproductive system disorders are often complicated by the stigma associated with the reproductive organs and by emotions related to reproductive health. Treatment and diagnosis may be delayed because of embarrassment, guilt, fear or denial.
Classification of reproductive system alterations Alterations of the reproductive systems that are most commonly seen are broadly the result of one of three different initial causes that display similar symptoms. The most common causes of sexual dysfunction are: (1) growths,
(2) problems associated with the endocrine system, and (3) structural and functional alterations of the reproductive system itself.
Growths
Growths within different parts of the reproductive system can be benign, pre-cancerous or cancerous. The growths themselves can be the problem (particularly if they are cancerous) or the effects of the growths can be the problem (if, for example, the growths impinge on another organ). Some growths lead to overproduction of hormones, resulting in a more varied set of symptoms in other parts of the reproductive system.
The endocrine system
Problems associated with the endocrine system may arise in utero and lead to abnormal structural development. For example, during development a genetically male fetus (XY) can fail to produce testosterone for a variety of reasons — some genetic, some environmental (see Chapter 38). Lack of testosterone or Mullerian inhibiting factor (MIH) in embryological development may lead to incomplete degeneration of the structures that both genetically male and female embryos share in the undifferentiated stage of development. This may result in ambiguous genitalia or hermaphrodism.1 Reproductive endocrine function may be normal during development in utero but secondary sex characteristics may develop too early (less than 8 years in girls and 9 years 6 months in boys) or too late. Precocious (early) puberty may be an indication of hypothalamic dysfunction or tumour growth, but may also be affected by genetics, body weight and environmental factors. Similarly, delayed puberty (no menarche within 3 years of breast development in girls and no testicular enlargement by 14 years in males) may indicate underlying pathology but have chromosomal abnormalities and environmental causes as well. Disruptions to the normal pubertal pattern may give rise to psychosocial maladaption, but also affect stature, bone growth and fertility. Treatment options are determined according to cause. For normal reproductive functioning in both males and females, there must be an intact relationship between the hypothalamus, pituitary and gonads. These relationships are essential to the stimulation of the ovary to produce oestrogen and progesterone as well as ova, and for the testis to produce testosterone and sperm. During adulthood, endocrine dysfunction of the gonads or the structures that are responsible for stimulating them can result in the failure of normal menstrual and ovarian cycling in females or the failure to produce sperm in males. This can cause impairments to fertility.
The reproductive system
Structural and functional abnormalities of the reproductive system can be the result of the abovementioned hormonal problems during development or they can arise as the
CHAPTER 32 Alterations of the reproductive systems across the life span
result of trauma to the body or bacterial or viral infection of the reproductive tract. Tissue damage can give rise to ectopic (in abnormal place) implants of endometrial tissue (endometrium) in the myometrium, or outside the uterus, leading to dysfunctional bleeding and pain. This may also occur following a caesarean section. Infection causes inflammation in which immune cells are recruited to the site of infection and release inflammatory cytokines (see Chapter 13). Inflammation can lead to scarring or adhesions developing and these can interfere with normal function.
Cancer Excluding non-melanoma skin cancers, cancers of the reproductive system in both sexes are the most prevalent of all cancers. Breast cancer is the most common cancer in females but is uncommon in males. Breast cancer has an incidence rate of almost 28% (expressed as a percentage of all cancers) with over 15 500 new cases detected in women in Australia each year.2 To put this in perspective, the number of females diagnosed with breast cancer each year is more than double the number diagnosed with colorectal cancer, the second most common cancer in females. In males, prostate cancer is by far the most commonly diagnosed cancer and accounts for 23% of all cancers.2 Like breast cancer in females, the rate of prostate cancer in males is more than double the rate of colorectal cancer, the second most common cancer in males. Breast cancer and prostate cancer are the main reproductive cancers in either sex, as the incidence of other cancers is extremely low. For instance, of all female cancers, the incidence rates of other cancers of the reproductive tract are as follows: cervical cancer 1.3%, uterine cancer 4.2%, ovarian cancer 2.7%, vulvar cancer 0.6%, vaginal cancer 0.1%, and cancers of all other gynaecological sites 0.2%.3 In males, the rates are testicular cancer 1.2%, breast cancer 0.2% and penile cancer 0.1%. The following discussion therefore focuses mainly on breast cancer and prostate cancer. Additional discussion of general features of cancer can be found in Chapter 37.
Cancers of the female reproductive system Breast cancer
Breast cancer is a disease in which abnormal cells proliferate and invade local tissue. Although benign tumours are not life threatening, the invasive malignant tumours may spread through the vascular and lymphatic systems to other organs (metastatic disease). One in 8 Australian women will develop breast cancer and 1 in 37 will die from the disease before the age of 85. Treatment and survival rates have improved in recent years, but early detection is a key.3 Mammographic screening every 2 years is recommended for women aged 40 and over in New Zealand, and in Australia while the target age is 50–74, it is also available
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to women from 40 years of age onwards. Younger women in high-risk groups may be screened by MRI. Symptoms can include: new lumps or thickening in the breast or under the arm, nipple sores, nipple discharge, breast skin dimpling, rash or red swollen breasts. Pain is rare, so regular checking of the breasts is recommended. If any symptoms are found, further diagnostic options such as imaging and biopsy are required. Staging is rated according to the TMN (tumour, metastasis, node) classification system, which makes use of information on the size of the primary tumour (T), lymph node involvement (N) and the absence or presence of distant metastases (M). Invasive breast cancers are classified in a range from stage I (early disease) to stage IV (advanced disease). If the cancer is limited to the breast, 96% of patients will survive (survival is considered as being free of cancer 5 years after the cancer is detected). If the cancer has spread to the regional lymph nodes, the survival rate drops to 85%.4 Causes of breast cancer are similar to causes for many cancers in that there is a hereditary component, but there are also cases (known as sporadic cases) in which there is no family history (see below). Other factors are increasing age, inheritance of specific gene mutations (in the genes BRCA2, BRCA1 and CHEK2), exposure to female hormones (natural and administered), past exposure to radiation, obesity (diet and exercise) and excess alcohol consumption.5 RISK FACTORS
Risk factors and possible causes of breast cancer can be classified as reproductive, hormonal, environmental and familial (see Table 32.1). Reproductive factors A woman’s age when her first child is born affects her risk for developing breast cancer, as increased age, particularly over 30 years, increases the risk.5 The main mechanism for the protective effect of pregnancy is controversial. The most widely accepted explanation proposes that the development and differentiation of the breast are completed only by the end of the first term of pregnancy. The protection seems to be the interval of time between menarche and the first pregnancy, because a greater risk is noted with an interval of more than 14 years. The protection conveyed early persists into old age, possibly because of lasting genetic change through differentiation. However, this is not entirely clear and research has shown evidence against this as well. The duration of a woman’s reproductive life also affects her risk of developing breast cancer. Early menarche (< 12 years) and late menopause (> 55 years) increases risk; a comparatively shorter reproductive life decreases the risk. Menarche marks the onset of the mature hormonal environment — that is, cyclic hormonal changes that result in ovulation, menstruation and cellular proliferation in the breast. Thus, the younger the age at menarche, the earlier a young woman experiences steroid hormone levels and ovulatory cycles. Although data are limited, women with earlier menarche may have higher levels of endogenous
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TABLE 32.1 Factors associated with increased risk of breast cancer CATEGORY
RISK FACTOR
RELATIVE RISK*
Family history
Postmenopausal in firstdegree relative
≤ 2.0
Breast cancer in firstdegree relative before age 60 years
2.0–3.0
BRCA1 or BRCA2 gene present
≥ 4.0
Premenopausal or bilateral > 4.0 breast cancer p53 (tumour-suppressor gene) mutation
> 4.0
Breast cancer in 2 firstdegree relatives
4.0–6.0
Previous medical Moderate or florid history mammary hyperplasia
1.5–2.0
Mammary papilloma
1.5–2.0
Atypical mammary hyperplasia
4.0–5.0
Ductal carcinoma in situ or lobular carcinoma in situ
8.0–10.0
Early menarche (before age 12 years)
1.1–1.9
Late menopause (after age 55 years)
1.1–1.9
Postmenopausal oestrogen therapy
1.4
Oral contraceptive use
1.5
Pregnancy
Nulliparous or late first pregnancy (after age 35 years)
1.1–1.9
Radiation
Repeated fluoroscopy (x-ray with a fluorescent screen)
1.5–2.0
Obesity and stature
Postmenopausal
1.2
Tallness
≤ 2.0
High alcohol consumption
1.4–2.0
High energy intake
≤ 2.0
Advanced age
2.0–4.0
Higher socioeconomic status
≤ 2.0
Low physical activity
≤ 2.0
Smoking
2.0–4.0
Chemical carcinogens
≤ 2.0
Infectious agents
≤ 2.0
Oestrogen exposure
Dietary/alcohol
Social
Environmental
*Relative risk is different to absolute risk (overall risk of developing a disease over time). Relative risk is the incidence rate of the disease among individuals exposed to the risk factor compared to the incidence rate of the disease in individuals not exposed to the risk factor. For instance, smokers have a higher risk of developing breast cancer than non-smokers.
oestrogen.5 Age of menarche is a relatively weak risk factor overall. Breastfeeding is associated with a slight decrease in risk of breast cancer, providing there is a minimum of at least 12 months total breastfeeding.6 Hormonal factors Endogenous hormones have long been implicated in the development of breast cancer. Most significant are the findings of: (1) the protective effect of an early first pregnancy; (2) the protective effect of bilateral oophorectomy (surgical removal of the ovary) before age 45 years; (3) the increased risk associated with early menarche, late menopause and nulliparity (never having carried a pregnancy); and (4) the hormone-dependent development and differentiation of mammary gland structures. A vast majority of breast cancers are initially hormone-dependent with oestrogen playing a crucial role in their development.7 Hormone replacement therapy (HRT), which includes the use of oestrogen, progesterone and other hormones, are those medications used by some women to assist with managing the symptoms of menopause. HRT, sometimes also known as oestrogen replacement, can be initiated during the menopause period, and may be used for several years. There is strong evidence that demonstrates an increased risk of breast cancer with HRT use.8 On the other hand, HRT may provide significant protection against coronary heart disease (see Chapter 23), a disease which overall has a greater impact on the women of Australia and New Zealand than breast cancer, as more deaths in women arise from heart disease than breast cancer. HRT can also provide protection against osteoporosis (see Chapter 21). There is also evidence that use of oral contraception during the reproductive years increases the risk of breast cancer.9 Both oral contraceptives and HRT provide some protection against ovarian cancer.8,9 Studies have shown that postmenopausal women who have elevated plasma levels of androgen of adrenal or ovarian origin or oestrogens have an increased risk of breast cancer.10 Studies assessing plasma levels of hormones among premenopausal women have produced conflicting results. These studies are more difficult because circulating levels of hormones vary greatly during the menstrual cycle and because of the low numbers of women with breast cancer among premenopausal women. Insulin-like growth factors (IGFs) regulate cellular functions involving cell proliferation, differentiation and apoptosis. Insulin-like growth factor-1 (IGF-1) is a protein hormone with a structure similar to insulin. The growth hormone-IGF-1 axis can stimulate proliferation of both breast cancer and normal breast epithelial cells.11 IGF-1 levels seem to be more of a risk factor for premenopausal women. In addition, premenopausal mammographic breast density (a risk factor for breast cancer) has been positively correlated with IGF-1 levels. This relationship has not been found in postmenopausal women.12,13 Environmental factors The environmental causes of breast cancer most likely affect the glandular epithelial cells of the breast during the early
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differential stages from undifferentiated cells to alveolar buds and lobules. During these early phases, mitotic activity and cell division are greater than later in life. • Radiation. High doses of ionising radiation are associated with an increased risk of all cancers including breast cancer, especially if exposure occurs during adolescence or pregnancy, when breast cells are proliferating rapidly. Ionising radiation causes damage to a cell’s DNA (i.e. it alters the sequence of genes). The genes most often affected are those that control the rate of cell division (proto-oncogenes) or the rate of programmed cell death or apoptosis (tumour suppressor genes). Radiological exposure of the upper spine, heart, ribs, lungs, shoulders and oesophagus also exposes breast tissue to radiation. • Smoking. This is known as a risk factor for development of all forms of cancer, not specifically breast cancer. The association is linked to the harmful chemicals in cigarette smoke, which cause DNA damage and thereby initiate the development of a tumour. • Diet. The association between individual foods and breast cancer is inconsistent and new data on dietary patterns are emerging. The pattern that reduces risk includes a higher intake of fruits, vegetables, whole grains, low-fat dairy products, fish and poultry. The Western pattern includes a high intake of red and processed meats, refined grains, sweets and desserts and high-fat dairy products. In general, however, neither pattern has been associated with an overall risk of postmenopausal breast cancer. However, a lower risk of oestrogen receptor-negative cancer has been observed in those on a prudent diet.14 Most studies have not supported a link between fibre intake and breast cancer;15 carbohydrate quality, rather than absolute amount, may be important for breast cancer risk, especially for premenopausal women. Substantial evidence exists that alcohol consumption increases breast cancer risk. Differences in alcohol intake, however, explain only a small fraction of breast cancer rates.16 The mechanisms by which alcohol intake increases the risk of breast cancer are unknown. It is not known whether decreasing or stopping alcohol consumption in midlife decreases the risk of breast cancer. • Obesity. Obesity has been associated with a reduced risk of premenopausal breast cancer. One mechanism suggested is the direct relationship between irregular menstrual cycling, especially anovulatory (lack of ovulation) cycling, and obesity. Anovulatory cycling would result in a decrease in both oestrogen and progesterone and thus a decreased risk of breast cancer. Some obese women have polycystic ovaries. With this condition they may have anovulatory cycling, abnormal menstrual periods, elevated androgens and hyperinsulinaemia (see Chapter 36). It is possible that higher insulin levels increase the enzymatic conversion of testosterone to dihydrotestosterone, rather than oestradiol (a type of oestrogen), lowering their oestrogen levels.17
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Obesity is associated with poor survival among women with breast cancer and the association of obesity with mortality from breast cancer appears to be stronger than its association with incidence. Obesity, however, is weakly related to increasing the risk of breast cancer in postmenopausal women:18 despite strong links with endogenous oestrogen levels, body fat has been consistently but weakly related to increased postmenopausal risk. This observation has been surprising because obese postmenopausal women have endogenous oestrogen levels nearly double those of lean women.19,20 This weak association is possibly due to the following: the premenopausal reduction in breast cancer risk related to being overweight may persist, opposing the adverse effect of elevated oestrogen after menopause. Thus, weight gain should be more strongly related to postmenopausal breast cancer risk than attained weight. The increase in breast cancer risk with increasing body mass index (see Chapter 35) among postmenopausal women is possibly the result of increases in oestrogen, especially with oestradiol. Studies do not support the concept that fat intake in middle life has a major relationship with breast cancer risk.21 • Physical activity. Regular physical activity may reduce the overall risk of breast cancer, especially in premenopausal or young postmenopausal women.22,23 Activity may also reduce invasive breast cancer.24 The mechanisms for this protective effect are not known but include alterations in endogenous free radical formation and oxidative damage (see Chapter 4), effects on DNA repair capacity, increased intestinal transit times (i.e. reduced exposures to carcinogens), weight loss and changes in endogenous sex hormone levels. • Other factors that have been linked to breast cancer include tallness which is associated with an increased risk of breast cancer in postmenopausal women, with the Million Women Study confirming a 17% increase in risk of breast cancer for every 10 centimetre increase in height above the baseline of 155 cm.25 Another factor is being a night-shift worker with altered sleep patterns which leads to reduced levels of melatonin — which has been shown to have anticarcinogenic properties. Melatonin also suppresses the production of other hormones that have been linked to an increased risk of breast cancer. There appears to be an increased risk of breast cancer associated with working night-shifts.26A recent study showed a 38% reduction in risk of breast cancer in women with the highest levels of the major melatonin metabolite, 6-sulfatoxymelatonin.26 The International Agency for Research on Cancer (IARC) classifies night-shift work as ‘probably carcinogenic to humans’.27 Familial factors Genetically, breast cancer can be divided into three main groups: (1) sporadic — the majority, or 40%, of women with breast cancer have no known family history; (2) inherited autosomal dominant cancer gene syndromes; and (3) polygenic, where there is a family history but
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it is not passed on to future generations as a dominant gene. A history of breast cancer in first-degree relatives (mother or sister) increases a woman’s risk two to three times. Risk increases even more if two first-degree relatives are involved, especially if the disease occurred before menopause and was bilateral. A small proportion of breast cancers (5–10%) are the result of highly penetrant dominant genes (i.e. hereditary breast cancers). BRCA1 and BRCA2 (breast cancer genes 1 and 2) are two autosomal dominant genes linked to breast cancer risk. They are located on the 17th and 13th chromosomes respectively. BRCA1 and BRCA2 mutations can be inherited from maternal or paternal gene lines. The presence of these genes also increases the risk of ovarian cancer. Up to age 40, a woman with a BRCA1 mutation is estimated to have a 20-times greater risk of breast cancer compared to the general population and a lifetime risk of 60–85%.25–29 Carriers of the BRCA1 gene are also at higher risk for ovarian cancer. BRCA1 is a tumour-suppressor gene; therefore, any mutation in the gene may inhibit or retard its suppressor function, leading to uncontrolled cell proliferation. Interestingly, men who develop breast cancer are more likely to have a BRCA2 mutation than a BRCA1 mutation. Another tumour suppressor gene, p53, is mutated in approximately 20–40% of individuals with breast cancer. p53 is a regulatory gene (i.e. it acts to turn mechanisms on or off) which increases DNA repair and, if damage is great, cell death (apoptosis) occurs in mutated cells. Thus, it helps to get rid of cancer proliferating cells. When p53 is mutated, its regulatory properties are radically altered, conferring a loss of tumour-suppressor activity and, possibly, allowing tumour growth.30 PATHOGENESIS
Most breast cancers (70%) arise from the epithelial linings of the lactiferous ducts. The reason that these types of tumours account for a high mortality is most likely due to the regular cycles of hormone-induced proliferation (see Chapter 31). It is important to realise that these types of tumours do not grow to a large size, but they often metastasise early, which makes treatment more difficult and contributes to an increased mortality. The pathogenesis (like that of other cancers) involves several main steps: 1 Modifications in the DNA of the breast epithelial ductal cells are caused by genetic alterations, environmental agents or their interactions. The initial DNA changes that develop into cancer provide a selective advantage to the cells and thus they proliferate, meaning that these cells grow rapidly and spread compared to normal body cells. Daughter cells of the initially mutated cells will carry the same mutation but may also have gained other DNA mutations. 2 DNA alterations lead to larger chromosomal alterations, further gene mutations and suppression of apoptosis (see
Chapter 4): the cells proliferate outside of the normal controls of cell division and will not carry out apoptosis. 3 The progressive modification of specific oncogenes (genes that can induce cancer, onco meaning tumour) or the loss of specific tumour-suppressor genes leads to advanced metastatic disease. Changes in malignant cells are accompanied by or preceded by alterations in the supporting tissue and stromal cells (connective tissue cells) because of genetic and epigenetic (changes in cell function without changing DNA) events and disruption of normal signalling pathways. Unlike most human organs that are differentiated at the end of fetal life, the mammary glands develop and differentiate after puberty. Factors that affect full differentiation of the breast may be essential for countering the development of breast cancer. Mammary epithelial cells achieve rapid renewal by a small number of mitotic divisions of immortal stem cells. Because the number of mutations is proportional to the rate and number of stem cell divisions, factors that accelerate cell division can have a carcinogenic effect. Hormones may act as accelerators, as well as initiators, and influence the susceptibility of the breast epithelium to environmental carcinogens, because hormones control the differentiation of the mammary gland epithelium and thereby regulate the rate of stem cell division. In each ovulatory cycle between puberty and either the first full-term pregnancy or menopause among nulliparous women, mammary epithelium stem cells show their greatest rate of division during the luteal phase. In this phase progesterone levels predominate and the breast cells display increased mitosis (the reasons for this are not yet clear). During the oestrogen follicular phase, terminal ductules are few and there is no mitotic activity. During the luteal phase, because of increased progesterone levels, perhaps resulting from the oestrogen priming or as a result of cooperation between the two hormones, there is increased mitotic activity. The in-situ lesion closely resembles the developing invasive carcinoma. For example, low-grade ductal carcinoma in situ (cells that have changed in the lining of the ducts of the breast) with well-differentiated carcinomas, high-grade ductal carcinoma in situ with high-grade carcinomas and lobular carcinomas are associated with lobular carcinoma in situ. Ductal carcinoma in situ is a clonal proliferation (genetically identical cells that rapidly multiply) usually confined to a single ductal system. Lobular carcinoma in situ, unlike ductal carcinoma in situ, has a uniform appearance in which the cells occur in non-cohesive clusters in ducts and lobules. It is important to understand that these are not invasive breast cancers, but rather abnormal changes in the cells. However, both are associated with an increased risk of developing invasive breast cancer. The majority of carcinomas of the breast occur in the upper outer quadrant, where most of the glandular tissue of the breast is located. The spread of cancer to the opposite breast, to lymph nodes in the base of the neck and to the
CHAPTER 32 Alterations of the reproductive systems across the life span
abdominal cavity is caused by obstruction of the normal lymphatic pathways or destruction of lymphatic vessels by surgery or radiotherapy. The less common inner quadrant tumours may spread to mediastinal nodes, which are located between the pectoral muscles. Internal mammary chain nodes are also common sites of metastasis. Metastases from the vertebral veins can involve the vertebrae, pelvic bones, ribs and skull. The lungs, kidneys, liver, adrenal glands, ovaries and pituitary gland are also sites of metastasis. CLINICAL MANIFESTATIONS
The first sign of breast cancer is usually a painless lump or thickening in the breast. Lumps caused by breast tumours do not have any classic characteristics. Other presenting signs include palpable nodes in the axilla (underarm), retraction of tissue (dimpling) or bone pain caused by metastasis to the vertebrae. Table 32.2 summarises the
TABLE 32.2 Clinical manifestations of breast cancer and associated pathophysiology CLINICAL MANIFESTATION
PATHOPHYSIOLOGY
Local pain
Local obstruction caused by the tumour
Dimpling of the skin
Can occur with invasion of the dermal lymphatics because of retraction of Cooper’s ligament or involvement of the pectoralis fascia
Nipple retraction
Shortening of the mammary ducts
Skin retraction
Involvement of the suspensory ligament
Oedema
Local inflammation or lymphatic obstruction
Nipple/areolar eczema
Paget’s disease
Pitting of the skin (similar to the surface of an orange)
Obstruction of the subcutaneous lymphatics, resulting in the accumulation of fluid
Reddened skin, local tenderness and warmth
Inflammation
Dilated blood vessels
Obstruction of venous return by a fast-growing tumour; obstruction dilates superficial veins
Nipple discharge in a nonlactating woman
Spontaneous and intermittent discharge caused by tumour obstruction
Ulceration
Tumour necrosis
Haemorrhage
Erosion of blood vessels
Oedema of the arm
Obstruction of lymphatic drainage in the axilla
Haemoptysis, chest pain, dyspnoea
Metastasis to the lung
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clinical manifestations of breast cancer. Manifestations vary according to the type of tumour and stage of disease. EVALUATION AND TREATMENT
Mammography, ultrasound, percutaneous needle aspiration, biopsy or minimally invasive biopsy called Mammotome, palpation and hormone receptor assays are generally used in evaluating breast alterations and cancer (see Fig. 32.1). Biopsy is the definitive diagnostic test. Treatment is based on the extent or stage of the cancer and the hormone receptor status of the tumour. Breast cancers typically have receptors, making them positive for the specific hormones, namely for oestrogen (ER; the capital letter E is based on the USA spelling of estrogen), progesterone (PR) or human epidermal growth factor 2 (HER2) on their cell surface; all of these substances and their receptors are normally present in the healthy adult female. The presence of specific receptors on the cancer cells provides an opportunity for treatment, as medications targeted to block those receptors can prevent oestrogen (such as tamoxifen), progesterone (most oestrogen receptor positive cancers are also progesterone positive) or human epidermal growth factor 2 (such as trastuzumab) being a stimulant for cancer growth. In addition, hormone replacement therapy should be ceased to avoid providing additional oestrogen and other hormones.
FIGURE 32.1
Invasive breast carcinoma. Two irregular carcinomas (arrowheads) are present in one quadrant, representing ‘multifocal’ carcinoma. The presence of a third lesion (arrow) in another quadrant leads to the designation ‘multicentric’.
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Some particularly aggressive tumours may not express any of these receptor types making it a more difficult cancer to treat; these are called triple negative breast cancer tumours (see ‘Research in Focus: Nanodiamonds targeting triple negative breast cancer tumours’). The extent of the tumour at the primary site, the presence and extent of lymph node metastasis and the presence of distant metastases are all evaluated to determine the stage of disease. For localised breast cancer, the most extensive surgical option would be removing the breast and lymph nodes under the arm. Removing the lump (lumpectomy) and just a section of the breast followed by radiotherapy results in the same rate of survival. If the first draining lymph node can be identified using dye or a nuclear medicine scan, it can be sampled and, if negative, further surgery avoided. For tumours at greater risk of recurrence, such as bigger more aggressive-looking tumours that have spread to the lymph nodes, additional treatment (adjuvant therapy) can be given after surgery. This may include hormone therapy of aromatase inhibitors or tamoxifen for women whose tumours have hormone receptors on their surfaces, chemotherapy and targeted therapies such as trastuzumab for those 25% of tumours that are HER2-positive (i.e. have the target for trastuzumab on their surfaces).31 Patients presenting with locally extensive cancer will have chemotherapy and radiotherapy initially to see whether these procedures can shrink the cancer to become operable. If breast cancer returns after initial treatment, local disease may be treated with surgery, while more widespread disease will be treated with combinations of similar drugs to those listed for the adjuvant setting, as is the case for patients who present with widespread disease. Common chemotherapy drugs include anthracyclines and taxanes. Patients with bone disease can receive bisphosphonates such as zoledronate to slow the erosion of bone as well as local radiotherapy for pain.
Cervical cancer
Cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is the potentially premalignant transformation and abnormal growth (dysplasia) of squamous cells on the surface of the cervix. It is more common than invasive cancer and occurs more often in younger women. The premalignant features of CIN, such as genetic abnormalities, loss of cellular function and some phenotypic characteristics of cancer, predict the risk of developing an invasive cancer. Human papillomavirus (HPV) is a necessary precursor to the development of the majority of cases of cervical cancer. Vaccination against HPV and cervical screening programs are impacting on the incidence of this cancer with the incidence in women under 20 years reducing by half since the introduction of the HPV vaccination program32 (see ‘Research in Focus: Gardasil vaccine provides cervical cancer prevention’). Some risk factors have been found to be important in developing CIN — for example, having multiple sexual partners, being infected with higher risk types of HPV, smoking and being immunodeficient. In addition, engaging
RESEARCH IN FOCUS Nanodiamonds targeting triple negative breast cancer tumours Triple-negative breast cancers are challenging to treat as they usually don’t respond to the ‘receptor-targeted’ treatments that are often effective in treating other types of breast cancer. They are typically more aggressive than the other breast cancers, more likely to reoccur and have a high mortality rate. A potentially more effective treatment for this aggressive cancer is being studied; it uses tiny diamond-like particles called nanodiamonds which are between 4 and 6 nanometres in diameter and are shaped like tiny soccer balls. Nanodiamonds are byproducts of mining and refining processes; the particles can form clusters following drug binding and have the ability to precisely deliver cancer drugs to tumours, significantly improving the drugs’ desired effects. Chemotherapeutic agents such as Epirubicin — a widely used chemotherapy drug that is often administered in combination with other cancer drugs — are combined on the nanodiamond surface. This new compound is then bound to a cell-membrane material coated with antibodies that were targeted towards the epidermal growth factor receptor, of which there are large numbers on the surfaces of triple negative breast cancer cells. This drug-delivery system is called a nanodiamond-lipid hybrid compound. The nanodiamond delivery system has been able to target triple negative breast cancer tumours and results in significant reduction in tumour size. The compound reduces the toxic side effects associated with conventional treatment.
FOCU S ON L EA RN IN G
1 Describe the known risk factors for breast cancer. 2 Discuss how some treatments for breast cancer are based on receptors for oestrogen, progesterone and human epidermal growth factor 2.
in sexual intercourse before the age of 16 and having intercourse with a male partner who has had multiple partners place a woman at risk. Cervical cancer is a progressive disease, moving from normal cervical epithelial cells to dysplasia to CIN to invasive cancer. Fig. 32.2 summarises the progressive degrees of CIN. Premalignant lesions usually occur 10–12 years before the development of invasive carcinoma. Cervical neoplasms are often asymptomatic, so regular Pap smears are necessary to monitor development. About 90% of cervical cancers can be detected early through the use of Pap smears and HPV testing. The incidence of cervical cancer is in fact already declining in Australia and New Zealand, which is likely to be due to regular Pap smear tests (see Chapter 37).
CHAPTER 32 Alterations of the reproductive systems across the life span
A
Basement membrane
Normal squamous epithelium
CIN 1
CIN 2
Mild
Moderate
CIN 3
Severe
Carcinoma in situ
Dysplasia
B
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and pelvic or back pain. When dysplasia is detected, cervical biopsy and endocervical curettage are required. Colposcopy (visualisation of the cervix using a camera and light source) is used to suggest sites for biopsy. If invasive carcinoma is found, loop excision or cone biopsy may be performed and lymphangiography (x-ray of lymph nodes and lymph vessels), CT scanning, ultrasonography or radio-immunodetection methods (use of radioactive antibodies to detect neoplasms) are used to assess lymphatic involvement.33 The treatment depends on the degree of neoplastic change, the size and location of the lesion and the extent of metastatic spread. With early detection and treatment, prognosis for invasive cervical cancer is excellent. Overall, the 5-year survival rate is 71%, with the lowest survival rates evident with increasing age at diagnosis.32,34
RESEARCH IN FOCUS Gardasil vaccine provides cervical cancer prevention
C
The Gardasil vaccine to protect against human papillomavirus (HPV) types 6, 11, 16, and 18 is used in Australia and New Zealand. HPV types 16 and 18 are responsible for 70% of all cervical cancers, and HPV types 6 and 11 are associated with benign genital warts. The vaccine is given in a series of 3 injections to girls and young women aged 9–26. The incidence of HPV in the target population has decreased by 80% overall in Australia since the introduction of the vaccine. Following the evidence seen in the Australian population Gardasil is now approved in New Zealand for use in boys and men, as it has been shown to reduce the risk of genital warts and precancerous lesions caused by HPV. However, Gardasil does not replace the need for screening with a Pap smear test, as it does not prevent all cervical cancers. Changes to the cervical HPV testing have been announced in Australia with the Renewed National Cervical Screening Program which was introduced in December 2017. Following evidence-based review, the main changes are that HPV screening is conducted every 5 years (rather than every 2 years) in women aged 25 and older.
FIGURE 32.2
Cervical intraepithelial neoplasia. A A diagram of cervical endothelium showing progressive degrees of CIN. B Normal multiparous cervix. C CIN stage 1. Note the white appearance of part of the anterior lip of the cervix associated with neoplastic changes.
There are often no symptoms but, if present, they may include a change in vaginal discharge or bleeding either after intercourse or between menstrual periods. At times, women will complain of abnormal menses or postmenopausal bleeding. A less common symptom may be a yellowish vaginal discharge. A new or foul odour may also be present. Pelvic or epigastric pain is experienced only with large lesions. Severe bleeding may cause anaemia. Advanced disease may cause urinary or rectal symptoms
Ovarian cancer
There are two main forms of ovarian cancer — those arising in the epithelial tissue of the ovary (90%), and the rarer form that arises from germ cell stroma (connective tissue). Germ cell tumours occur in younger women, whereas those from epithelial tissue occur in women over 40 (see Fig. 32.3). The cause of ovarian cancer is unknown, but low parity, infertility, early menarche and late menopause are risk factors which suggest an interplay of factors which relate to mutations occurring in the epithelium of the ovary over time.35 About 10% of all ovarian cancer is hereditary and linked to the presence of the breast and ovarian cancer genes BRCA1 and BRCA235 and mutation of the tumour suppressant gene p53.36 The most obvious symptoms are pain and abdominal swelling that arise from the primary
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Pleura
Diaphragm
Stomach
Liver Serosal bowel implants
Omentum
Nodes
Colon FIGURE 32.3
Ovarian tumours. The ovarian tumours can be seen as large, darkened masses; the normal size of an ovary is approximately 3–5 cm.
ovarian tumour mass. Gastrointestinal complaints resulting from mechanical obstruction by the tumour may include dyspepsia (abdominal discomfort, such as indigestion), vomiting and alterations in bowel habits. Abnormal vaginal bleeding may occur if the postmenopausal endometrium is stimulated by a hormone-secreting tumour. As with other cancers the risk of thromboembolism is increased. Difficulties in diagnosis due to nonspecific symptoms and lack of effective screening tests, means that late stage disease is present in 75% of patients at initial diagnosis.37,38 Hence it is often considered a silent disease, as it progresses considerably prior to development of specific symptoms. Ovarian cancers exhibit a distinctive pattern of progression, spreading intraabdominally over the surface of the peritoneum (see Fig. 32.4). Transvaginal ultrasound and a tumour marker (CA-125) may assist diagnosis but are not recommended for routine screening. The initial approach to treatment is surgery, performed to determine the stage of disease and to remove as much of the tumour as possible. Radiation therapy may follow if the tumour is smaller than 2 cm in size and is confined to the abdominopelvic area without involvement of the kidneys or liver. The success of chemotherapy depends on the extent of disease, whether the tumour is a discrete mass and whether there has been prior exposure to chemotherapeutic agents. Chemotherapy may be given intravenously or intraperitoneally. Targeted therapy with bevacizumab shows promise as an adjuvant or maintenance therapy.
Ovaries Pelvic peritoneal implant
FIGURE 32.4
Metastasis of ovarian cancers. Pattern of spread of epithelial cancer of the ovary.
Cancers of the male reproductive system Prostate cancer
Prostate cancer is the most common cancer in men, with 85% of cases being diagnosed in those over the age of 65 years. About 19 000 cases of prostate cancer (20–30% of male cancers) are diagnosed each year in Australia and it has been noted that Australia and New Zealand have the highest global incidence of this disease.39 The risk of prostate cancer rises with age, increasing rapidly after age 50. Family history increases the chances of developing the disease. There has been some association with a diet high in fats and low in fresh fruit and vegetables. Men of African descent are at higher risk than men of European descent and there is an association with high testosterone levels. Other possible causes are those of genetic predisposition (familial and hereditary forms). Tobacco smoking is associated with an increased risk of recurrence of the disease as well as increased mortality compared to non-smokers.40 RISK FACTORS
F OC US O N L E ARN IN G
1 Human papillomavirus is implicated in cervical cancer. Discuss why immunisation of both young men and women is a way of controlling this disease. 2 What role do exogenous oestrogens play in the development of endometrial cancers in the postmenopausal woman?
Diet The worldwide distribution of prostate cancer suggests that diet may play a role in its development, especially if the diet affects hormone levels. Consistency across studies indicates that a high intake of fat (total and especially saturated fat) is a risk factor for prostate cancer.41,42 Several hypotheses exist concerning the enhancing effect of fat on prostate carcinogenesis, including hormonal and the
CHAPTER 32 Alterations of the reproductive systems across the life span
generation of free radicals (see Chapter 4). Fat intake from dairy products increases calcium, itself a proposed risk factor. Calcium can suppress circulating levels of vitamin D, a possible protective factor for prostate cancer.43 In addition, a low intake of dietary fibre and complex carbohydrates and a high intake of protein are associated with an increased risk of prostate cancer.41 It remains controversial whether obesity or an increased body mass index is a risk factor for prostate cancer. Evidence does exist to suggest that a diet rich in lycopenes (found in tomatoes, grapefruit and watermelon) may be preventative.44 Isoflavones, found in soy products have also been shown in epidemiological studies to reduce risk, because they may influence androgen-receptor activity. Diets high in dairy and zinc have been inconsistently associated with an increased risk of the disease.43 Individual nutrients or foods and their associations with prostate cancer risk are not strong, yet migration of individuals from low-risk geographic areas of the world, such as Japan, to high-risk countries, such as Australia and New Zealand, increases risk considerably. These changes in risk probably reflect differences in lifestyle and dietary habits. Geographically, individuals who reside in regions with less sunlight have a higher risk of prostate cancer. The highest rates of mortality from prostate cancer are in Scandinavian countries, where exposure to ultraviolet light is low; the possible link is less vitamin D induced by less sun exposure. Hormones Prostate cancer develops in an androgen-dependent epithelium and is usually androgen sensitive. Population studies have not, however, provided clear and convincing patterns involving associations between circulating hormone concentrations and prostate cancer risk.45 Investigations directed at understanding the hormonal basis of prostate (as well as breast) carcinogenesis have numerous problems. The complexities of interacting hormones and separating out the effects of a single hormone are profound. In addition, only single blood samples are generally available, tissue hormone samples are not consistently measured and within-subject variations over time and differences in circadian rhythms cannot be adequately measured. Therefore, while the role of hormones in the implication of prostate cancer development may be relevant, the evidence is yet to find a direct link. Chronic inflammation The results of a 5-year, longitudinal study have demonstrated a strong relationship between chronic inflammation and prostate cancer.46 Biopsies revealed prostatic hyperplasia (see ‘Disorders of the male reproductive system’ below) and inflammatory atrophy in those with chronic inflammation. Upon repeat biopsy, new cancers were diagnosed.46 In contrast, of the men initially showing no inflammation, only a small number were found to have adenocarcinoma. Thus, chronic inflammation may be an important risk factor for prostatic adenocarcinoma. An inflammatory process could possibly account for the evidence that antioxidants
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and non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, may be protective.47,48 Familial factors Other possible causes are those of genetic predisposition (familial and hereditary forms). Genetic studies suggest that strong familial predisposition may be responsible for 5–10% of prostate cancers.48 Hereditary cancer differs from the familial form, which occurs in individuals with a positive family history but who do not exhibit early age of onset. The hereditary form constitutes about 9% of all prostate cancers and approximately 43% of cancers in men younger than 55 years of age.49 There is no clear evidence of a causal link between benign prostatic hyperplasia and prostate cancer, even though they may often occur together in the same prostate gland though in different prostatic zones. PATHOGENESIS
More than 95% of prostatic neoplasms are adenocarcinomas,50 and most occur in the peripheral zone of the prostate. The biological aggressiveness of the neoplasm appears to be related to the degree of differentiation rather than the size of the tumour (see Box 32.1). Although steroid hormonal factors are strongly implicated in prostate carcinogenesis, little is known about their involvement. Testosterone is the major circulating androgen, whereas dihydrotestosterone (a metabolite of testosterone, important in the development of male sexual characteristics) predominates in prostate tissue and binds to the androgen receptor with greater affinity than testosterone.51 Testosterone is the major androgen that comes from the interstitial cells of the testis interstitial (Leydig cells). The adrenal cortex produces far less potent androgen than the testis.
BOX 32.1
Prostatic cancer grades
Grade 1. The cancer cells closely resemble normal cells. They are small, uniform in shape, evenly spaced and well differentiated (i.e. they remain separate from one another). Grade 2. The cancer cells are still well differentiated, but they are arranged more loosely and are irregular in shape and size. Some of the cancer cells have invaded the neighbouring prostate tissue. Grade 3. This is the most common grade. The cells are less well differentiated (some have fused into clumps) and are more variable in shape. Grade 4. The cells are poorly differentiated and highly irregular in shape. Invasion of the neighbouring prostate tissue has progressed further. Grade 5. The cells are undifferentiated. They have merged into large masses that no longer resemble normal prostate cells. Invasion of the surrounding tissue is extensive.
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There are significant age-dependent alterations in the hormones, although these vary in different prostate tissues. In epithelium, the level of dihydrotestosterone decreases with age; whereas in stroma (connective tissue), the dihydrotestosterone level does not decrease. Interestingly, the oestrogen levels (males do produce small amounts of oestrogen) in the stroma increase with age; therefore, the ratio of oestrogen to dihydrotestosterone alters significantly with age. From all of these observations, the following multifactorial general hypothesis of prostate carcinogenesis emerges. Androgens act as strong tumour promoters to enhance the weak but continuously present carcinogen to affect genes and possibly unknown environmental carcinogens. All of these factors are modulated by diet and genetic determinants, including multifactorial inheritance which is influenced by multiple genes (see Chapter 37). These genes encode receptors and enzymes involved in the metabolism and action of steroid hormones. The microenvironment (stroma) surrounding the prostatic tumour actively fuels the progression of prostate cancer from localised growth, to invasion, to development of distant metastases. The most common sites of distant metastasis are the lymph nodes, bones, lungs, liver and adrenals. The pelvis, lumbar spine, femur, thoracic spine and ribs are the most common sites of bone metastasis. Local extension is usually posterior, although late in the disease the tumour may invade the rectum or encroach on the prostatic urethra and cause bladder outlet obstruction (see Fig. 32.5). The spread of cancer through blood vessels is illustrated in Fig. 32.6. CLINICAL MANIFESTATIONS
Prostatic cancer often causes no symptoms until it is far advanced. Therefore, routine screening is recommended for
asymptomatic men beginning at age 50 — or 45 if they are considered at high risk. The first manifestations of disease are those of bladder outlet obstruction — the same as those seen in benign prostatic hyperplasia which occurs in all men as they age. Since the urethra passes through the prostate (see Chapter 31) any enlargement will have an effect on the flow of urine from the bladder. Symptoms therefore include frequent low-volume urination (particularly at night), pain on urination, blood in the urine and a weak stream. Local extension of prostatic cancer can obstruct the upper urinary tract ureters as well. Rectal obstruction also may occur, causing the individual to experience large bowel obstruction or difficulty in defecation. Symptoms of late disease include bone pain at the sites of bone metastasis, oedema of the lower extremities, enlargement of the lymph nodes, liver enlargement, pathological bone fractures and mental confusion associated with brain metastases. Prostatic cancer and its treatment can affect sexual functioning. EVALUATION AND TREATMENT
Diagnosis is made using a digital rectal examination to feel the prostate and a blood test for prostate-specific antigen (PSA) (see Box 32.2). Most cancers occur in the peripheral zone of the prostate. Bone scans and CT scans are used to determine spread. Treatment of prostate cancer depends on the stage of the disease (see Box 32.1), the anticipated effects of treatment and the age, general health and life expectancy of the individual. Options range from hormonal, radiation therapy, chemotherapy and surgery (contemporary nerve sparing or robotic surgery), to any combination of these or no treatment. Low-grade disease confined to the prostate can be watched (surveillance) if not causing symptoms. It is
Lung 46% Pleura 21% Liver 25% Adrenal glands 13% Bone 90%
FIGURE 32.6 FIGURE 32.5
Carcinoma of prostate. Schematic of carcinoma of the prostate (see arrow).
Distribution of metastases in prostate cancer. Most common sites of prostate cancer metastases are the bone, lungs and liver.
CHAPTER 32 Alterations of the reproductive systems across the life span
BOX 32.2
Prostate-specific antigen testing
In Australia, the profile of prostate cancer has risen significantly due to media coverage and many more men over the age of 40 are seeking prostate-specific antigen (PSA) and digital rectal exam (DRE) testing. There is growing pressure on state health authorities to initiate widespread screening, but this is being resisted for several reasons. For example, multiple stages of testing (PSA/DRE and biopsy) are required before a definitive diagnosis of prostate cancer can be given. In addition, PSA levels can be elevated for up to 10 years before any prostate cancer has developed, and invasive procedures (biopsy) can lead to urological problems and infections giving otherwise healthy men immediate problems. There is no clear evidence from population-based studies that a positive (raised) PSA level indicates that prostate cancer will develop. Thus, there can be no real justification for widespread PSA screening of all men over 40 years. The issue will be resolved only with more research into prostate cancer and more definitive and less invasive subsequent testing.
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Palliative treatment is aimed at relieving urinary, bladder outlet or colon obstruction, spinal cord compression and pain.
RESEARCH IN FOCUS Metformin as a treatment for ovarian, breast and prostate cancer Metformin is a common drug used in the treatment of type 2 diabetes, worldwide. Recent evidence suggests that this may be a useful adjunct therapy in ovarian and prostate cancers. Metformin decreases androgen production and also reduces insulin, which is a substance that may promote tumour growth. It may also have both direct and indirect effects on the mTOR (mammalian target of rapamycin) pathway, which contributes to cancer growth. While formal evaluation is awaited, and treatment for ovarian cancer is not yet recommended, the limited studies that have been done suggest that prostate tumour growth is slowed, and there is better short-term survival in ovarian cancer patients.
Testicular cancer desirable to avoid the side effects of surgery; however, early surgery may be of benefit. Surgery with curative intent removes the whole prostate (radical prostatectomy). The main side effects are impotence and incontinence. Radical radiotherapy can also be given with curative intent, either with external radiation or by implanting radioactive seeds (brachytherapy). Side effects are similar to surgery, and bowel problems may also occur. (See also ‘Research in Focus: Metformin as a treatment for ovarian, breast and prostate cancer’.) For widespread disease, hormone therapy reduces the stimulus of the male hormones. Removal of the testis or injecting luteinising hormone-releasing hormone (LHRH) or anti-androgen hormones can hold the disease for 3–4 years and may improve outcomes if undertaken early with radiation in high-risk patients. When cancer growth becomes independent of the presence of androgen, chemotherapy with docetaxel can be used or mitoxantrone can control symptoms. Bisphosphonates (e.g. zoldedronate) can be used to help control bone metastases. Nearly all patients who present with localised disease will live beyond 5 years, with the 10- and 15-year survival rates being 93% and 77%, respectively.52 Treatment for prostate cancer may lead to loss of urinary control, which can return to normal after several weeks or months. Mild stress incontinence can occur after surgery and mild urge incontinence after radiation therapy. Prostate cancer and its treatment can affect sexual functioning. Most men will need assistance (medication) with obtaining an erection for 3–12 months after surgery. Sensation of orgasm is not usually affected, but smaller amounts of ejaculate will be produced or men may experience a ‘dry’ ejaculate because of retrograde ejaculation.
Testicular cancer is among the most curable of cancers, with cure rates greater than 95%. Overall, testicular cancer is uncommon, accounting for approximately 1.2% of all male cancers. However, it is the most common solid tumour of young adult men.39 Cancer of the testis occurs most commonly in men between the ages of 15 and 35 years. Testicular tumours are slightly more common on the right side than on the left, a pattern that parallels the occurrence of cryptorchidism (lack of one testis or both testes from the scrotum) and they are bilateral in 1–3% of cases. PATHOPHYSIOLOGY
Some 90% of testicular cancers are germ cell tumours, arising from the male gametes. Germ cell tumours include seminomas, embryonal carcinomas, teratomas and choriosarcomas. Testicular tumours can also arise from specialised cells of the gonadal stroma. These tumours, which are named for their cellular origins, are the interstitial (Leydig) cell, sustentacular (Sertoli) cell, granulosa cell and theca cell tumours. The cause of testicular neoplasms is unknown. A genetic predisposition is suggested by the fact that the incidence is higher among brothers, identical twins and other close male relatives. Genetic predisposition is supported by statistics showing that the disease is relatively rare among Africans, Asians and Māori New Zealanders. A history of trauma or infection is also associated with the development of testicular neoplasms, but it may be that coexisting testicular tumours are discovered by accident in men who undergo examination because of trauma or infections. CLINICAL MANIFESTATIONS
Painless testicular enlargement is commonly the first sign of testicular cancer (Fig. 32.7). Occurring gradually, it may
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usually elevated. Chest x-ray films, lymphangiograms, intravenous pyelograms, abdominal ultrasound or CT scan and measurement of serum markers are used in clinical staging of the disease. Besides surgery, treatment involves radiation and chemotherapy singly or in combination. Factors influencing the prognosis include histology of the tumour stage of the disease and selection of appropriate treatment. Most patients treated for cancer of the testis can expect a normal life span; some have persistent paraesthesia (tingling or numbness over the skin) or infertility. Almost 90% of disease-related deaths occur in the first 2 years after cessation of therapy. A person who is disease-free after 3 years is considered to be cured. Orchiectomy does not affect sexual function.
FOCU S ON L EA RN IN G
1 Describe the current understanding of the role of hormones in the pathophysiology of prostate cancer. FIGURE 32.7
Testicular cancer. Testicular cancer is present in the left testicle (shown on the right of image).
be accompanied by a sensation of testicular heaviness or a dull ache in the lower abdomen. Occasionally acute pain occurs because of rapid growth resulting in haemorrhage and necrosis. Of those affected, 10% have epididymitis (see ‘Disorders of the scrotum, testis and epididymis’ below), 10% have hydrocoeles (fluid collection in the scrotal sac) and 5% have breast enlargement (gynaecomastia). At the time of initial diagnosis, approximately 10% of individuals already have symptoms related to metastases. Lumbar pain may also be present and is usually caused by retroperitoneal node metastasis. Signs of metastasis to the lungs include cough, dyspnoea (difficulty breathing) and haemoptysis (bloody sputum). Supraclavicular node involvement may cause difficulty swallowing (dysphagia) and neck swelling. With metastasis to the central nervous system, alterations in vision or mental status and seizures may be experienced. EVALUATION AND TREATMENT
Evaluation begins with careful physical examination, including palpation of the scrotal contents with the individual in the erect (standing) and supine positions. Signs of testicular cancer include abnormal consistency, nodularity or irregularity of the testis. The abdomen and lymph nodes are palpated to seek evidence of metastasis and tumour type is identified after orchiectomy. Testicular biopsy is not recommended because it may cause dissemination of the tumour and increase the risk of local recurrence. Primary testicular cancer can be assessed rapidly and accurately by scrotal ultrasonography. Tumour markers, alpha-fetoprotein and beta-gonadotrophin, and lactate dehydrogenase are
2 Identify the populations most at risk of testicular cancer. Outline your own ideas for the design of a public health campaign that could facilitate early detection of this disease.
Disorders of the female reproductive system Benign growths and proliferative conditions Benign ovarian cysts
Benign (non-cancerous) cysts of the ovary may occur at any time of life but are most common during the reproductive years and, in particular, at the extremes of those years. An increase in benign ovarian cysts occurs when hormonal imbalances are more common, around puberty and menopause. Two common causes of benign ovarian enlargement in ovulating women are follicular cysts and corpus luteum cysts. These are called functional cysts because they are caused by variations of normal physiological events. Follicular and corpus luteum cysts are usually unilateral and are produced when a follicle or a number of follicles are stimulated but no dominant follicle develops and completes the maturity process to ovulation. Benign cysts of the ovary are typically 5–6 cm in diameter but can grow as large as 8–10 cm. Follicular cysts can be caused by a transient condition in which the dominant follicle fails to rupture or one or more of the non-dominant follicles fail to regress. This disturbance is not well understood. It may be that the hypothalamus does not receive or send a message strong enough to increase follicle-stimulating hormone (FSH) levels to the degree necessary to develop or mature
CHAPTER 32 Alterations of the reproductive systems across the life span
a dominant follicle. Clinical symptoms of follicular cysts or even a single cyst are pelvic pain, a sensation of feeling bloated or irregular menses. After several subsequent cycles in which hormone levels once again follow a regular cycle and progesterone levels are restored, cysts are usually absorbed or will regress. Follicular cysts can be random or recurrent events. Corpus luteum cysts can develop due to an intracystic haemorrhage that occurs in the vascularisation stage; the affected cyst then consists of blood. In normal cycles, the vascularisation is replaced by a clear fluid that accumulates in the cavity of the corpus luteum. Corpus luteum cysts are less common than follicular cysts, but luteal cysts typically cause more symptoms, particularly if they rupture. Manifestations include dull pelvic pain and amenorrhoea (absence of menstruation) or delayed menstruation, followed by irregular or heavier-than-normal bleeding. Rupture can cause massive bleeding with excruciating pain and can require immediate surgery. Corpus luteum cysts usually regress spontaneously in non-pregnant women. The combined contraceptive pill may be used to prevent cysts from forming as the contraceptive prevents the development of the follicles.
Endometrial polyps
An endometrial polyp is a mass of endometrial tissue containing a variable amount of glands, stroma and blood vessels. Endometrial polyps are usually found singly at the fundus but about 20% are multiple or originate from lower in the uterine body or upper endocervix and contain mixed epithelium. Most polyps are asymptomatic. However, some endometrial polyps cause intermenstrual bleeding or even excessive menstrual bleeding. Although polyps most often develop in women between the ages of 40 and 60 years, they can occur at all ages.
Leiomyomas
Leiomyomas (or uterine fibroids) are benign tumours that develop from smooth muscle cells in the myometrium. They are the most common benign tumours of the uterus and usually occur in multiples in the fundus; the majority remain small and asymptomatic. Prevalence increases in women aged 30–50 years but decreases with menopause. PATHOPHYSIOLOGY
The cause of uterine leiomyomas is unknown, although their size appears to be related to hormonal fluctuations (particularly oestrogen). Uterine leiomyomas are not seen before menarche and those that develop during the reproductive years generally shrink after menopause. Leiomyomas are classified as subserous, submucous or intramural, according to their location within the various layers of the uterine wall (see Fig. 32.8). Degenerative changes, such as ulceration and necrosis, may occur when the leiomyoma outgrows its blood supply and are therefore more common in larger tumours.
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Subserous
Submucous Intramural
FIGURE 32.8
Leiomyomas. Depiction of uterine section showing whorl-like appearance and locations of leiomyomas.
CLINICAL MANIFESTATIONS
Although leiomyomas rarely present problems, they occasionally cause cramping, excessive bleeding and symptoms related to pressure on nearby structures. Because tumours are relatively slow growing, adjacent structures adapt to pressure so symptoms of abdominal pressure develop slowly. Pressure on the bladder may contribute to urinary frequency, urgency and dysuria. If the tumours are large enough, pressure on the lower colon may lead to constipation and abdominal heaviness. EVALUATION AND TREATMENT
Uterine leiomyomas are suspected when manual examination finds irregular, non-tender nodes on the uterus. Ultrasonography is used for diagnosis. Treatment depends on symptoms, tumour size and the individual’s age, reproductive status and overall health. Most leiomyomas can be treated conservatively by shrinking the tumour using pharmacological agents, such as the gonadotrophin-releasing hormone agonist, progesterone, or oral contraceptives. Mifepristone, an antiprogesterone, may also be useful as a conservative treatment. Leiomyoma is a common reason for hysterectomy, although this is not an option for women who wish to retain their reproductive capacity. Other options include myomectomy (surgical removal of leiomyoma), or uterine artery embolisation.53
Adenomyosis
In this condition endometrial tissue (the inner lining of the uterus) is present within the myometrium (the thick, muscular layer of the uterus). Some endometrial tissue is therefore ectopic (out of place), possibly as a result of uterine trauma. Adenomyosis commonly develops during the late
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reproductive years, with the highest incidence among women in their 40s and women taking tamoxifen (used to treat hormone-positive breast cancer). It may be asymptomatic or it may be associated with abnormal menstrual bleeding, dysmenorrhoea, uterine enlargement and uterine tenderness during menstruation. Secondary dysmenorrhoea becomes increasingly severe as the disease progresses. On examination, the uterus is enlarged, globular and most tender just before or after menstruation. Diagnosis is confirmed with transvaginal ultrasonography or MRI. Treatment, when necessary, includes surgical resection of localised areas of adenomyosis or, if severe, hysterectomy. Adenomyosis is typically unresponsive to hormone treatment.
Endometriosis
Endometriosis is a condition in which endometrial-like cells appear and flourish in areas outside the uterine cavity (see Fig. 32.9). Like normal endometrial tissue, the ectopic endometrial implants respond to the hormonal fluctuations of the menstrual cycle. They behave like normal endometrium and proliferate, break down and bleed in conjunction with the normal menstrual cycle. The bleeding causes inflammation and pain in surrounding tissues. The inflammation may lead to fibrosis, scarring and adhesions. Endometriosis affects 10–15% of reproductive-age women and 50% of infertile women: this equates to 130 000 girls and women in New Zealand.54 The clinical manifestations of endometriosis vary in frequency and severity and include primarily infertility and pain, dysmenorrhoea, dyschezia (pain on defecation), dyspareunia (pain on intercourse) and, less commonly, constipation and abnormal vaginal bleeding. Dyschezia, a hallmark symptom of endometriosis, occurs with bleeding of ectopic endometrium in the rectosigmoid musculature and subsequent fibrosis. Medical therapies for endometriosis include suppression of ovulation with various medications.
Up to one-third of individuals with endometriosis are infertile, presumably because of a combination of the following: • mechanical interference with ovulation or ovum transport through the uterine tubes due to adhesions • phagocytosis (engulfment) of sperm by macrophages (immune cells) in the reproductive tract • changes in prostaglandin secretion • defects in the luteal phase of the menstrual cycle • unruptured luteinising follicle syndrome • hyperprolactinaemia • autoimmune and genetic factors. Treatment for the disease includes non-steroid anti-inflammatory drugs, combination oral contraceptives, medroxyprogesterone and GnRH analogues. Laparoscopic ablation of endometriomas may be used to treat both pain and infertility.55
Polycystic ovary syndrome
Polycystic ovary syndrome is a condition in which excessive androgen production is triggered by inappropriate secretion of gonadotrophins (see Chapter 31 for normal cycling of gonadotrophins). It is the most common endocrine disturbance affecting women and is diagnosed in between 4% and 8% of women of reproductive age; Australian population rates of 8–11% have been reported using the Rotterdam and NIH criteria for diagnosis. This syndrome is seen at higher rates in Australian Aboriginals (15–21%) and is associated with insulin resistance and high body mass index.56 This hormonal imbalance prevents ovulation and causes enlargement and cyst formation in the ovaries (Fig. 32.10), excessive endometrial proliferation and often hirsutism (excessive female hair growth in areas where hair growth is usually minimal or absent), acne and male pattern
FIGURE 32.9
Common pelvic sites of endometriosis. Endometriosis commonly develops on the outside of reproductive structures, as well as other abdominal structures.
FIGURE 32.10
Polycystic ovary. Both ovaries shown are enlarged with multiple cysts.
CHAPTER 32 Alterations of the reproductive systems across the life span
baldness. There is an associated impaired insulin sensitivity (refer to Chapter 36). The diagnostic criteria are: • menstrual irregularity due to anovulatory cycles or oligomenorrhoea • clinical hyperandrogenism (acne, hirsutism, male pattern baldness or biochemical evidence of elevated serum androgens • ultrasonic evidence of polycystic ovaries (12 or more enlarged follicles in each ovary either 2–9 mm in diameter or > 10 mL in volume). Polycystic ovary syndrome is estimated to affect 20–21% of women.57 PATHOPHYSIOLOGY
CONCEPT MAP
Although common, polycystic ovary syndrome remains poorly understood with no clear aetiology. While it has been classified as an ovarian disease, it is associated with other long-term health issues, including hypertension, dyslipidaemia and hyperinsulinaemia.58 Hyperinsulinaemia plays a key role in androgen excess, anovulation and pathogenesis of polycystic ovary syndrome.59 Insulin stimulates androgen secretion by the ovarian stroma and reduces serum sex hormone-binding globulin directly and independently. The net effect is an increase in free testosterone levels. Excessive androgens affect follicular growth and insulin affects follicular decline by suppressing apoptosis and enabling follicles, which would normally disintegrate, to survive (see Fig. 32.11). Furthermore, there seems to be a genetic ovarian defect in polycystic ovary syndrome that makes the ovary either more susceptible to Hyperinsulinaemia leads to ↓ SHBG ↑ Ovarian androgen production production
Disordered LH/FSH release
causes
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or at least sensitive to insulin’s stimulation of androgen production in the ovary.58 Inappropriate gonadotrophin secretion triggers a vicious cycle that perpetuates anovulation. Typically, levels of FSH are low or below normal and the LH level is elevated. Persistent LH elevation causes an increase in androgens. Androgens are converted to oestrogen in peripheral tissues and increased testosterone levels cause a significant reduction (approximately 50%) in sex hormone-binding globulin which, in turn, causes increased levels of free oestradiol. Elevated oestrogen levels trigger a positive-feedback response in LH and a negative-feedback response in FSH. Because FSH levels are not totally depressed, new follicular growth is continuously stimulated, but not to full maturation and ovulation (see Fig. 32.11).58 CLINICAL MANIFESTATIONS
Clinical manifestations of polycystic ovary syndrome are related to anovulation and elevated testosterone levels and include dysfunctional bleeding or amenorrhoea, hirsutism and infertility (see Box 32.3). Approximately 38% of women with polycystic ovary syndrome are obese and 20% are asymptomatic. In addition, 30% of women with polycystic ovary syndrome will develop diabetes by the age of 30 years. Other pathological conditions resulting from polycystic ovary syndrome include type 2 diabetes mellitus, cardiovascular disease and endometrial carcinoma. Pregnant women with polycystic ovary syndrome may be at increased risk for glucose intolerance. EVALUATION AND TREATMENT
Diagnosis of polycystic ovary syndrome is based on evidence of androgen excess, chronic anovulation and inappropriate gonadotrophin secretion. Treatment with insulin sensitisers seems to increase fertility while decreasing predisposition to type 2 diabetes. Adding an anti-androgen agent may enhance results. Hormonal contraception may be used to suppress androgen production and reduce endometrial hyperplasia. FOCU S ON L EA RN IN G
Hyperandrogenism
Anovulation
1 Explain why benign ovarian cysts may develop in women who ovulate.
results in
results in
2 Describe the difference in hormonal secretion between a follicular cyst and a corpus luteum cyst.
Polycystic ovary syndrome FIGURE 32.11
Insulin resistance and hyperinsulinaemia in polycystic ovary syndrome. High levels of insulin can lead to alterations in the balance of LH, FSH and androgens, which contributes to anovulation and polycystic ovary syndrome. FSH = follicle-stimulating hormone; LH = luteinising hormone; SHBG = sex hormonebinding globulin.
3 Describe the clinical symptoms of endometriosis and relate these to the woman’s ovarian and menstrual cycles. 4 Outline the hormonal influences implicated in the development of polycystic ovary syndrome.
Hormonal and menstrual alterations Dysmenorrhoea
Primary dysmenorrhoea is painful menstruation associated with the release of prostaglandins in ovulatory cycles but
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Clinical manifestations of polycystic ovary syndrome
BOX 32.3
Presenting signs and symptoms (percentage of women affected) Obesity (38%) Menstrual disturbance (66%) Oligomenorrhoea (47%) Amenorrhoea (19%) Regular menstruation (48%) Hyperandrogenism (48%) Infertility (73% of anovulatory infertility) Asymptomatic (20% of those with polycystic ovary syndrome) Hormonal disturbances Increased insulin (independent of obesity) Increased androgens (testosterone androstenedione) Increased luteinising hormone Increased prolactin Increased leptin, especially in obesity (independent of insulin) Possible decreased oestrogen receptors (intraovarian and along hypothalamic–pituitary axis) Possible late sequelae Dyslipidaemia: increased low-density lipoproteins, decreased high-density lipoproteins, increased triglycerides Diabetes mellitus (30% of women with or without obesity will develop type 2 diabetes mellitus by age 30 years) Cardiovascular disease; hypertension Endometrial carcinoma Other It is controversial if women with polycystic ovary syndrome are at increased risk of glucose intolerance and preeclampsia during pregnancy
not with pelvic disease. Between 50% and 75% of women aged 15–25 years are affected — some (up to 15%)60 are affected severely enough to cause missed work or school. Primary dysmenorrhoea begins with the onset of ovulatory cycles. The incidence steadily rises, peaks in women in their mid-20s and decreases slowly thereafter. Primary dysmenorrhoea results from excessive prostaglandin F production by the secretory endometrium. Prostaglandins are lipid-based hormones that can increase contractions of the myometrium and constrict endometrial blood vessels. Reduced blood flow to the endometrium causes ischaemia resulting in the shedding of the endometrium. In addition, prostaglandins and prostaglandin metabolites can cause gastrointestinal complaints, headache and syncope (fainting). The primary symptom of dysmenorrhoea is pelvic pain associated with the onset of menses. The severity is directly
related to the length and amount of menstrual flow, and pain often radiates into the groin and may be accompanied by backache, anorexia, vomiting, diarrhoea, syncope and headache. Dysmenorrhoea may be relieved with hormonal contraceptives, which stop ovulation and prevent growth of the endometrium, thereby decreasing the production of prostaglandins and myometrial contractility. Prostaglandin inhibitors work in a majority of women with primary dysmenorrhoea and should be taken before or at the onset of bleeding or cramping. Regular exercise may prevent or reduce symptoms. Other comfort measures include local application of heat, massage or relaxation techniques. Secondary dysmenorrhoea is related to pelvic pathology, manifests later in the reproductive years and may occur any time in the menstrual cycle. Secondary dysmenorrhoea results from disorders such as endometriosis, pelvic adhesions, pelvic inflammatory disease, uterine fibroids or adenomyosis.
Amenorrhoea
Amenorrhoea means lack of menstruation from any cause. Primary amenorrhoea is defined as either the failure of menarche and the absence of menstruation by age 14 years with no development of secondary sex characteristics, or the absence of menstruation by age 16 years regardless of the presence of secondary sex characteristics. Causes include congenital defects of gonadotrophic hormone production, genetic disorders (such as Turner’s syndrome), congenital or acquired central nervous system defects (e.g. hydrocephalus, trauma, infection and tumours) and congenital malformations of the reproductive system (e.g. absence of vagina or uterus, imperforate hymen). A major cause of primary amenorrhoea is the failure of the hypothalamic–pituitary–gonadal axis (see Chapter 31); as a result, the ovaries do not receive the hormonal signals (FSH and LH) that normally initiate menarche. Diagnosis of primary amenorrhoea is based on the history and physical examination to investigate: • levels of gonadotrophins (FSH and LH) and ovarian hormones (oestrogen, progesterone) • appearance of the ovaries and reproductive tract. Treatment involves correction of any underlying disorders and hormone replacement therapy to induce the development of secondary sex characteristics. Secondary amenorrhoea is the absence of menstruation for a time equivalent to 3 or more cycles or 6 months in women who have previously menstruated. Secondary amenorrhoea is normal during early adolescence, pregnancy, lactation and in older women approaching menopause. Pregnancy is the most common cause of secondary amenorrhoea and must be ruled out before any further evaluation. The pathophysiology of secondary amenorrhoea is summarised in Fig. 32.12. The major manifestation of secondary amenorrhoea is the absence of menses. Depending on the underlying cause of the amenorrhoea, infertility, vasomotor flushes (dilation of blood vessels leading to ‘hot flushes’), vaginal
CHAPTER 32 Alterations of the reproductive systems across the life span
Normal ovarian hormone secretion Pregnancy Uterine dysfunction caused by: Hysterectomy Uterine adhesions
Decreased ovarian hormone secretion
With high gonadotrophin levels Menopause Congenital ovarian failure caused by: Gonadal dysgenesis Resistance to gonadotrophins Acquired ovarian failure caused by: Autoimmune disease Chemotherapy Resistance to gonadotrophins Environmental toxins
Increased ovarian hormone secretion Ovarian dysfunction caused by: Masculinising tumours Polycystic ovary syndrome
With low gonadotrophin levels Secondary ovarian failure caused by: Hyperprolactinaemia Intrinsic hypothalamic–pituitary disorders (e.g. tumour, head trauma) Extrinsic hypothalamic–pituitary disorders (e.g. starvation, psychogenic disturbance, endocrine disease)
CONCEPT MAP
AMENORRHOEA
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FIGURE 32.12
Causes of secondary amenorrhoea. Main causes include alterations in the secretion of ovarian hormones.
atrophy, acne and hirsutism may also be present. Diagnosis involves identifying underlying hormonal or anatomical alterations. Depending on the cause of the amenorrhoea, treatment may involve hormone replacement therapy or a corrective procedure, such as surgical removal of pituitary tumours.
Abnormal uterine bleeding
The most common cause of abnormal uterine bleeding is failure to ovulate related to age or pathology of the endocrine (hormone) function. Common causes of abnormal bleeding based on age group and frequency are presented in Table 32.3. The mechanisms involved in abnormal bleeding in ovulatory cycles are unclear. Excessive fibrinolytic activity and changes in prostaglandin production may be implicated. Infection or structural abnormalities may also be present. Dysfunctional uterine bleeding is characterised by unpredictable and variable bleeding in terms of amount and duration. When a woman is close to menopause, dysfunctional bleeding may involve flooding and the passing of large clots.61 Heavy bleeding may be preceded by episodes of amenorrhoea and be perceived by individuals as a miscarriage. Dysfunctional uterine bleeding is the diagnosis when other conditions that could cause abnormal bleeding are eliminated. Goals of therapy are to control bleeding, prevent hyperplasia, prevent or treat anaemia and treat concurrent endocrine problems if present.
Premenstrual syndrome
Premenstrual syndrome (PMS) is characterised by quite distressing pain and mood swings in the luteal phase of the menstrual cycle (post-ovulation, in which the corpus luteum produces progesterone and oestrogen; see Chapter 31). Premenstrual symptoms affect many adolescent females, with studies suggesting an incidence range of 31–80% in this age group.62,63 An estimated 5–10% of menstruating women have severe to disabling symptoms, and 3–8% of these have a cyclic exaggerated feeling of depression (dysphoria), known as premenstrual dysphoric disorder, which requires treatment and is now classified as a mental health disorder. Evidence suggests that symptoms are experienced to some degree by all ovulating adolescent and adult women, and they may occur throughout the menstrual phases — the presence and severity of symptoms in any one woman may be inconsistent from month to month and the menstrual phase for peak symptom severity may differ depending on the population studied.64 PATHOPHYSIOLOGY
The aetiology (cause) of PMS is unknown but it is considered to be multifactorial. Fluctuating oestrogen and progesterone levels may trigger this biological response but are not sufficient alone to cause PMS. Research suggests that serotonin levels play a role in the type and severity of symptoms. Low-dose fluoxetine, a selective serotonin re-uptake inhibitor, significantly reduces premenstrual
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TABLE 32.3 Common causes of abnormal vaginal/genital bleeding AGE GROUP
CAUSE
Prepubescence
Sexual assault Trauma Presence of foreign bodies Precocious puberty
Adolescence
Anovulation (immature hypothalamic– pituitary–ovarian axis) Trauma and sexual abuse Pregnancy Pelvic inflammatory disease Coagulation disorder
Reproductive years
Pregnancy Pelvic inflammatory disease Complication of contraceptives Endometriosis Benign neoplasms (submucosal fibroids) Anovulation
Premenopause
Anovulation Malignancy Pregnancy Endometriosis Benign neoplasms (leiomyomas, adenomyosis)
Postmenopause
Malignancy
mood-related symptoms, and higher doses also decrease breast tenderness, bloating and joint/muscle pain. A predisposition for PMS runs in families, perhaps because of genetics or shared environment. A woman’s menstrual experience tends to be similar to her mother’s or her sister’s experience. Further evidence supports a relationship between the severity and frequency of premenstrual symptoms and reports of major affective disorders, personality characteristics and family conflict. In turn, when premenstrual symptoms are perceived as distressing, the quality of interpersonal relationships and self-image are negatively affected. CLINICAL MANIFESTATIONS
The pattern of symptom frequency and severity is more important than specific complaints. More than 200 physical, emotional and behavioural symptoms have been attributed to PMS. Emotional symptoms — particularly depression, anger, irritability and fatigue — have been reported as the most prominent and the most distressing, whereas physical symptoms seem to be the least prevalent and problematic.
Approximately 6% of women have classic PMS (distressing luteal symptoms) and 7% report premenstrual magnification of symptoms that are present during the entire cycle. A typical premenstrual symptom pattern may appear after the treatment of a systemic disease. Likewise, underlying physical or psychological disease may be aggravated before menstruation. EVALUATION AND TREATMENT
Diagnosis of PMS is based on health history and symptoms. Research and diagnostic criteria for premenstrual dysphoric disorder are presented in Box 32.4. Current treatment for PMS is symptomatic as the cause is complex and cannot be reduced to a single biological explanation and because the occurrence and severity are mediated by lifestyle, social and psychological factors. Non-pharmacological therapies, with or without medication, tend to be more effective in controlling symptoms than medication alone. Initial treatment focuses on education about PMS, self-help techniques and elimination of contributing factors or coexisting disorders. The following dietary changes are beneficial — eating six small meals each day; increasing the intake of complex carbohydrates, fibre and water; and decreasing caffeine, alcohol, sugar and animal fat consumption. If the criteria for diagnosis of premenstrual dysphoric disorder are met, drugs such as selective serotonin re-uptake inhibitors, antiprostaglandins and GnRH analogues may be prescribed. Selective serotonin reuptake inhibitors relieve symptoms in about 60% of women and may be given continuously or only during the premenstrual period. Oedema associated with PMS is a result of local fluid shifts rather than fluid retention, so diuretics are not recommended. In severe cases, menses is stopped, which eliminates cyclic ovarian hormones and thus the biological trigger for PMS. This is accomplished by the use of oral contraceptives.
Infection and inflammation
Infections of the genital tract by bacteria or fungi lead to inflammation due to the increased blood flow and the
General criteria for premenstrual dysphoric disorder
BOX 32.4
Premenstrual dysphoria is the predominant feature of premenstrual dysphoric disorder and is triggered (not caused) by the endocrine changes that occur in the late luteal phase of the menstrual cycle. Premenstrual dysphoric disorder is strongly associated with depression. This gives recognition to the severe and incapacitating dysphoria that characterises the disorder. Criteria for premenstrual dysphoric disorder include a rigorous prospective assessment confirming a regular premenstrual pattern of severe depressive symptoms.
CHAPTER 32 Alterations of the reproductive systems across the life span
Pelvic inflammatory disease
F O CUS O N L E A R N IN G
1 Explain the reasons for primary and secondary amenorrhoea. 2 Relate the symptoms of primary dysmenorrhea to the pathophysiology. 3 Discuss the causes of dysfunctional uterine bleeding. 4 Outline the pathophysiology of premenstrual syndrome. 5 Relate the physiological changes during the menopause to the withdrawal of oestrogens and progesterone.
presence of immune cells, which are attracted to the site of infection. The bacteria or fungi causing the infection may be an overgrowth of the flora normally resident in the vagina, bowel or vulva (endogenous) or they may be foreign organisms (exogenous) transmitted to the site of infection. Exogenous pathogens are most often sexually transmitted, but can be the result of poor hygiene. Endogenous causes of infection occur if resident microorganisms migrate to a new location or over-proliferate. Infections can result in inflammation of almost any part of the reproductive tract of both men and women and, given the anatomy of the reproductive system (Chapter 31), can spread easily to other parts of the reproductive system and to sexual partners. Infection and inflammation can occur in the vagina (vaginitis), the cervix (cervicitis), the vulva (vulvitis) and the Bartholin’s glands (bartholinitis). The labia can also become inflamed and oedematous if irritated or if infection is present in the vagina or vulva. The following is a summary of the most common presentations in healthcare settings in Australia and New Zealand.
Pelvic inflammatory disease (PID) is an acute inflammatory process caused by infection (see Fig. 32.13). It may involve any organ, or combination of organs, of the upper genital tract (the uterus, uterine tubes or ovaries) and, in its most severe form, the entire peritoneal cavity. Inflammation of the uterine tubes is termed salpingitis (see Fig. 32.14); inflammation of the ovaries is called oophoritis. Most cases of pelvic inflammatory disease are caused by sexually transmitted microorganisms that migrate from the vagina to the uterus, uterine tubes and ovaries.65 Pelvic inflammatory disease is generally the result of a polymicrobial (many microorganisms) infection and although mostly initiated by gonorrhoea or Chlamydia (50–60% of cases), mixed bacteria (Gardnerella vaginalis, Haemophilus influenzae and streptococci) also contribute. Neisseria gonorrhoeae and Chlamydia trachomatis induce necrosis with repeated infections and predispose an individual to develop pelvic inflammatory disease. After one episode of pelvic infection, 15–25% of women develop long-term complications such as infertility, ectopic pregnancy, chronic pelvic pain, dyspareunia (painful intercourse), pelvic adhesions, perihepatitis (inflammation of the serous or peritoneal coating of the liver) and uterine tube and ovary abscess. The clinical manifestations of pelvic inflammatory disease vary from sudden, severe abdominal pain with fever to no symptoms at all. The pain of pelvic inflammatory disease may worsen with walking, jumping or intercourse, and dysuria (difficult or painful urination) and irregular bleeding are often present. An asymptomatic cervicitis (inflammation of the cervix) may be present for some time before pelvic inflammatory disease develops. The first sign of the ascending infection may be the onset of low bilateral abdominal pain,
A Uterine tube (bilateral, tender)
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B Uterus
Violin string adhesions
Uterine tube (bilateral, tender)
Ovary
Ovary Movement of cervix painful
FIGURE 32.13
Pelvic inflammatory disease. A In this illustration, both ovaries and uterine tubes are involved in the disease. B Total abdominal hysterectomy and bilateral salpingooophorectomy specimen showing unilateral pyosalpinx.
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A
B Uterus Uterine tube
Uterine tube
Ovary
Ovary
Advanced pyosalpinx FIGURE 32.14
Salpingitis. A Note the swollen uterine tubes. B Bilateral, retort-shaped, swollen sealed tubes and adhesions of ovaries are typical of salpingitis.
often characterised as dull and steady with a gradual onset. Symptoms are more likely to develop during or immediately after menstruation. The diagnosis of pelvic inflammatory disease is based on a number of factors including the history, abdominal tenderness, the presence of uterine and cervical movement, tenderness on bimanual pelvic examination, mucopurulent (mucus and pus) discharge at the cervical os (opening), white blood cells in the cervical discharge, leucocytosis (an increase in the number of white blood cells) and an increased erythrocyte sedimentation rate. To support the diagnosis, tests for Chlamydia and gonorrhoea are performed. Other conditions that cause pelvic pain must be excluded, including ectopic pregnancy, threatened abortion or appendicitis. Because of the significance of the complications of pelvic inflammatory disease, aggressive treatment (bed rest, avoidance of intercourse and combined antibiotic therapy) is recommended. Hospitalisation may be required for intravenous antibiotics and treatment of peritonitis or a tubo-ovarian abscess. To prevent recurrence, sexual partners are also treated with antibiotic.
Vaginitis
Vaginitis is usually caused by sexually transmitted pathogens, bacterial vaginosis or Candida albicans. The incidence of sexually transmitted vaginitis remains highest in women 10–24 years of age.65 Vaginitis can occur when either the skin of the vagina is damaged or the pH of the vaginal secretions changes. The pH of the vagina depends on cervical secretions and the presence of normal flora (Lactobacillus acidophilus) that help maintain an acidic environment. The acidic environment acts as a barrier to infectious organisms; however, if the pH of the secretions becomes higher (less acidic), then the vagina becomes predisposed to infection. The vaginal pH can be altered by douching; use of soaps, spermicides, feminine hygiene sprays or deodorant menstrual
pads or tampons; conditions associated with increased glycogen content of vaginal secretions, such as pregnancy or diabetes; and conditions that compromise the immune system. In addition, the use of antibiotics for other conditions may kill the normal vaginal flora, resulting in an increase in alkalinity and making the vagina more susceptible to trichomoniasis (bacterial vaginosis) and an overgrowth of Candida albicans.
Cervicitis
Cervicitis is a nonspecific term used to describe inflammation of the cervix before the identification of pathogens. Mucopurulent cervicitis is usually caused by one or more sexually transmitted pathogens, such as Trichomonas, Neisseria gonorrhoeae, Chlamydia, Mycoplasma or Urea-plasma. Infection causes the cervix to become red and oedematous. A mucopurulent (mucus- and pus-containing) exudate drains from the external cervical os and may be accompanied by vague pelvic pain, bleeding or dysuria. The infectious organisms are cultured or identified and then treated by oral antibiotic therapy. Sexual partners are usually treated to prevent reinfection.65
Vulvitis
Acute vulvitis is an inflammation of the skin (dermatitis) of the vulva and often of the perianal area. It can be caused by contact with perfumed and scented hygiene products (soaps, detergents, lotions, hygienic sprays, shaving creams, menstrual pads or toilet paper) and can be aggravated by non-absorbent or tight-fitting clothes. The inflammation can increase susceptibility to a vaginal infection or may be caused by a vaginal infection that spreads to the labia. The vulva also can be affected by other skin diseases, such as tinea cruris, lichen sclerosis, psoriasis and inflammation of the apocrine (sweat) glands (see Chapter 19).
CHAPTER 32 Alterations of the reproductive systems across the life span
Avoidance of irritants, wearing loose cotton clothing and appropriate antimicrobial/antifungal treatment for recurrent vaginitis are usually effective cures for acute vulvitis. Chronic vulvitis is usually treated with fluorinated hydrocortisone. Biopsy specimens of persistent lesions are examined for the presence of malignancy.
Bartholinitis
Bartholinitis (Bartholin’s cyst) is an inflammation of one or both of the ducts that lead from the introitus (vaginal opening) to the Bartholin’s glands (see Fig. 32.15). The usual causes are microorganisms that infect the lower female reproductive tract, such as streptococci, staphylococci and sexually transmitted pathogens. Acute bartholinitis may be preceded by an infection, such as cervicitis, vaginitis or urethritis. Cultures for gonorrhoea and Chlamydia are recommended. Infection is treated with antibiotics and pain is relieved with analgesics and warm sitz baths (where the pelvic region is immersed in warm water; from the German word sitzen mean ‘to sit’) or icepacks. If an abscess forms, it may be surgically drained.
Pelvic relaxation disorders
The uterus, bladder, urethra and rectum are supported by the endopelvic fascia and perineal muscles. This muscular and fascial tissue loses tone and strength with ageing and after giving birth and may fail to maintain the pelvic organs in the proper position. Uterine displacement can be caused by progressive relaxation of the pelvic support structures or trauma such as childbirth or pelvic surgery that damages
FIGURE 32.15
Inflammation of Bartholin’s glands. The tissue on the left of the image is swollen due to Bartholin’s gland inflammation.
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or weakens the supporting structures. The bladder, urethra or rectum (and hence the uterus) may become displaced many years after an initial injury to the supporting structure. A strong familial tendency and, possibly, a multifactorial genetic component place some women at risk for the development of prolapse. Vaginal prolapse can result from one of the following: • the descent of the bladder and the anterior vaginal wall into the vaginal canal (cystocele) • the bulging of the rectum and posterior vaginal wall into the vaginal canal (rectocele) • herniation of the rectouterine pouch into the rectovaginal septum (between the rectum and posterior vaginal wall) (enterocele). Fig. 32.16 shows vaginal prolapse caused by cystocele and rectocele. In severe cases of cystocele the bladder and anterior vaginal wall bulge outside the introitus (vaginal opening). Cystocele can cause stress incontinence in which the woman leaks urine when she laughs, sneezes, coughs or does anything that strains the abdominal muscles. Cystocele is usually accompanied by urethrocele, or sagging of the urethra. Urethrocele is usually caused by the shearing effect of the fetal head on the urethra during childbirth. If rectocele is severe, defecation can be difficult and may be accomplished only by applying manual pressure to the posterior vaginal wall. Enterocele is usually associated with other pelvic relaxation disorders, such as uterine prolapse, cystocele and rectocele. Table 32.4 summarises the causes, symptoms and treatment of cystocele, urethrocele and rectocele. Uterine prolapse is descent of the cervix or entire uterus into the vaginal canal (see Fig. 32.17). In severe cases, the uterus falls completely through the vagina and protrudes from the introitus. First-degree uterine prolapse is not treated unless it causes discomfort. Second- and third-degree prolapses cause feelings of fullness, heaviness and collapse through the vagina. Symptoms of other pelvic relaxation disorders may also be present. Treatment in these cases is the insertion of a pessary, which is a removable mechanical device that holds the uterus in position.66 Fifteen per cent of women undergo surgical repair or hysterectomy for the prolapse.66 The pelvic fascia may be strengthened through Kegel exercises (repetitive, isometric tightening and relaxing of the pubococcygeal muscles) or by a course of oestrogen therapy, particularly if the woman is past menopause. Surgical repair with or without hysterectomy may be necessary. Prevention of constipation, maintaining a healthy body mass index and early treatment of respiratory ailments that cause coughing may help.
Reproductive and sexual dysfunction
Increased awareness of female sexual dysfunction is relatively new. Most of what is known comes from clinical observations and anecdotal reports from women, as adequate research is lacking. Both organic and psychosocial disorders can be
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B
A
Bulge
Bulge
C
D Bulge
Bulge FIGURE 32.16
Vaginal prolapse. A Anatomical positioning involving cystocele. B Large cystocele. C Anatomical positioning involving rectocele. D Rectocele associated with ulceration of vaginal wall.
implicated in sexual dysfunction. Organic problems may be the underlying cause in 10–20% of cases and may contribute to another 15%. Chronic illness can affect sexual functioning and response. Table 32.5 outlines possible effects of specified chronic diseases on sexual functioning. Disorders of desire (inhibited sexual desire, decreased libido) may be a biological manifestation of depression, alcohol or other substance abuse, prolactin-secreting pituitary tumours or testosterone deficiency. Beta (β)adrenergic blocker medication, such as propranolol and metoprolol, used in the treatment of heart disease may also inhibit sexual desire. Vaginismus is an involuntary muscle spasm of the pubococcygeal muscle in response to attempted penetration. Common psychological causes include prior sexual trauma or fear of sex. Organic causes are similar to those that cause dyspareunia. Even after the underlying organic problem is detected and successfully treated, vaginismus may persist. Anorgasmia (orgasmic dysfunction) is the inability of a woman to reach or achieve orgasm. Specific disorders that may block orgasm are diabetes, alcoholism, neurological
disturbances, hormonal deficiencies and pelvic disorders, such as infections, trauma and surgical scarring. Other inhibitors include drugs such as narcotics, tranquillisers, antidepressants and antihypertensive medications. There may be a psychogenic cause in some cases. Dyspareunia (painful intercourse) is common; women may experience pain at any time from the beginning of arousal to after intercourse. The pain may have a burning, sharp, searing or cramping quality and may be described as external, vaginal, deep abdominal or pelvic. A variety of psychosocial and organic causes have been identified. Inadequate lubrication may make penetration or intercourse difficult or painful. Drugs with a drying effect, such as antihistamines, tranquillisers and marijuana, and disorders such as diabetes mellitus, vaginal infections and oestrogen deficiency can decrease lubrication. Other causes include skin problems (e.g. herpes simplex infection). Sexual dysfunction may develop as a coping mechanism. Women with a history of sexual trauma such as rape or incest often have problems with desire, arousal or orgasm or experience pain with sexual activity. In extreme cases,
CHAPTER 32 Alterations of the reproductive systems across the life span
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TABLE 32.4 Cystocele, urethrocele and rectocele CONDITION
AETIOLOGY
SYMPTOMS
TREATMENT
Cystocele
Laceration, stretching or weakening of supporting fascial tissue; usually caused by prolonged labour, multiple births or birth of a large baby
Urinary frequency, urgency, incontinence
Depending on the age of the woman and the severity of the condition, includes the following:
Difficulty in complete emptying of the bladder Low backache Symptoms become problematic before and after menopause
Isometric exercises to strengthen the pubococcygeal muscle Oral or topical oestrogen to improve tone and vascularity of fascial support Pessary, a removable device that holds the bladder in position Surgical correction
Urethrocele
Pressure of fetal head on urethra and attachments beneath the symphysis pubis Familial or genetic predisposition
Rectocele
Trauma to the fascia and levator ani muscles; usually caused by childbirth
Asymptomatic unless it occurs in conjunction with cystocele Stress incontinence Constipation or feeling of rectal fullness Difficult defecation Pressure and sensation of fullness in the vagina
A
Isometric exercises to strengthen the pubococcygeal muscle
B
Isometric exercises Diet counselling to prevent constipation Stool softeners or laxatives Surgery
total sexual aversion may develop. At other times, sexual dysfunction may be a symptom of marital or relationship problems. Management usually requires careful assessment of the cause and appropriate supportive therapies.
FOCU S ON L EA RN IN G
1 Discuss the impact of pelvic inflammatory disease on reproductive health.
C
D
FIGURE 32.17
Degrees of uterine prolapse. A Normal positioning of the uterus. B First-degree prolapse: descent within the vagina. C Second-degree prolapse: the cervix protrudes through the introitus. D Third-degree prolapse: the vagina is completely everted.
Disorders of the male reproductive system Male reproductive disorders can arise from hormonal dysfunction, structural abnormalities or infections. For example, the testes are easily damaged by trauma, which can lead to infertility as well as further hormonal balance changes if testosterone-producing cells are damaged. Men are on the whole less likely to seek medical assistance for problems and so the incidence of male reproductive disorders is underreported.
Disorders of the urethra Urethritis
Urethritis is a common disorder of the urethra and is an inflammatory process that is usually, but not always, caused
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TABLE 32.5 Possible effects of chronic disease on sexual functioning in women and men DISEASE
SEXUAL FUNCTION
Cerebral palsy
Intact genital sensations Difficulty with sexual activity/positioning because of muscle spasticity, rigidity or weakness Pain with positioning caused by contracture of knees and hips or because of increased spasms with arousal
Stroke
Difficulties in sexual positioning and sensitivity because of impaired motor strength, coordination or paralysis Decreased sex drive with stroke on the dominant side of the brain
Diabetes mellitus
Diminished intensity of orgasm and gradual decline in ability to achieve orgasm Decreased lubrication or recurrent vaginal infections with resultant dyspareunia and erectile dysfunction +/- retrograde ejaculation in male
End-stage kidney disease
Decreased arousal
Rheumatoid arthritis
Painful sexual activity/positions because of swollen, painful joints, muscular atrophy and joint contracture
Increasingly rare and less intense orgasms; decreased lubrication Decreased sex drive because of pain, fatigue or medication Genital sensations remain intact
Systemic lupus erythematosus
Similar to rheumatoid arthritis, decreased lubrication and vaginal lesions result in painful penetration
Cardiac disease
Erectile dysfunction, decreased arousal and/or desire in either sex
Multiple sclerosis
Diminished genital sensitivity
Erectile dysfunction in male
Decreased lubrication Declining orgasmic ability Difficulty with sexual activity because of muscle weakness, pain or incontinence Spinal cord injury
Reflex sexual response with injury above sacral area, lack of psychogenic response Disrupted response with lesion at or below sacrum Loss of sensation, decreased lubrication in female Spasticity, incontinence or pain with arousal Continued orgasmic sensations or sensations diffused in general or to specific body parts, such as breast or lips
by a sexually transmitted infection. Infectious urethritis caused by Neisseria gonorrhoeae is often called gonococcal urethritis. Urethritis caused by other microorganisms is called nongonococcal urethritis. Non-sexual origins of urethritis include inflammation or infection as a result of urological procedures, insertion of foreign bodies into the urethra, anatomical abnormalities or trauma. Symptoms of urethritis include a tingling, itching or burning sensation of the urethra, and the frequency and urgency of urination increases. The individual may note a purulent or clear mucus-like discharge from the urethra. Early detection of Neisseria gonorrhoeae and Chlamydia trachomatis in urine tests is possible. Treatment consists of appropriate antibiotic therapy for infectious urethritis and avoidance of future exposure or mechanical irritation.
Urethral strictures
A urethral stricture is a narrowing of the urethra caused by scarring. The scars may be congenital but are more likely to result from trauma (e.g. injury by urological instrument) or untreated or severe urethral infections. Prostatitis and infection secondary to urinary stasis are common complications. Severe and prolonged obstruction can result in hydronephrosis and renal failure (refer to Chapter 30). Clinical manifestations include a desire to urinate frequently, but often with a hesitant urine flow with lower force than normal, dribbling after voiding and nocturia. Urethral stricture is diagnosed on the basis of the history, physical examination and cystoscopy. Treatment is usually surgical and may involve urethral dilation, urethrotomy or a variety of open surgical techniques. The choice of surgical
CHAPTER 32 Alterations of the reproductive systems across the life span
intervention depends on the age of the individual and the severity of the problem.
Disorders of the penis Phimosis and paraphimosis
Phimosis and paraphimosis are both disorders in which the foreskin (prepuce) is ‘too tight’ to move easily over the glans penis (see Fig. 32.18). Phimosis is a condition in which the foreskin cannot be retracted back over the glans. The inability to retract the foreskin is normal in infancy (caused by congenital adhesions between the foreskin and glans). During the first 3 years of life these congenital adhesions separate naturally with penile erections and are not an indication for circumcision. Phimosis can occur at any age and is most commonly caused by poor hygiene and chronic infection. It rarely occurs with normal foreskin. Reasons for seeking treatment include oedema, erythema,
A
B
C
D
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tenderness of the prepuce and purulent discharge; inability to retract the foreskin is a less common complaint. Circumcision, if needed, is performed after infection has been eradicated. Complications of phimosis include inflammation of the glans (balanitis) or prepuce (posthitis) and paraphimosis. There is a higher incidence of penile carcinoma in uncircumcised males, but chronic infection and poor hygiene are usually the underlying factors in such cases. Box 32.5 outlines the use of circumcision in Australia and New Zealand. Paraphimosis is a condition in which the foreskin is retracted and cannot be moved forward (reduced) to cover the glans. This can constrict the penis, causing oedema of the glans. If the foreskin cannot be reduced manually, surgery must be performed to prevent necrosis of the glans caused by constricted blood vessels. Severe paraphimosis is a surgical emergency.
FIGURE 32.18
Phimosis and paraphimosis. A Phimosis: the foreskin has a narrow opening that is not large enough to permit retraction over the glans. B Lesions on the prepuce secondary to infection cause swelling, and retraction of foreskin may be impossible. Circumcision is usually required. C Paraphimosis: the foreskin is retracted over the glans but cannot be reduced to its normal position. Here it has formed a constricting band around the penis. D This oedematous foreskin is the result of paraphimosis.
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BOX 32.5
Circumcision in Australia and New Zealand
Circumcision of males has been undertaken for religious and cultural reasons for many thousands of years and remains an important ritual in some religious and cultural groups. In Australia and New Zealand, the circumcision rate has fallen considerably in recent years and it is estimated that currently only 10–20% of male infants are routinely circumcised. Circumcision is generally performed with local or general anaesthesia and when the procedure is carried out for a medical indication this is usually outside the neonatal period. The best recognised medical indication for circumcision is phimosis. The Paediatrics and Child Health Division of the Royal Australasian College of Physicians (RACP) has found that there was evidence that routine circumcision may provide some benefit in prevention of urinary tract infections, HIV and cancer of the penis. For example, urinary tract infections affect 1–2% of boys and may be about five times less frequent in circumcised boys. However, the complication rate of neonatal circumcision is about 1–4%. Complications range from mild bleeding, local infection and skin removal damage to more serious complications such as septicaemia and severe bleeding in rare cases. Circumcision may provide some protection from HIV in areas where rates of HIV are high, such as Sub-Saharan Africa (although data are conflicting), but Australia and New Zealand have low incidence rates of HIV due to increased public awareness and the relatively extensive use of condoms (a good preventative measure against sexually transmitted infections including HIV). Finally, since penile cancer is a rare disease with an incidence rate of about 1 per 100 000 in developed countries, the rarity of the condition does not justify the routine circumcision of males, even though evidence suggests that circumcision reduces the risk ten-fold. The RACP states that routine neonatal circumcision is not warranted, and that there may be ethical and human rights implications of performing circumcision on a minor where there is no proven medical benefit in so far as the procedure may contravene the human rights of the child. This has been critiqued as failing to be evidence based. The RACP also states that: ‘When parents request a circumcision for their child the medical attendant is obliged to provide accurate unbiased and up to date information on the risks and benefits of the procedure. Parental choice should be respected. When the operation is to be performed it should be undertaken in a safe, child-friendly environment by an appropriately trained competent practitioner, capable of dealing with the complications, and using appropriate analgesia.’
Peyronie’s disease
Peyronie’s disease (‘bent nail syndrome’) is a connective tissue disorder involving the growth of fibrous plaques in the soft tissue of the penis affecting as many as 1–4% of men. Specifically, the fibrosing process occurs in the tunica albuginea, a fibrous envelope surrounding the penile corpora cavernosa causing an abnormal curvature of the penis (see Fig. 32.19). A dense, fibrous plaque is usually palpable on the dorsal side of the penile shaft whether erect or flaccid. A local vasculitis-like inflammatory reaction occurs and decreased tissue oxygenation results in fibrosis and calcification. The exact cause is unknown. The problem usually affects middle-aged men and is associated with painful erection, painful intercourse (for both partners) and poor erection distal to the involved area. In some cases, impotence or unsatisfactory penetration occurs. When the penis is flaccid, there is no pain. Peyronie’s disease is associated with Dupuytren’s contracture (a flexion deformity of the fingers or toes caused by shortening or fibrosis of the palmar or plantar fascia), diabetes, a predisposition to keloid scarring and, in rare cases, use of β-blocker medications. Treatments include surgical options such as intracavernosal plaque excision and minimally invasive repair strategies, as well as oral therapy such as tocopherol and L-carnitine.67
FIGURE 32.19
Peyronie’s disease. This individual complained of pain and deviation of the penis to one side during erection.
CHAPTER 32 Alterations of the reproductive systems across the life span
Priapism
Priapism is an uncommon condition of prolonged penile erection that is not associated with sexual arousal (Fig. 32.20). It is the result of imbalance between arterial inflow and venous outflow, resulting in extended engorgement of the corpus cavernosum. It has two general forms — low flow (ischaemic) and high flow (arterial and non-ischaemic). Low flow priapism may result in irreversible tissue damage and is considered to be a medical emergency, as the passage of urine is limited. This form of the condition is generally painful and has similarities with other compartment syndromes. Causes include vascular occlusion (e.g. thrombi or sickle cell) spinal cord damage and trauma. Treatment is symptomatic pain relieve (nerve block) and intracavernosal injection of phenylephrine. Topical ice may also assist with decreasing the tissue engorgement with blood. High flow priapism is associated with perineal trauma, cocaine use and metastatic disease. It is not generally painful and treatment is conservative. Potency is dependent on cause and the effectiveness of treatment, but impotence is a significant long-term consequence in about half of men with low flow priapism. Early treatment for both forms improves the outcome.68
Disorders of the scrotum, testis and epididymis Disorders of the scrotum
The scrotum is a multilayered skin sac housing the testes, epididymis and blood vessels supplying the testes. Swelling of the testes or scrotum is fairly common and has a number of underlying causes, the three most common being varicocele, hydrocoele and spermatocele: • Varicocele affects 10–15% of males. The veins (particularly of the pampiniform plexus), like other bodily veins, can experience a failure of the valves. Since venous valves
ensure one-way blood flow, if they are non-functional the blood pools in veins, resulting in veins becoming varicose. Varicocele is classically described as a ‘bag of worms’ (see Fig. 32.21). Varicoceles result in reduced blood flow through the testis interfering with spermatogenesis and causing infertility. They occur largely (95%) on the left side and may be painful or tender. • Hydrocoele is the most common cause of scrotal swelling. It is a collection of fluid within the tunica vaginalis (see Fig. 32.22) and can range in size from slightly larger than the normal testes to a grapefruit size or larger. Hydrocoeles occur in 6% of male newborns and are congenital malformations that often resolve spontaneously in the first year of life. Surgical ligation is recommended if hydrocoele persists after age 1 year.69 The exact mechanism of idiopathic hydrocoele is unknown. Secondary hydrocoele may result from trauma or infection of the testis or epididymis or from a testicular tumour. Rapid accumulation of fluid occurs after local injury, radiotherapy or infection, or it may accompany testicular neoplasm. Chronic hydrocoele is more common and occurs in men over 40 years of age because of an imbalance between fluid secretion and resorption in the tunica vaginalis. Treatment for uncomplicated hydrocoele is aspiration of the fluid and injection of a sclerosing agent into the scrotal sac (cystic dilation) to excise the tunica vaginalis. • Spermatocele is a painless diverticulum of the epididymis located between the head of the epididymis and the testis. Spermatoceles are filled with a milky fluid containing sperm (see Fig. 32.23). Both spermatoceles and
FIGURE 32.20
Priapism. This patient experienced 18 hours of priapism after penile selfinjection of papaverine as therapy for impotence.
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FIGURE 32.21
Schematic of a variocele. Dilation of the veins within the spermatic cord.
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Cryptorchidism
Normal epididymis
Parietal layer of tunica vaginalis Visceral layer of tunica vaginalis
Normal testis
Collection of clear fluid (plasma transudate)
FIGURE 32.22
Schematic of a hydrocoele. Accumulation of clear fluid between the visceral (inner) and parietal (outer) layers of the tunica vaginalis (covering of the testis).
In cryptorchidism, one or both testes fail to descend into the scrotum. This is the most common congenital condition involving the testes, with about 3–6% of all full-term males and 20–30% of all premature males (< 36 weeks gestation) having undescended testes at birth. The testes may remain in the abdomen or descent may be arrested in the inguinal canal or the puboscrotal junction. In approximately 75–90% of infants with cryptorchidism, the testes descend into the scrotum by 1 year of age, leaving a true incidence of 0.8% of the male population. Cryptorchidism may result from a developmental delay, a defect of the testis, or some mechanical factor that prevents descent through the inguinal canal. Mechanical possibilities include a short spermatic cord, fibrous bands or adhesions in the normal path of the testes, or a narrowed inguinal canal. Chromosomal studies do not support a genetic component. Untreated cryptorchidism is associated with a lowered sperm count and, therefore, impaired fertility. Impaired spermatogenesis is caused by higher temperatures within the abdomen. Cryptorchidism does not prevent puberty or maintenance of secondary sex characteristics if the testis is otherwise normal. Undescended testes are susceptible to neoplastic processes. The risk of testicular cancer is 35–50 times greater for men with cryptorchidism or a history of cryptorchidism than for the general male population. Physical examination discloses the absence of one or both testes in the scrotum. Ultrasonography or a CT scan can help clinicians locate a non-palpable testis that has migrated intraabdominally. Treatment often begins with hormonal therapy. If hormonal therapy is not successful, to preserve fertility, surgical correction (orchiopexy) of cryptorchidism is attempted when the child is about 2 years of age. Orchiopexy is recommended no later than age 5 or 6 years. Placement of the cryptorchid testis into the scrotal sac does not decrease the potential for malignancy, but it does facilitate examination and tumour detection.
Torsion of the testis
FIGURE 32.23
Spermatocele. Retention cyst of the head of the epididymis or an aberrant tubule or tubules of the rete testis. The spermatocele lies outside the tunica vaginalis; therefore, on palpation it can be readily distinguished and separated from the testis.
epididymal cysts present clinically as discrete, firm, freely mobile masses distinct from the testis. Spermatoceles that cause pain or discomfort are excised. Usually, however, they are asymptomatic or produce mild discomfort that is relieved by scrotal support. Neither hydrocoeles nor spermatoceles are associated with infertility.
In torsion of the testis, the testis rotates on its vascular pedicle, interrupting its blood supply (Fig. 32.24). Torsion of the testis is one of several conditions that cause an acute scrotum (testicular pain and swelling). This event can occur at any age but is most common among neonates and adolescents, particularly at puberty.69 Onset may be spontaneous or follow physical exertion or trauma. Torsion twists the arteries and veins in the spermatic cord, reducing or stopping circulation to the testis. Vascular engorgement and ischaemia develop, causing scrotal swelling and pain not relieved by rest or scrotal support. Diagnostic testing includes urinalysis (for infection) and Doppler ultrasonography.70 Torsion of the testis is a surgical emergency. If it cannot be reduced manually (scrotal elevation), surgery must be performed within 6 hours after the onset of symptoms to preserve normal testicular function.71
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is sudden, occurring 3–4 days after the onset of parotitis (inflammation of one or both parotid glands, the major salivary glands located on either side of the face). Signs and symptoms include high fever, reaching 40°C, marked prostration, bilateral or unilateral erythema, oedema and tenderness of the scrotum and leucocytosis. An acute hydrocoele may develop. Atrophy with irreversible damage to spermatogenesis may result in 30% of affected testes.
Impairment of sperm production and quality
FIGURE 32.24
Torsion of the testis. The testes appear dark red and necrotic.
FIGURE 32.25
Schematic of orchitis. The testicle is enlarged and inflamed.
Orchitis
Orchitis is an acute inflammation of the testes (see Fig. 32.25) and is uncommon except as a complication of systemic infection. Infectious organisms may reach the testes through the blood or the lymphatics or, most commonly, by ascent through the urethra, ductus deferens and epididymis. Mumps is the most common infectious cause of orchitis and usually affects postpubertal males. The onset
This is a major cause of male infertility (see Table 32.7 later in the chapter). Spermatogenesis requires: • adequate secretion of FSH by the pituitary gland • adequate secretion of LH by the pituitary gland • sufficient secretion of testosterone by the testes. Inadequate secretion of gonadotrophins has a variety of causes related to the function of the hypothalamic– pituitary–gonadal axis in males. In the absence of adequate gonadotrophin levels, the interstitial (Leydig) cells are not stimulated to secrete testosterone and inhibin, and sperm maturation is not promoted in the sustentacular (Sertoli) cells. Spermatogenesis also depends on an appropriate response by the testes, so defects in the testicular response to the gonadotrophins result in decreased secretion of testosterone and inhibin B. In the absence of adequate testosterone levels, spermatogenesis is impaired. Defects in the testes can be congenital, caused by trauma, infection, atrophy of the testes, systemic illness involving high fever, ingestion of various drugs, exposure to environmental toxins and cryptorchidism. Fertility is adversely affected if spermatogenesis is normal but the sperm are chromosomally or morphologically abnormal or are produced in insufficient quantities. Sperm must also be capable of capacitation, and normal seminal fluid contributes to this, so the accessory organs are also important. Chromosomal abnormalities are caused by genetic factors and by external variables, such as exposure to radiation or toxic substances. Treatment for impaired spermatogenesis involves correcting any underlying disorders, avoiding radiation and toxins, and using hormones to enhance spermatogenesis. In addition, semen can be modified to improve sperm motility; modifications are followed by artificial insemination.
Epididymitis
Epididymitis, or inflammation of the epididymis, generally occurs in sexually active young males (younger than 35 years of age) and is rare before puberty. Approximately 54 000 patient encounters for epididymitis take place in Australian general practice each year.71 The pathogenic microorganism usually reaches the epididymis by ascending the ductus deferens from an already infected urethra or bladder. The main symptom is scrotal or inguinal pain caused by the resulting inflammatory response in the epididymis and surrounding tissues (see Fig. 32.26). The pain is usually acute and severe. Flank pain may occur if, as the urethra passes over the spermatic cord,
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FIGURE 32.26
Epididymitis secondary to gonorrhoea or nongonococcal urethritis. This infection spread to the testes, and rupture through the scrotal wall is threatened.
oedematous swelling of the cord obstructs the urethra. The individual may have pyuria, bacteriuria and a history of urinary symptoms, including urethral discharge. A history of recent urinary tract infections or urethral discharge suggests the diagnosis of epididymitis. Definitive diagnosis is based on culture or gram stain of a urethral swab. Treatment includes antibiotic therapy for the infection itself and various measures to provide symptomatic relief. Complete resolution of swelling and pain may take several weeks to months. The individual’s sexual partner should be treated with antibiotics if the causative microorganism is a sexually transmitted pathogen.
F OC US O N L E ARN IN G
1 Explain why low flow priapism and testicular torsion are considered urological emergencies. 2 Describe the different disorders of the scrotum, testis and epididymis. 3 Describe the principle changes in the male sexual response with ageing.
Disorders of the prostate gland Benign prostatic hyperplasia
Benign prostatic hyperplasia is the enlargement of the prostate gland (see Fig. 32.27), which is an abnormal expansion of cell numbers within the prostate gland. This condition becomes problematic as prostatic tissue compresses the prostatic urethra, resulting in an interrupted urine flow and increased frequency of lower urinary
tract symptoms. About 80% of men will have prostatic enlargement before age 80 years and there is a 25–30% lifetime chance of needing prostatectomy for benign prostatic hyperplasia once a man reaches 50 years of age. At birth, the prostate is pea-sized and growth of the gland is gradual until puberty. At that time, there is a period of rapid development that continues until the third decade of life when the prostate reaches adult size. Within the third decade, benign hyperplastic growth begins and continues slowly until death. The exact trigger for the onset of cell proliferation is unknown but is likely to be multifactorial. Benign prostatic hyperplasia occurs in the peri-urethral glands, which are the inner glands or layers of the prostate adjacent to the urethra. The prostate enlarges as nodules form and grow (nodular hyperplasia) and glandular cells enlarge (hypertrophy). As nodular hyperplasia and cellular hypertrophy progress, tissues that surround the prostatic urethra compress it, usually but not always causing bladder outflow obstruction. Symptoms include the urge to urinate often, some delay in starting urination and decreased force of the urinary stream. As the obstruction progresses, often over several years, the bladder cannot empty all the urine and the increasing volume leads to long-term urine retention. The volume of urine retained may be great enough to produce uncontrolled ‘overflow incontinence’ with any increase in intraabdominal pressure. At this stage, the force of the urinary stream is significantly reduced and much more time is required to initiate and complete voiding. Digital rectal examination and prostate-specific antigen (PSA) are conducted to determine hyperplasia. PSA density may be helpful in differentiating benign prostatic hyperplasia from prostatic cancer. PSA density is calculated by dividing PSA serum levels by the volume of prostate tissue, which is determined by transrectal ultrasound. Treatment depends on the severity of symptoms, including postvoid (after urination) residual urine, pressure-flow study, creatinine and blood nitrogen levels, and subjective symptoms. Alpha adrenergic blockers and 5-a-reductase inhibitors may be used as combination therapy to reduce prostate spasm and inhibit the conversion of testosterone to dihydrotestosterone thereby eliminating the androgen effect on the prostate gland. Candidates for surgical intervention include those with postvoid residual urine, severe symptoms or complications or those who fail to improve with medical therapy.
Prostatitis
Prostatitis is an inflammation of the prostate. Some degree of prostatic inflammation is present in 4–36% of the male population, increasing to 50% in older men. Inflammation is usually limited to a few of the gland’s excretory ducts. Prostatitis is characterised as one of the following: • acute bacterial prostatitis • chronic bacterial prostatitis • non-bacterial prostatitis.
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B A
C
FIGURE 32.27
Benign prostatic hyperplasia. A The condition becomes a problem as prostatic tissue compresses the urethra (arrow indicates prostate). B Gross appearance of hyperplastic prostatic tissue obstructing the prostatic urethra, forming ‘lobes’. C A view of the bladder obtained during an intravenous pyelogram shows a smooth defect impressing on the inferior aspect of the bladder (arrows) caused by a benign enlargement of the prostate (P).
BACTERIAL PROSTATITIS
Acute bacterial prostatitis is an ascending infection of the urinary tract that tends to occur in men between the ages of 30 and 50 years but is also associated with benign prostatic hyperplasia in older men. Infection stimulates an inflammatory response in which the prostate becomes enlarged, tender, firm or boggy. The onset of prostatitis may be acute and unrelated to previous illnesses or it may follow catheterisation or cystoscopy. Clinical manifestations of acute bacterial prostatitis are those of urinary tract infection or pyelonephritis (see Chapter 30). Sudden onset of malaise, low back and perineal pain, high fever (up to 40°C) and chills is common, as are dysuria, an inability to empty the bladder, nocturia and urinary retention. The individual may also have symptoms of lower urinary tract obstruction, such as a slow, small, ‘narrowed’ urinary stream, which may be a medical emergency. Acute inflammatory prostatic oedema can
compress the urethra, causing urinary obstruction. Prostatic pain may occur, especially when the individual is in an upright position, because the pelvic floor muscles tighten with standing and compression of the prostate gland occurs. Some individuals experience low back pain, painful ejaculation and rectal or perineal pain. Infections causing prostatitis are treated with long-term, broad-spectrum antibiotic therapy (up to 6 weeks). Chronic bacterial prostatitis is characterised by recurrent urinary tract symptoms and persistence of pathogenic bacteria (usually gram-negative) in urine or prostatic fluid. This form of prostatitis is the most common recurrent urinary tract infection in men. Symptoms may be similar to those of an acute bladder infection and the prostate may be only slightly enlarged or boggy, but may be fibrotic because repeated infections can cause it to be firm and irregular in shape. A pelvic x-ray or transurethral ultrasound may show prostatic calculi (stones formed in
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the body; see Fig. 32.28), which can harbour pathogens making it difficult to eradicate infection from the urinary tract. Permanent treatment requires surgical removal of the stones through transurethral prostatectomy, which may not be a viable option for young men. More common symptoms are tempered with chronic suppressive therapy. Comfort measures include NSAID therapy and the liberal use of sitz baths or icepacks. NON-BACTERIAL PROSTATITIS
Non-bacterial prostatitis is the most common prostatitis syndrome and is essentially prostatic inflammation without evidence of bacterial infection. Symptoms tend to be milder but are persistent and annoying. There are several hypothesised causes of non-bacterial prostatitis such as reflux of sterile urine into the ejaculatory ducts, allergies, autoimmune diseases and aetiologies of the bladder neck.72 Quinolones are the treatment of choice, because of their bioavailability and penetration into prostatic tissue. Drug therapy lasts for a minimum of 3–4 weeks. If symptoms do not subside, other infectious microorganisms are considered and treated accordingly.
FIGURE 32.28
Prostatic calcification. Calcification situated immediately behind the pubis (arrows) in a male patient usually represents the sequelae of previous prostatitis.
Symptoms include pain or a dull ache that is continuous or spasmodic in the suprapubic, infrapubic, scrotal, penile or inguinal area, pain on ejaculation and urinary symptoms, such as frequency of urination. The prostate gland generally feels normal on palpation. Non-bacterial prostatitis is a diagnosis by exclusion of bacterial presence. There is no generally accepted treatment for non-bacterial prostatitis. Hot sitz baths, bed rest, a-blockers, anticholinergics and anti-inflammatory drugs can relieve symptoms.
Sexual dysfunction
In males, the normal sexual response involves erection, emission and ejaculation. Sexual dysfunction is the impairment of any or all of these processes and can be caused by various physiological, psychological and emotional factors. Until the late 1970s, most cases of male sexual dysfunction were considered psychogenic — that is, the origin was thought to be in the individual’s mind. Now there is evidence that some 90% of cases involve factors such as: • vascular, endocrine and neurological disorders • chronic disease, including renal failure and diabetes mellitus • penile diseases and penile trauma • iatrogenic factors (inadvertent adverse effects resulting from medical treatment or advice), such as surgery and pharmacological therapies.73 Sexual dysfunction can have a specific physiological cause, can be associated with many chronic diseases and their treatment, or may be related to low energy levels, stress or depression. For example, vascular disease may cause impotence and endocrine disorders or conditions that cause decreased testosterone levels or testicular atrophy can diminish sexual functioning or libido. In addition, neurological disorders and spinal cord injuries can interfere with sympathetic, parasympathetic and central nervous system mechanisms required for erection, emission and ejaculation. Drug-induced sexual dysfunction manifests as decreased desire, decreased erectile ability or decreased ejaculatory ability. Alcohol and other central nervous system depressants, antihypertensives, antidepressants, antihistamines and hormonal preparations are commonly used drugs that affect sexual functioning. Other pharmacological agents may diminish the quality or quantity of sperm. Evaluation of sexual dysfunction includes a thorough history and physical examination. Psychological evaluation is indicated for younger men with a sudden onset of sexual dysfunction or men of any age who can achieve but not maintain an erection. If no physiological cause is found and the condition does not improve with psychotherapy, the man is referred for further investigation of organic causes. Treatments for organic sexual dysfunction include both medical and surgical approaches. The drug Viagra (sildenafil) has created much enthusiasm for its ability to assist with maintaining an erection. For a small
CHAPTER 32 Alterations of the reproductive systems across the life span
percentage of men (1%), however, this improvement in sexual function is accompanied by myocardial infarction and sudden death. Non-surgical approaches include correction of underlying disorders, particularly drug-induced dysfunction and endocrinopathy-related dysfunction (such as reduced testosterone associated with chronic renal failure). Vasodilators and cessation of smoking can benefit individuals with erectile dysfunction arising from vascular origins. Surgical approaches include penile implants, penile revascularisation and correction of other anatomical defects contributing to sexual dysfunction. F O CUS O N L E A R N IN G
1 Describe the symptoms of benign prostatic hyperplasia and identify the lifestyle modifications that a sufferer of this condition may need to make. 2 Differentiate between acute bacterial prostatitis, chronic bacterial prostatitis and non-bacterial prostatitis.
or caused by systemic disorders, drugs or neoplasms. It is usually caused by an imbalance of the oestrogen/testosterone ratio. The normal oestrogen/testosterone ratio can be altered in one of two ways: 1 oestrogen levels may be excessively high, although testosterone levels are normal — this is the case in drug-induced and tumour-induced hyperoestrogenism 2 testosterone levels may be extremely low, although oestrogen levels are normal, as is the case in hypergonadism. Gynaecomastia can also be caused by increased or decreased sensitivity of breast tissue to hormone levels. Breast tissue may have increased responsiveness to oestrogen or decreased responsiveness to androgen. Alterations of responsiveness may cause many cases of idiopathic gynaecomastia. The diagnosis of gynaecomastia is based on physical examination. Identification and treatment of the cause are likely to be followed by resolution of the gynaecomastia. The man should be taught to perform breast self-examination and is re-examined at 6- and 12-month intervals if the gynaecomastia persists.
Disorders of the breast
Fertility
Disorders of the female breast
Control of fertility
Galactorrhoea is the production of breast milk at inappropriate times (namely, not during or post-pregnancy). The excreted fluid can be milky in appearance, and range in colour from white to yellow or green. It is usually bilateral. When associated with amenorrhoea, the usual cause is hyperprolactinaemia. Prolactin is a pituitary hormone that initiates breast milk production after the withdrawal of placental hormones following birth (refer to Chapter 10).74 Galactorrhoea occurs mainly in females, but can also occur in men and may involve one or both breasts. It is not associated with breast cancer.60 Galactorrhoea is not a breast disorder but, rather, a manifestation of pathophysiological processes elsewhere in the body. These processes are chiefly hormone imbalances caused by hypothalamic–pituitary disturbances, pituitary tumours, renal insufficiency or neurological damage. Causes include drugs, oestrogen (e.g. in oral contraceptives) and manipulation of the nipples. Diagnosis is made on physical examination, review of prolactin levels, and MRI for the presence of a pituitary tumour, while breast pathology should be excluded. Treatment depends on the cause.
Disorders of the male breast
Gynaecomastia is the overdevelopment of breast tissue in a male and accounts for approximately 85% of all masses that develop in the male breast. Incidence is greatest among adolescents and men older than 50 years. Gynaecomastia results from hormonal alterations, which may be idiopathic
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A range of techniques are available to prevent conception. These techniques interfere with the ability of sperm and ova to meet and implant in the uterus, and may be structural or hormonal barriers. Some options are more reliable than others.
Surgical sterilisation
Sterilisation procedures involve surgical interruption of the reproductive ducts in either the male or the female. Overall, they should be considered as permanent, as they cannot be reliably reversed. Vasectomy in males is the removal of part of the ductus deferens, which was previously known as the vas deferens — hence the term vasectomy refers to the severing of this duct. This procedure is performed under local anaesthetic as an outpatient. The ejaculate is free of sperm after 2–3 months; otherwise, sexual function remains unchanged. There may be adverse effects, such as leakage from the cut end of the ductus deferens, which may cause chronic inflammation and tenderness; and leakage of sperm into the blood, which may elicit an (auto-)immune response resulting in inflammation and a danger of destruction of the spermatocytes. Tubal ligation in females is essentially interruption of the uterine tubes by ligation (tying), electrocoagulation or surgical section (cutting). It is usually performed laparoscopically under general anaesthetic. This operation prevents sperm from reaching the oocyte and the oocyte from travelling down the uterine tubes into the uterus. The adverse effects are associated with surgical trauma and anaesthetics.
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The Essure method of tubal interruption is an alternative permanent sterilisation technique. A catheter-like instrument is guided through the cervix and uterus into the uterine tubes. A microinsert (a soft, spring-like coil made of polyester fibres and nickel titanium alloy) is placed in each uterine tube. The microinsert has an inner coil and an outer coil and polyethylene fibres in a tightly wound configuration. Once in place, the outer coil expands to anchor the microinsert in the uterine tube. Over a period of approximately 3 months, tissue grows into the coil to permanently block the uterine tube and hence the oocyte can no longer meet the sperm. An x-ray is taken 3 months after the procedure to assess whether the blockage is complete. The first clinical trial of this technique in Australia showed the method to be safe and highly acceptable to women with 100% efficacy.75 A 5-year follow up involving 1200 women did result in three pregnancies giving an overall success rate of 99.75%.76 This is a safer method than tubal ligation, as it does not involve laparoscopic surgery.
Barrier methods
Barrier methods of contraception are designed to prevent sperm from reaching the oocyte and are reliable only if properly used. The condom needs to be put on the penis prior to physical contact between the penis and vagina; its reliability can be increased by concurrent use of a spermicide. The condom has the added advantage of providing protection for both partners against sexually transmitted infections. The cervical cap fits around the cervix and is held there by suction. Similarly, the diaphragm has a sprung margin that allows it to block the top of the vagina as well as the cervix itself. Both the cap and diaphragm can be inserted a considerable time before intercourse and must be left in place for 6 hours after intercourse as the sperm will remain in the vagina for some time. The cap or diaphragm should be used only in combination with a spermicide, since they are unreliable on their own. Spermicides contain a chemical in either a cream or a foam that will kill sperm. The spermicide must be applied shortly before intercourse and does not provide reliable contraception on its own. The disadvantages of the cap or diaphragm plus spermicide include: they need to be in place before sexual intercourse and so forethought is required; the cap and diaphragm must be carefully fitted to prevent sperm accessing the uterus; and spermicides can cause irritation of the vagina and cervix.
Hormonal methods
Oral contraceptive medications are referred to as the contraceptive pill (or ‘the pill’). Combined oral contraceptives contain both oestrogen and progesterone. These hormones suppress ovulation by feeding back on the hypothalamus and anterior pituitary to inhibit the secretion of FSH and LH. Thus follicles do not mature (lack of FSH) and oocytes are not released (lack of LH). The hormones in the combined pill thus mimic the actions of the corpus luteum in the luteal phase of a normal cycle or of the placenta in pregnancy.
Typically, the pill is taken for 21 days, during which FSH and LH are suppressed and follicle development does not occur; however, the endometrium develops and is maintained by the steroids in the pill. For the next 7 days, no active pills are taken and the endometrium breaks down in a ‘simulation’ of normal menstruation. Progesterone alone has a number of contraceptive effects: it inhibits ovulation in some (but not all) cycles; it inhibits the development of the endometrium under the influence of oestrogen (as seen in the proliferative phase of the menstrual cycle); and, most importantly, it causes thickening of the cervical mucus, making it impenetrable by sperm. The minipill contains progesterone only. The contraceptive action on cervical mucus lasts only 22–26 hours, so the pill must be taken at the same time each day (successive pills no more than 24 hours apart). Other means of delivery of progesterone-only preparations are by implantation, such as Norplant capsules or Depot injection (e.g. Depo-Provera). Norplant implants may last for 5 years, while Depo-Provera lasts for 3 months. The most significant side effects of oral contraceptives are an increased risk of blood clotting and hypertension in women who smoke or have a history of cardiovascular disease. The risk was higher in older forms of combined contraceptives, which incorporated much higher hormone concentrations than are currently used. Irregular bleeding is often associated with the use of progesterone-only preparations. The association of steroid contraceptives with cancers of the breast and reproductive system is controversial. Major life-threatening side effects are rare. Contraceptives for men containing testosterone are in the human trial stage. Testosterone feeds back on the hypothalamus and anterior pituitary to inhibit the secretion of FSH and LH. Without FSH, sustentacular cells cannot carry out their crucial functions in supporting spermatogenesis; thus sperm concentrations in semen fall below those required for fertility. This method of contraception appears effective, with minor side effects of weight gain and acne; long-term effects on the prostate gland are under investigation.
Other methods of contraception
Coitus interruptus (withdrawal) requires the penis to be withdrawn prior to ejaculation. If practised diligently, there is some contraceptive effect. However, often the penis is either not withdrawn at all or only partially withdrawn, and this practice will almost inevitably lead to a high failure rate. In the rhythm method, the couple monitors the menstrual cycle over a few months to ensure a good record of the cycle. They then pick the point of the cycle where they are relatively certain that they will have little chance of fertilising an oocyte. This could be at least 6 days before ovulation (sperm can survive for up to 5 days inside the female body) or 2 days post-ovulation (when the oocyte is no longer capable of being fertilised). The problem with this method of contraception is that few couples really understand the
CHAPTER 32 Alterations of the reproductive systems across the life span
menstrual cycle well enough to successfully chart the progress. Furthermore, most women do not have an absolutely regular cycle and, since timing is crucial, the failure rate is high. The intrauterine device (IUD) acts as foreign body in the uterus to produce a low-grade, chronic inflammatory response. In this state, the uterus inhibits sperm transport and prevents successful implantation of a fertilised ova. Modern IUDs are now made of plastic rather than copper. Adverse effects of IUDs include cramping and bleeding and increased risk of infection. If pregnancy occurs, there is an increased risk that it may be ectopic. The ‘morning after’ pill interferes with transport of the fertilised ova and with implantation. A combined pill is given within several hours of unprotected intercourse. Mifepristone (also known as RU486) is a progesterone antagonist that blocks progesterone receptors in the uterus. This progesterone-blocking action in the endometrium could prevent implantation; however, the more significant use of this drug is to produce early abortion. Administration of the drug within 2 months of conception causes erosion of the endometrium and increased contraction of the myometrium. The administration of RU486 is followed after 48 hours by administration of prostaglandin, to complete the process of expulsion of the embryo.
The failure of contraception
Failure rates for contraception are shown in Table 32.6. Several of the techniques in Table 32.6 are quite reliable, with sterilisation procedures being the most successful. However, sterilisation procedures are often avoided due to the difficulty in reversing them at a later stage. Oral contraceptive pills and implants based on hormones are widely used, as they are effective and can be ceased relatively easily if conception is desired. The only completely reliable method of preventing conception is abstinence (avoiding sexual intercourse). If no method is used at all, the failure rate is 80–90% in women under the age 35 and 40–50% in women over the age of 35.
Impaired fertility
Infertility affects approximately 15% of all couples and is defined as the inability to conceive after 1 year of unprotected intercourse. Fertility can be impaired by factors in either the man or the woman, or both partners. Male factors include diminished quality and production of sperm (see Table 32.7). Causes include infections or inflammation, endocrine or hormonal disorders, immunological problems in which men produce antibodies to their own sperm, and environmental or lifestyle factors. Female infertility factors are associated with malfunctions of the uterine tubes, the ovaries or the reproductive hormones. Adhesions from pelvic infection may cause blockage of one or both uterine tubes, preventing the sperm from accessing the ovum. Hormonal or local factors may disrupt ovulation or prevent a fertilised ova from implanting. Endometriosis may also contribute to infertility.
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TABLE 32.6 Failure rates for contraception (number of pregnancies per 100 women per year) TECHNIQUE
PRINCIPLE
FAILURE RATE
Sterilisation
Male: vasectomy
Male: 0–0.2%
Female: tubal ligation
Female: 0–0.5%
Condom
Physical barrier, worn on the penis
Up to 15%
Cap or diaphragm
Physical barrier, inserted into the vagina
Up to 15%
Spermicide
Cream or foam, kills sperm
Up to 25%
Oral contraceptive pill
Hormonal control, main effect is by preventing ovulation
Oestrogen and progesterone: up to 3% Progesterone only: up to 4%
Progesterone implant or injection
Hormonal control
Up to 1%
Intrauterine device
Inserted into the uterus (by a doctor)
Up to 5%
Withdrawal
Removal of the penis from the vagina prior to ejaculation
Up to 20%
Rhythm method
Avoiding sexual intercourse around the day of ovulation
Up to 25%
Having an understanding of the normal structure and function of the male and female reproductive systems will help you to grasp the reasons for impaired fertility. Male and female factors are equally responsible, with infertility in a couple being due to the male in 30% of cases, and due to the female in 30% of cases; the remaining time is either due to both partners, or the cause being unknown.77 A number of diagnostic procedures are required in the routine investigation of the infertile couple. Initial procedures include semen analysis and determination of ovulation. Treatment is aimed towards correcting problems identified during diagnosis. Each couple is different and the specific cause of the infertility must be assessed by health professionals. However, altering lifestyle choices such as giving up smoking (which negatively impacts on spermatogenesis) or reducing kilojoule intake and exercising more to reduce weight (obesity negatively impacts on spermatogenesis and oogenesis) could have significant impact. Some couples benefit from education about the optimum timing of intercourse to facilitate fertilisation. In addition, immediate treatment of a sexually transmitted infection will help prevent scarring and the formation of adhesions in the reproductive tract of either the man or
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TABLE 32.7 Known causes of male infertility Sperm production problems
Chromosomal or genetic causes Undescended testes (failure of the testes to descend at birth) Infections (breakdown of the blood– testis barrier) Torsion (twisting of the testis in the scrotum) Heat Varicocele Drugs and chemicals Radiation damage (destruction/ damage to primary spermatocytes)
Blockage of sperm transport
Infections (inflammation/adhesions in sperm pathway) Prostate-related problems (sperm must pass through the prostate) Absence of ductus deferens
Sperm antibodies
Vasectomy (leakage of sperm from the cut end) Injury or infection in the epididymis (breakdown of the blood–testis barrier)
Sexual problems (erection and ejaculation problems)
Retrograde and premature ejaculation Failure of ejaculation Infrequent intercourse Spinal cord injury (damage to spinal nerves controlling ejaculation) Prostate surgery Damage to nerves Some medicines
Hormonal problems
Pituitary tumours Congenital lack of LH/FSH (pituitary problem from birth) Anabolic (androgenic) steroid abuse
the woman and so reduce the chances of impaired fertility developing as a consequence of the infection.
Assisted reproductive technologies Assisted reproductive technology is a general term referring to methods used to achieve pregnancy by artificial or partially artificial means. Assisted reproductive technologies are increasing in both number and success as we understand more about the processes of fertilisation and implantation. Knowledge of hormonal control of the ovarian and menstrual cycles and spermatogenesis, combined with
understanding of the anatomical aspects of both men and women (see Chapter 31), is leading to the development of new technologies and the refinement of existing technologies. If the main cause of infertility is related to ovulation, the process can be artificially stimulated by the administration of hormones related to the gonodotrophins. This stimulates the development of ovarian follicles (sometimes multiple) and a mid-cycle injection of β-human chorionic gonadotrophin (β-hCG) results in ovulation. Normal intercourse can then result in fertilisation. If sperm quality is poor, prepared sperm from the partner or a donor may be introduced into the uterus and fertilisation in vivo may occur. Manipulation of the ovarian cycle may result in ovarian hyperstimulation syndrome (OHSS) in 0.5% of women which, if severe, can be life threatening due to endocrine disturbance, fluid shifts and thromboembolic disease. A common treatment for infertility involves the use of fertility medications (based on the gonadotrophins) to stimulate the female’s ovaries to develop multiple eggs. This is followed by an injection of hCG (human chorionic gonadotrophin) to release the oocytes and then transvaginal aspiration to collect them (termed transvaginal ovum retrieval). The male is required to donate sperm, the quality of which is assessed by microscopic examination of both the quantity and the quality of sperm produced. There are a variety of abnormal morphologies (shapes) of sperm and this could be the cause of infertility in the male. If this is the case, healthy individual sperm can be isolated and injected into the oocyte (termed intracytoplasmic sperm injection). If the male is not producing enough sperm, which could be the cause of the infertility, intracytoplasmic sperm injection can be performed or the sperm can be concentrated and IVF carried out. The zygote (the result of successful fertilisation) is incubated until the blastocyst develops. Before transferring the blastocyst to the female, cells may be taken for pre-implantation genetic diagnosis if there is an identified risk. Pre-implantation genetic diagnosis is currently used for two principal reasons: • to screen for aneuploidy (an abnormal chromosome number) in the gametes of those couples who have experienced recurrent failure using assisted reproductive technologies or recurrent miscarriage, or who are of advanced age, are known carriers of chromosomal rearrangements or have a previous history of fetal aneuploidy • to test for single gene disorders (X-linked, autosomal dominant or autosomal recessive; see Chapter 38) in those couples with a family history or who have previously had an affected child. Other uses of intracytoplasmic sperm injection — such as sex selection and tissue-matching for bone marrow donation — must be approved by the relevant authority. A couple can use their own gametes, but third-party conception is possible with donor procedures (donated
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oocytes, sperm or embryos) or surrogate arrangements. In New Zealand and Victoria, children conceived as a result of such procedures have the right to be told the identity of the donor (biological) parents when they turn 18 years of age. Gametes and embryos can be stored (frozen) but storage is regulated under local jurisdictions. Time limits are generally imposed (5 years for embryos, 10 years for gametes) to ensure that those who produce the gametes and embryos retain the responsibility for decision making as to the fate of those gametes and embryos. Although scientific progress has led to a huge improvement in the success of assisted reproductive technologies, the science is not the only issue that society has to deal with in this field. This success has opened up the possibilities of surrogacy, genetic screening and single (younger or older) individuals having offspring, and it challenges the current cultural and ethical values of many in society.
F O CUS O N L E A R N IN G
1 List the main causes of female infertility. 2 Identify the reasons for suboptimal sperm production. 3 Describe the hormonal stimulation of ovulation during fertility treatment. Discuss the side effects and their causes.
Major sexually transmitted infections Infectious diseases of the reproductive system are often transmitted through sexual activity. Over 70 000 cases of sexually transmitted infections are reported each year in Australia and approximately78 10 000 cases are reported in New Zealand — including human immunodeficiency virus (HIV), the virus that can cause acquired immunodeficiency syndrome (AIDS). However, reporting of sexually transmitted infections is not mandatory in Australia or New Zealand, so the actual number of cases may be higher. In fact, the number may be even higher still as many people who have had unprotected sex have not been tested for infection. A wide range of organisms, such as bacteria, viruses, fungi and protozoa, may cause sexually transmitted infections, the effects of which range from asymptomatic to lethal. The pathogens of many sexually transmitted infections do not survive well outside their hosts, thus intimate contact is usually required for infection to occur. Fomites such as toilet seats are not likely sources of infection! The current increase in the severity and incidence of sexually transmitted infections can be attributed to demographic, lifestyle and behavioural factors. Indulgence in high-risk sexual behaviours and poor health habits, such
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as failure to use a condom, non-monogamous relationships, drug use and douching, increase an individual’s risk of exposure or the severity of infection if exposed. Many infected individuals do not seek treatment because symptoms are absent, minor or transient. Also, a more liberal acceptance of alternate sexual behaviours such as bisexuality and multiple partners may contribute to an increase in the number of lifetime sexual partners and the increased exposure to sexually transmitted infections. Adolescents tend to be at highest risk for sexually transmitted infections which may be related to lack of targeted education, risk-taking behaviours or experimentation of sexuality. The following points should be appreciated. • Infections may be transmitted by means other than sexual activity, blood–blood contact being the most important (e.g. HIV infection). • Sexual contact with sites outside the reproductive system — such as the mouth or anus — may cause infection and disease of those areas (e.g. pharyngeal or rectal gonorrhoea). • Sexually transmitted infections can affect organs and systems in addition to the reproductive system — for example, syphilis may affect the nervous system and HIV affects the immune system. • Long-term sequelae of untreated or undertreated sexually transmitted infections may be disastrous and can impact a person’s physical, emotional and financial wellbeing. • Apart from considerations of sexual behaviour, control of sexually transmitted infections in the community is difficult because many infections may be asymptomatic for extended periods and so may be spread ‘silently’ by carriers; and different infections may occur together in the one host, with one infection facilitating transmission of another — for example, infections that cause open sores provide portals of entry for HIV. • Fortunately, barrier methods of contraception, especially the careful use of condoms, are effective in preventing the spread of sexually transmitted infections. We now look at some of the more common sexually transmitted infections — see also Table 32.8 and the images that follow the table.
Gonorrhoea
Gonorrhoea is caused by the gram-negative coccus, Neisseria gonorrhoeae (gonococcus). The bacteria attach by pili to epithelial cells in the mucous membrane of the urethra (males) or cervix (females), multiply and ascend into deeper tissue layers. In this process they resist, by means of their pili, the tendency of urine or vaginal secretions to wash them away and defend themselves against immunoglobulin A (IgA) of the mucosal surfaces by producing an enzyme (IgA protease) that breaks down this antibody. Tissue damage and inflammation ensue and symptoms usually develop within a few days of infection.
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TABLE 32.8 Major sexually transmitted infections SOURCE OF INFECTION
EPIDEMIOLOGY/CLINICAL MANIFESTATIONS
EVALUATION AND TREATMENT
Bacterial vaginosis (Haemophilus, Corynebacterium, Gardnerella vaginalis/Mycoplasma hominis)
Occurs almost exclusively in sexually active women, but does not infect men
Diagnosed from a specimen of vaginal secretions (wet mount)
Risk factors include multiple or new male partners
Week-long treatment with oral or vaginal antibiotics
Chancroid (Haemophilus ducreyi)
Women are generally asymptomatic, whereas men develop inflamed, painful genital ulcers
Definitive diagnosis is from cultured specimens
Secondary infections can occur
Treat with antibiotics
Can cause ectopic pregnancy; the leading cause of blindness worldwide; often asymptomatic
Diagnosed by amplified DNA or fluorescent monoclonal antibody screening of discharge; urine assay
Bacteria
Chlamydial infections (Chlamydia trachomatis)
Manifestations include discharge (sometimes ‘fishy’ odour); males generally asymptomatic; may predispose women to other sexually transmitted infections or preterm labour
Acute course is fairly self-limited followed by chronic, low-grade, persistent infections over years; infections in men can cause urethritis and epididymitis; Chlamydia trachomatis causes acute urethral syndrome (dysuria, polyuria, pus in urine) in young women; newborns can be infected; perinatal exposure involves the eye, oropharynx, urogenital tract and rectum Gonorrhoea (Neisseria gonorrhoeae)
Adolescents aged 15–19 years at high risk; transmitted by oral, anal or vaginal intercourse; mother-to-child transmission during vaginal delivery Manifestations include urethral or anorectal infections; vaginal discharge; bleeding or spotting and heavy menses; women may be asymptomatic
Treatment of sex partner is not recommended
Treatment of both sexual partners with antibiotics
Gram-stained slides; DNA screening or culture of endocervical, pharyngeal and anal secretions; concomitant screening for Chlamydia Treat both sexual partners with antibiotics
Lymphogranuloma Often confused with syphilis, herpes or chancroid venereum (LGV) (Chlamydia Begins as skin lesion, spreads to lymphatic tissue; trachomatis) appears as multivesicular ulcer on penis or scrotum in men and appears on vaginal wall, cervix or labia in women; anorectal lesions, from anal intercourse, can appear in both men and women
Diagnosed through tissue culture and monoclonal antibody tests
Syphilis (Treponema pallidum)
Dark-field or fluorescent antibody examination of fluid from syphilitic chancre
Hard chancre develops in primary stage; systemic symptoms include low-grade fever, malaise, sore throat, hoarseness, anorexia, headache, joint pain, skin rashes; latent (tertiary) stages usually asymptomatic
Treated with antibiotics
Treatment includes penicillin injections Neurosyphilis and life-threatening hypersensitivities can for primary or secondary infections develop without treatment Can be transmitted to fetus during pregnancy
Viruses Condylomata acuminata (human papillomavirus (HPV))
Risk factors include multiple sexual partners, early onset of sexual activity (16–25 years of age); HPV is associated with cervical and vulvar cancer in females and anorectal and squamous cell carcinoma of the penis in men; genital warts contagious; infants can be infected during delivery; HPV can be asymptomatic Warts are soft, skin-coloured, whitish pink to reddish brown; may occur singly or in clusters
Diagnosis based on clinical manifestations, Pap smears and HPV DNA tests Treated with topical acids, cryosurgery or immune system modifiers; cervical and extensive vaginal lesions treated with chemotherapy agents or surgical excision Treatment is not curative
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TABLE 32.8 Major sexually transmitted infections—cont’d SOURCE OF INFECTION
EPIDEMIOLOGY/CLINICAL MANIFESTATIONS
EVALUATION AND TREATMENT
Genital herpes (type 1 (HSV1) or type 2 (HSV2))
Neonatal infections can occur in utero, intrapartum and postpartum; virus undergoes local replication in dermis and epidermis leading to vesicles; can remain in latent stage until reactivated; cause of reactivation unknown but may be related to stress, sun exposure, hormonal fluctuations or illness
Diagnosis based on clinical manifestations, tissue culture or serological antibody testing
Commonly transmitted sexually, causes ‘crabs’; most common in single persons aged 15–25 years
Definitive diagnosis by examination
No curative treatment; oral acyclovir, famciclovir, or valacyclovir (antiviral agents) may be used; intravenous acyclovir reserved for the severely immunocompromised
Parasites Pediculosis pubis (Phthirus pubis (crab louse))
Ranges from mild itching to severe, intolerable itching Scabies (Sarcoptes scabiei)
First human disease with known cause; worldwide distribution; transmitted by close skin-to-skin contact, typically occurring within families or between sexual partners
Treated with lotion, cream or shampoo Diagnosed from clinical manifestations, microscopic identification Treated with topical cream or lotion
Predominant manifestation is intense itching Trichomoniasis (Trichomonas vaginalis)
Common cause of lower genital tract infection; found in both partners; urethra most common site of infection in men, primarily involves vagina in women
Definitive diagnosis through microscopic confirmation of trichomonads in vaginal secretions
Manifestations range from none to severe, including pain on intercourse, dysuria and spotting; most men remain asymptomatic
Treat with antibiotics for both sexual partners
Bacterial sources GONOCOCCCAL INFECTIONS
Symptomatic gonococcal urethritis
BACTERIAL VAGINOSIS
Endocervical gonorrhoea
Vaginal examination showing mild bacterial vaginosis
SYPHILIS
Erythematous penile plaques of secondary syphilis
Multiple primary syphilitic chancres of the labia and perineum
Popular secondary syphilis
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CHLAMYDIAL INFECTIONS
Beefy red mucosa in chlamydial infection
Chlamydial epididymitis
Viral sources GENITAL HERPES
Early lesions of primary genital herpes
Primary vulvar herpes
Generalised herpes simplex in a patient with atopic dermatitis
HUMAN PAPILLOMAVIRUS (HPV)
Human papillomavirus infection of the cervix Exophytic (outward-growing) condyloma, subclinical human papillomavirus infection and high-grade cervical intraephithelial neoplasia
In females, infection is often mild or asymptomatic. In symptomatic infection, vaginal discharge occurs and pain on urination (dysuria) or intercourse (dyspareunia) is common. Even when infection appears to be asymptomatic, inflammation of the uterine tubes may occur. Inflammation of the tubes (salpingitis) and other pelvic sites such as the ovaries is termed pelvic inflammatory disease (PID). Damage to the uterine tubes resulting from such infection can lead to infertility or ectopic pregnancy. Other pathogens, notably Chlamydia trachomatis, can also cause pelvic inflammatory disease. In males, infection may be mild or asymptomatic, but it usually causes urethral discharge with dysuria. The diagnosis of gonorrhoea is made from culture of appropriate specimens (e.g. discharge) and microscopic
identification of intracellular gram-negative cocci. People with gonorrhoea may be suffering concurrently from other sexually transmitted infections. Infection can be treated with antibiotics. Gonorrhoea can be transmitted from a mother to her baby (congenital infection). This occurs during passage of the baby through the birth canal and usually results in a characteristic eye infection (ophthalmic gonorrhoea).
Syphilis
Syphilis is caused by the spirochaete (spiral-shaped bacterium) Treponema pallidum. It is transmitted from lesions in the skin or mucous membranes of infected people
CHAPTER 32 Alterations of the reproductive systems across the life span
to mucous membranes or small skin lesions in the recipient. This pathogen grows more slowly than Neisseria gonorrhoeae and its incubation period is longer (average 3 weeks). If untreated, the disease typically follows a course of three stages (but this is not seen in all cases): 1 Primary syphilis: 2–10 weeks postinfection, a lesion develops at the site of infection (penis or cervix) and develops into a painless hard chancre. These lesions contain large numbers of bacteria and are highly infectious, and are a neutrophil response (and later lymphocytes and macrophages) to replicating bacterial cells at the site of entry. Chancres appear to heal spontaneously within a few weeks. In 50% of cases, the disease progresses to secondary syphilis. 2 Secondary syphilis: some weeks later, the bacteria have spread from the site of entry through local lymph nodes to the blood. A skin rash, which is itself infectious, may appear anywhere on the body, accompanied by malaise and mild fever. In addition to the skin, many other organs may be involved, such as the liver, joints or muscles. These symptoms, like those of primary syphilis, disappear spontaneously. 3 Tertiary syphilis: after an asymptomatic period of years, renewed growth of bacteria and the development of cell-mediated hypersensitivity cause characteristic lesions in a number of organs. These lesions are soft granulomas termed gummas. Invasion and tissue damage of the aorta and nervous system are particularly significant. Damage to the thoracic section of the aorta may lead to aneurysm and rupture. Damage to the nervous system may cause dementia, paresis (muscle weakness or paralysis) or tabes dorsalis (poor muscle coordination and unstable gait). Many aspects of the pathogenesis of syphilis remain unclear. It is not known, for example, how lesions develop or resolve or how host defence responses give rise to the symptoms of tertiary syphilis. Syphilis is diagnosed by microscopic identification of Treponema pallidum from primary or secondary lesions. Special microscopic techniques are required, as the organism is too thin to be seen in a standard gram-stained preparation. If lesions are not present, serological testing of blood can be performed. Infection is treated with antibiotics. Syphilis can be transmitted from a mother to her baby through the placenta, and it can cause malformation of the developing baby.
Chlamydia trachomatis
Chlamydia trachomatis is an unusual, small bacterium that replicates only within host cells. It has only recently been shown to cause urethritis. Some varieties cause trachoma, an eye infection that can lead to blindness, while others cause genital infections. Chlamydia trachomatis is extremely common — perhaps the most common of all sexually transmitted infections — and many of the resulting infections are asymptomatic. Infection in males may cause
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urethritis. In females, symptomatic infection may be evident as cervicitis (inflammation of the cervix) or as salpingitis and pelvic inflammatory disease. These symptoms are similar to those of other sexually transmitted infections such as those caused by Neisseria gonorrhoeae (which may indeed be concurrent with the chlamydial infection). Therefore, laboratory examination of specimens is required for diagnosis. Chlamydial infection can be treated with antibiotics. Chlamydia trachomatis can infect the baby during birth, causing eye disease and sometimes pneumonia.
Herpes simplex virus
There are two major types of herpes simplex virus (HSV): • type 1 (HSV1) predominates around the mouth, causing cold sores • type 2 (HSV2) causes genital infection. HSV2 is transmitted by contact with mucosal surfaces or through secretion of infected people. It is able to invade intact mucous surfaces and minimally damaged skin. Infection may in many cases be asymptomatic. Symptomatic infection is characterised by the development of small vesicles filled with clear fluid on the genital or anal region and surrounded by an area of inflammation. The vesicles break down, leaving painful ulcers; while these lesions heal, the virus itself travels up the local sensory nerve to the sensory (dorsal) root ganglion. There it may persist for life, ‘hidden’ from the body’s defences. At times it may reactivate, travel back down the nerve and produce new lesions. The frequency of such recurrent attacks varies greatly. Carriers of the virus are infectious when lesions are present but may also be infectious when asymptomatic. HSV2 infection is diagnosed when the virus can be cultured from vesicle fluid or other samples. There is no cure for HSV infection although acute outbreaks can be managed with the use of antiviral drugs such as acyclovir. Safe sex practices are required to prevent transmission. HSV2 can be transmitted from a mother to her baby before, during or after birth. This may have severe consequences for the baby such as mental retardation, blindness or deafness or it may be fatal to the baby. For this reason, delivery by caesarean section may be recommended if lesions are present.
Human papillomavirus
Papillomaviruses cause warts of the skin or mucous membranes. Many varieties are known, of which a restricted number are regularly associated with genital infections. Genital or anal warts caused by these viruses may appear after an incubation period of months and then disappear within 1–2 years. Asymptomatic infection is also very common. The major significance of human papillomavirus (HPV) is that certain varieties are strongly associated with cervical cancer. Damage to cervical cells may occur even where warts are not present; this damage can often be
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detected in a Pap smear. The Gardasil vaccine is available to young women and men to prevent HPV infection and reduce the risk of precancerous lesions and cervical cancer. The Genital Warts Surveillance Network noted a more than 80% reduction in genital warts among Australian-born women and heterosexual men in 2015; encouragingly similar declines were seen in Aboriginal and Torres Strait Islander peoples.78 There is a direct correlation between the decline and the implementation of the vaccination program. The Gardasil™vaccine was offered to boys in New Zealand from 2017.
Human immunodeficiency virus
The human immunodeficiency virus (HIV) is the infective agent and cause of the fatal disease known as AIDS (acquired immunodeficiency syndrome). An estimated 25 313 people were living with HIV in Australia at the end of 2011.78 HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a body fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid or breast milk.79 The three main transmission routes of HIV are (1) sexual contact, (2) exposure to infected body fluids or tissues, and (3) from mother to fetus or child during the perinatal period. The virus infects the cells of the immune system that are normally responsible for fighting infections (CD4+ T lymphocytes). Over time, infection of these cells leads to their death and thus the individual’s immune system is compromised and cannot fight other infections. The individual is essentially immunocompromised and as a result acquires infections and tumours (opportunistic infections) that would not normally infect a person with a healthy immune system (see Chapter 15). A person infected with HIV passes through stages of infection. • The first stage lasts for a few weeks and is often accompanied by flu-like symptoms as the virus rapidly replicates and the body produces anti-HIV antibodies and cytotoxic lymphocytes. This process is known as seroconversion. If an HIV antibody test is done before seroconversion is complete, it may not be positive (i.e. the virus may not be detected). • The second stage can last for 10 years or more and is generally asymptomatic. HIV is not dormant during this stage, but is very active in the lymph nodes. A test is available to measure the small amount of HIV that escapes the lymph nodes. This test, which measures HIV RNA (HIV genetic material), is referred to as the viral load test and it has an important role in the treatment of HIV infection.80 • In the third stage the viral load is very high and the number of CD4+ T lymphocytes is so low (< 250 ×
109) that the individual begins to acquire opportunistic infections. As this progresses and the immune system becomes more compromised the diagnosis of AIDS is made and the individual suffers more debilitating illnesses from the opportunistic infections. AIDS is a progressive disease and current treatment regimens have had excellent patient results leading to those living with the virus having long and productive lives. It was recently reported that an infant born HIV positive in the United States received aggressive combination antiretroviral therapy and has since tested HIV negative and remains so 1 year after treatment. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection,81 and it has become much more available globally with increased funding.
Other infections
Nonspecific urethritis in males is urethral inflammation other than that caused by Neisseria gonorrhoeae or Chlamydia trachomatis. The symptoms are urethral discharge and dysuria, similar to those of gonorrhoea. Vaginosis is vaginal discharge, with or without inflammation of the vaginal mucosa (vaginitis). It may result from opportunistic infection by a variety of microbes that normally form part of the flora of this part of the body. The healthy vagina is acidic with a mixed flora of bacteria and fungi. The major component is Lactobacillus, a bacterium that ferments glycogen to produce acid. If the acidity of the vagina is reduced, minor components of the flora may overgrow to cause disease. The usual reason for such a change is disturbance of the normal flora, especially Lactobacillus, by antibiotic treatment for a problem elsewhere in the body or by immunosuppression, pregnancy or diabetes. Disease symptoms are discharge and often soreness or itchiness, and there may follow the overgrowth of bacteria such as Gardnerella vaginalis or fungi such as Candida albicans (commonly known as thrush). Diagnosis may be made by microscopic examination of the discharge. Treatment differs according to the causative agent. It may also be necessary to treat sexual partners of the affected woman.
FOCU S ON L EA RN IN G
1 Identify the factors that can contribute to increased incidences of sexually transmitted infections in populations of young people. 2 List the main causative agents of STIs. What measures can be used to control the spread of these conditions in the population?
CHAPTER 32 Alterations of the reproductive systems across the life span
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chapter SUMMARY Classification of reproductive system alterations
Disorders of the female reproductive system
• The most common causes of sexual dysfunction are: (1) growths, (2) problems associated with the endocrine system, and (3) structural and functional alterations of the reproductive system. • Growths within the reproductive system can be benign, pre-cancerous or cancerous. The growths themselves can be the problem or the effects of the growths can be the problem. • Endocrine dysfunction can result in the failure of normal menstrual and ovarian cycling in females or the failure to produce sperm in males. • Structural and functional abnormalities of the reproductive system can result from hormonal problems during development or they can arise as the result of trauma to the body or bacterial or viral infection of the reproductive tract.
• The female reproductive system can be altered by benign or malignant proliferative conditions, hormonal imbalances, infectious microorganisms, inflammation and structural abnormalities. • Non-malignant growths that remain in place and do not metastasise most often grow slowly. • Benign ovarian cysts develop from mature ovarian follicles that do not release their ova (follicular cysts) or from a corpus luteum that persists abnormally instead of degenerating (corpus luteum cysts). Cysts usually regress spontaneously. • Endometrial polyps consist of overgrowths of endometrial tissue; they often cause abnormal bleeding in the premenopausal woman. • Leiomyomas, also called uterine fibroids, are benign tumours arising from the muscle layer of the uterus, the myometrium. • Adenomyosis is the presence of endometrial glands and stroma within the uterine myometrium. • Endometriosis is the presence of functional endometrial tissue (i.e. tissue that responds to hormonal stimulation) at sites outside the uterus. Endometriosis causes an inflammatory reaction at the site of implantation and is a cause of infertility. • Polycystic ovary syndrome is a condition in which excessive androgen production is triggered by inappropriate secretion of gonadotrophins. This hormonal imbalance prevents ovulation and causes enlargement and cyst formation in the ovaries, excessive endometrial proliferation and often hirsutism. Hyperinsulinaemia plays a key role in androgen excess. • Primary dysmenorrhoea is painful menstruation not associated with pelvic disease. It results from excessive production of prostaglandin F. Secondary dysmenorrhoea results from endometriosis, pelvic adhesions, inflammatory disease, uterine fibroids or adenomyosis. • Primary amenorrhoea is the continued absence of menarche and menstrual function by 14 years of age without the development of secondary sex characteristics or by 16 years of age if these changes have occurred. • Secondary amenorrhoea is the absence of menstruation for a time equivalent to more than 3 cycles or 6 months in women who have previously menstruated. Secondary amenorrhea is associated with anovulation. • Dysfunctional uterine bleeding is heavy or irregular bleeding caused by a disturbance of the menstrual cycle.
Cancer • Breast cancer is the most prevalent cancer in women. The major risk factors for breast cancer are reproductive factors, such as nulliparity; hormonal factors and growth factors, such as excessive oestradiol; familial factors, such as a family history of breast cancer; and environmental factors, such as ionising radiation. Physical activity and some dietary factors may have a protective effect. • Most breast cancers arise from the ductal epithelium and may metastasise to the lymphatics, opposite breast, abdominal cavity, lungs, bones, kidneys, liver, adrenal glands, ovaries and pituitary glands. • Most cancers of the female genitalia involve the uterus (particularly the endometrium), the cervix and the ovaries. Cancer of the vagina is rare. Cervical cancer arises from the cervical epithelium and is triggered by human papillomavirus (HPV). • Prostate cancer is the most prevalent cancer in men. Even at an early stage, it results in impaired urine flow and sperm transport. Routine screening is recommended for early detection of disease. • Possible causes of prostate cancer include genetic predisposition, environmental and dietary factors, alterations in hormones (testosterone, dihydrotestosterone and oestradiol) and growth factor. • Testicular cancer is the most common malignancy in males aged 15–35 years. Although its cause is unknown, high androgen levels, genetic predisposition and a history of cryptorchidism, trauma or infection may contribute to tumorigenesis.
Continued
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Part 5 Alterations to continuity
• Premenstrual syndrome is the cyclic recurrence of physical, psychological or behavioural changes distressing enough to disrupt normal activities or interpersonal relationships. Emotional symptoms — particularly depression, anger, irritability and fatigue — are reported as the most distressing symptoms; physical symptoms tend to be less problematic. Treatment is symptomatic and includes self-help techniques, lifestyle changes, counselling and medication. • Infection and inflammation of the female genitalia can result from microorganisms from the environment or overproliferation of microorganisms that normally populate the genital tract. • Pelvic inflammatory disease is an acute ascending infection of the upper genital tract caused by a sexually transmitted pathogen. If untreated, it can lead to infertility. • Vaginitis, a vaginal infection, is usually caused by sexually transmitted pathogens or Candida albicans, which causes candidiasis. • Cervicitis, which is infection of the cervix, can be acute (mucopurulent cervicitis) or chronic. Its most common cause is a sexually transmitted pathogen. • Vulvitis is an inflammation of the skin of the vulva. It can be caused by chemical irritants, allergens, skin disorders, irritation from tight-fitting clothing or spread of vaginal infections such as candidiasis. • Bartholinitis is an infection of the ducts that lead from the Bartholin’s glands to the surface of the vulva. Infection blocks the glands, preventing the outflow of glandular secretions. • The pelvic relaxation disorders — uterine displacement, uterine prolapse, cystocele, rectocele and urethrocele — are caused by the relaxation of muscles and fascial supports, usually with age or after childbirth or other trauma, and are more likely to occur in women with a familial or genetic predisposition. • Chronic illness, medications, infection, sexual trauma and a variety of psychosocial concerns have been implicated as causes of female sexual dysfunction.
•
•
•
•
• •
•
• •
Disorders of the male reproductive system • Disorders of the urethra include urethritis (infection of the urethra) and urethral strictures (narrowing or obstruction of the urethral lumen caused by scarring). • Most cases of urethritis result from sexually transmitted pathogens. Urethritis causes urinary symptoms, including a burning sensation during urination (dysuria), frequency, urgency, urethral tingling or itching, and clear or purulent discharge. • The scarring that causes urethral stricture can be caused by trauma or by severe untreated urethritis. Manifestations of urethral stricture include those of bladder outlet obstruction: urinary frequency and hesitancy, diminished force and calibre of the urinary stream, dribbling after voiding and nocturia. • Phimosis and paraphimosis are penile disorders involving the foreskin (prepuce). In phimosis, the foreskin cannot be retracted over the glans. It is caused by poor hygiene and chronic infection and can lead to
•
•
•
•
paraphimosis. In paraphimosis, the foreskin is retracted and cannot be reduced (returned to its normal anatomic position over the glans). It can constrict the penile blood vessels, preventing circulation to the glans. Peyronie’s disease consists of fibrosis affecting the corpora cavernosa, which causes penile curvature during erection. Fibrosis prevents engorgement on the affected side, causing a lateral curvature that can prevent intercourse. Priapism is a prolonged, painful erection that is not stimulated by sexual arousal. The corpora cavernosa (but not the corpus spongiosum) fill with blood that does not drain out, probably because of venous obstruction. Priapism is associated with spinal cord trauma, sickle cell disease, leukaemia and pelvic tumours. It can also be idiopathic. A varicocele is an abnormal dilation of the veins within the spermatic cord caused by either congenital absence of valves in the internal spermatic vein or acquired valvular incompetence. A hydrocoele is a collection of fluid between the testicular and scrotal layers of the tunica vaginalis. Hydrocoeles can be idiopathic or caused by trauma or infection of the testes. A spermatocele is a cyst located between the testis and epididymis that is filled with fluid and sperm. Cryptorchidism is a congenital condition in which one or both testes fail to descend into the scrotum. Uncorrected cryptorchidism is associated with infertility and significantly increased risk of testicular cancer. Testicular torsion is the rotation of a testis, which twists blood vessels in the spermatic cord. This interrupts the blood supply to the testis, resulting in oedema and, if not corrected within 6 hours, necrosis and atrophy of testicular tissues. Orchitis is an acute infection of the testes. Complications of orchitis include hydrocoele and abscess formation. Spermatogenesis (sperm production by the testes) can be impaired by disruptions of the hypothalamic– pituitary–testicular axis that reduce testosterone secretion and by testicular trauma, infection or atrophy from any cause. Epididymitis, an inflammation of the epididymis, is usually caused by a sexually transmitted pathogen that ascends through the vasa deferentia from an already infected urethra or bladder. Benign prostatic hyperplasia is the enlargement of the prostate gland. This condition becomes symptomatic as the enlarging prostate compresses the urethra, causing symptoms of bladder outlet obstruction and urine retention. Bacterial prostatitis is an infection of the prostate. Acute bacterial prostatitis causes an inflammatory response in which the prostate becomes enlarged, tender and firm. Infection may spread to the bladder. Chronic bacterial prostatitis is recurrent prostatic infection that eventually causes fibrosis. Sexual dysfunction in males can be caused by any physical or psychological factor that impairs erection, emission or ejaculation.
CHAPTER 32 Alterations of the reproductive systems across the life span
Disorders of the breast • Galactorrhoea, or inappropriate lactation, is the persistent secretion of a milky substance by the breasts of a woman who is not in the postpartum state or nursing an infant. It is a manifestation of pathophysiological processes elsewhere in the body, chiefly hormone imbalances caused by hypothalamic– pituitary disturbances, pituitary tumours or neurological damage. • Gynaecomastia is the overdevelopment (hyperplasia) of breast tissue in the male. It is caused by hormonal or breast tissue alterations that cause oestrogen to dominate. These alterations can result from systemic disorders, drugs, neoplasms or idiopathic causes.
Fertility • Surgical sterilisation procedures are vasectomy in the male, and tubal ligation and Essure in the female. • Barrier methods include condoms, a cervical cap and spermicides. • Hormonal methods of contraception include formulations of oestrogen and progesterone; they are available for oral or implantation methods of delivery. • Coitus interruptus and the rhythm method are highly unreliable methods of contraception. • Infertility is the inability to conceive after 1 year of unprotected intercourse. It affects approximately 15% of all couples. Fertility can be impaired by factors in the male or female or in both partners.
1029
• There are many different causes of infertility, including environmental, chemical, hormonal, structural and congenital causes. For example, it may result from a failure of gametogenesis, a failure of implantation or gestational difficulties (linked to uterine, ovarian and hormonal dysfunctions).
Assisted reproductive technologies • Assisted reproductive technologies are artificial methods of bringing sperm and oocyte together and then implanting the zygote into a receptive uterus. Improvements in techniques are making it possible for more infertile couples to conceive.
Major sexually transmitted infections • Sexually transmitted infections are infections contracted by intimate as well as sexual contact. • The aetiology of a sexually transmitted infection may be bacterial, viral, protozoan, parasitic or fungal. Although the majority of sexually transmitted infections can be treated, viral-induced infections are considered incurable. • Sexually transmitted infections have different specific effects but generically result in inflammation, which can cause damage to the gonads and impair fertility. • Most common sexually transmitted infections are bacterial. They remain prevalent in society despite the ability to kill the organisms with antibiotics due to current attitudes and behaviours regarding sexual activity.
CASE STUDY
A DU LT Matthew and Sarah are in their mid-30s (Matthew is 34 and Sarah 36). They have been trying to have a baby together for more than 2 years without success. They are attending a fertility clinic to seek advice and possibly intervention with assisted reproductive technology. Sarah is a non-smoker and works as a secretary in a small accountancy business. She has had a previous ectopic pregnancy and had to have a uterine tube removed. She has also had a number of reproductive tract infections. Matthew works in a chemicals manufacturing plant. He is a cigarette smoker and has a heavy cough. He has an undescended testicle and has also previously had a sexually transmitted infection. Upon examination, it is found that Matthew has a slightly enlarged prostate, but he says that his urine flow is normal.
1 2 3
4
5
Describe the occupational and environmental conditions that may affect Matthew and Sarah’s fertility. Explain how pelvic inflammatory disease could have affected Sarah’s fertility. Outline where sperm are produced in the testes and how sexually transmitted infections can affect sperm production. Describe how many eggs are released at ovulation during a normal ovarian cycle and how different it would be in Sarah. Discuss factors that indicate Sarah may have a blocked uterine tube.
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Part 5 Alterations to continuity
CASE STUDY
AD U LT Lisa is 56 and works as a teacher at a local high school. Four years ago she had a mastectomy of her right breast and clearance of lymph nodes following a diagnosis of grade II breast cancer with micrometastases in a sentinel node. She had radiotherapy and chemotherapy and was then prescribed ongoing tamoxifen as the tumour was oestrogen sensitive. Both of Lisa’s younger sisters have had bilateral mastectomies and her mother died of breast cancer at the age of 50. Lisa has a diet high in fibre and tries to eat healthily. She smoked
for 15 years but has been a non-smoker since she was 35. As her job is very busy she does not get as much exercise as she would like. 1 Outline the risk factors for breast cancer. 2 Explain how genetics may be involved in Lisa and her family’s disease. 3 Outline how environmental factors may influence the disease process and recovery. 4 Describe how the drug tamoxifen affects tumour growth and why it may be used in Lisa’s treatment.
CASE STUDY
AG EING Robert is a 72-year-old man who is in general good health with no diagnosed health issues. He keeps fit and enjoys gardening and exercising his dogs and has a full social life with a supportive wife and family. He enjoys a drink at his rugby club and is a non-smoker. Robert has presented at his GP following several months of urinary discomfort. He has been feeling as if he cannot fully empty his bladder, has difficulty initiating and stopping micturition, frequency, urgency and has a weak dribbling stream of urine. He is worried that he has prostate cancer as he has been talking to some friends who are currently undergoing cancer treatment. He undergoes a number of diagnostic procedures and is told that he has
benign prostatic hyperplasia and is commenced on 5-αreductase inhibitors and α-blockers. 1 Describe how prostate disorders are diagnosed including the use of the PSA test. 2 Outline the differences in pathology between benign prostatic hyperplasia and prostate cancer. 3 Describe why prostatic hyperplasia results in the urinary symptoms that Robert is experiencing and the long-term effect these symptoms may have on his urinary tract. 4 Outline the rationale for prescribing 5-α-reductase inhibitors and α-blockers in the treatment of Robert’s condition.
REVIEW QUESTIONS 1 2 3 4
Discuss common neoplasms of the uterus. How is embryonic development related to cryptorchidism? Describe the risk factors for breast cancer in women. Outline the role of diet and lifestyle in reproductive cancers. 5 Describe the hyperplastic processes that lead to benign prostate disease.
6 Explain the difficulty of early diagnosis of ovarian cancers. 7 Describe the role of infection in pelvic inflammatory disease. 8 Describe how polycystic ovary syndrome affects fertility. 9 Discuss the causes of male infertility. 10 Describe the relationship between lifestyle and sexually transmitted infections.
CHAPTER
Introduction to contemporary health issues
33
Margaret Williamson Chapter outline Introduction, 1034 Australia and New Zealand: demographics, 1034 Current population, 1034 Population projections, 1034 Ageing, 1035 Hospitalisations, 1036 Mortality, 1036 Chronic diseases, 1039
Mental health, 1040 Indigenous health, 1040 Contemporary lifestyle, 1041 Stress, 1041 Dietary factors, 1041 Physical activity, 1042 Obesity, 1043 Health promotion initiatives, 1046
1033
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Part 6 Contemporary health issues
Introduction Until this point in the textbook, we have explored pathophysiological processes at both a cellular level and an organ level. We have examined diseases of an organ system and explained how the pathophysiology and clinical manifestations of signs and symptoms arise. However, many diseases, such as atherosclerosis, affect more than one organ system, resulting in a range of clinical disorders. Moreover, while some diseases such as hepatitis may be primarily associated with only one organ system, they can greatly affect other body systems too. For instance, hepatitis can alter the coagulation, digestive, immune and nervous systems. Unfortunately, in industrialised Western countries such as Australia and New Zealand, a large percentage of the population have been, or are currently, exposed to conditions that predispose them to altered health status and diseases that can affect several organ systems. The most obvious example of this is obesity, which can lead to a range of diseases. While most Australians and New Zealanders have a life expectancy that is among the longest in the world,1 our contemporary lifestyles expose us to a range of environmental circumstances that significantly contribute to poor health and morbidity (illnesses that contribute to decreased quality of life). Add to this a genetic predisposition to particular diseases and it can be seen that many individuals may not have optimum health. The areas of greatest concern are the expanding ageing population and the associated risk of disease (particularly cancer), increasing rates of obesity and diabetes mellitus in adults and children, the impact of stress on disease, the prevalence of mental health issues, and groups within the population who have poor health outcomes, such as the Indigenous population. Health services in Australia and New Zealand face an overarching and paradoxical problem: on the one hand the population is getting older and advances in medical technology mean that life can be prolonged, but on the other hand, rates of morbidity and disease are increasing, due predominately to environmental and lifestyle factors. Many individuals you will encounter in the health service are likely to have poor health, with complicated pathophysiological conditions due to an increasing number of comorbidities. Accordingly, this section explores common contemporary health conditions affecting our populations. We also examine relationships between these altered health conditions and how they affect the whole body, rather than a single organ. Contemporary health refers to the current health of individuals and the health status of the populations as a whole. In Western countries like Australia and New Zealand, individuals typically have a long life expectancy; life expectancy has increased as a result of comprehensive national childhood and at-risk group immunisation programs, improvements in public hygiene and an elevation in living standards. Furthermore, the majority of individuals have access to advanced medical technology, which significantly contributes to their quality of life. However, despite these factors, a number of health conditions and diseases significantly contribute to the poor health and morbidity of a large percentage of the population. The
majority of diseases causing mortality in Australia and New Zealand are not the same as those causing mortality in developing nations. The World Health Organization identifies the leading cause of death in high income countries as coronary heart disease, followed by stroke and other cerebrovascular disease, then tracheal, bronchial and lung cancers.2 Although the medical management of such diseases has improved dramatically, lengthening life expectancy, larger numbers of individuals are now living with these diseases, which impact on their lifestyle.3 In this section, we address the issue of why these ‘Western diseases’ are so prevalent in our population.
Australia and New Zealand: demographics Current population
Compared with the rest of the world, the populations of Australia and New Zealand are tiny. Collectively, as of 2016 the population of the two countries was approximately 29.0 million people (Australia: 24.3 million, New Zealand: 4.7 million),4,5 within a global population of just over 7.5 billion, making Australia and New Zealand the 53rd and 127th most populous countries in the world, respectively.6 Australia is one of the most sparsely populated countries in the world, but it is highly urbanised. Population density varies greatly across Australia, ranging from very low population density in remote areas to very high population density in some major cities, with almost 71% of Australia’s population living in metropolitan areas, mostly near the coast, and concentrated in the south-east corner (see Fig. 33.1). More than three out of every four New Zealand residents live in the North Island, and the majority live in one of New Zealand’s major cities (see Fig. 33.2).7 Collectively, these findings highlight the fact that rural residents are in the minority and that the majority of people choose to live in coastal regions, particularly urban settlements near the coast. This has several implications, as geographical location influences rates of morbidity and mortality. For example, it has been shown that rural residents have a lower life expectancy and higher rates of injury and disease than their urban counterparts.8 The reasons for this are likely to be multifactorial, but are strongly influenced by higher rates of behaviours that adversely affect their health, poorer access to education, employment and health services and a significantly lower life expectancy for the Indigenous population (see ‘Indigenous health’ below).
Population projections
The Australian Bureau of Statistics projects the population in Australia will increase to between 36.8 and 48.3 million people by 2061, and to between 42.4 and 70.1 million people by 2101.9 New Zealand’s projected population is approximately 5.4 million by 2036 and 6 million by 2061.10 The main reasons for this increase are a longer life expectancy and immigration.
CHAPTER 33 Introduction to contemporary health issues
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Darwin
Brisbane
Perth Sydney Canberra
Adelaide Melbourne
Hobart FIGURE 33.1
Geographical distribution of the Australian population. Most of the Australian population is located in coastal regions, particularly in the south east. The darker coloured regions represent the most heavily populated areas.
While these two populations do not appear to be large, especially compared with countries such as China (1.4 billion), large sections of Australia are uninhabitable, and so the population growth will be predominantly in the cities. This future growth in the population will greatly expand the size of the ageing population.
Ageing
The Australian population is continuing to age, and this trend is expected to continue. This is due to a combination of sustained low levels of fertility combined with increasing life expectancy at birth. The median age of Australia’s population is projected to increase to between 38.6 years and 40.5 years in 2031 and to between 41.0 years and 44.5 years in 2061.9 This change in age composition is projected to change considerably as a result of population ageing. By 2056 there will be a greater proportion of people aged 65 years and over and a lower proportion of people aged less than 15 years. The proportion of people between 5 and 15 years is projected to decrease to between 10% and 12% in 2061. The number of individuals aged 85 years and over in Australia is projected to grow rapidly to between 4.5% and 6% by 2061 and to between 5.6% and 7.8% by 2101. As a result, the population is becoming more elderly.11 The median age of New Zealand’s population is projected to increase from 37.1 years in 2016, to 41.9 years in 2038
and to 46 years in 2068. Overall population growth is likely to slow after 2018, while the population aged 65 years and over is expected to double between 2016 and 2068, as the large baby-boomer generation enters this age group.10 By 2068, there will be 1.84 million New Zealanders aged 65 years and over, who are expected to make up 28% of all New Zealanders by 2068. In 2016, there are about three-quarters as many elderly New Zealanders as children. By 2068, there are projected to be at least twice as many elderly New Zealanders as children. However, the dramatic increase in life expectancy seen over the last century is unlikely to continue in both countries, as projections are that while life expectancy in general is still increasing slightly, there is also an expectation of this decreasing due to obesity (refer to Chapter 35). Based on assumptions about continuing living standards, by 2055 projected life expectancy is expected to increase to 96.6 years of age for females and 95.1 years for males in Australia (see Table 33.1).11 In New Zealand, median life expectancy will increase to 89.1 years for males and 91.3 years for females by 2068.10 This highlights an important paradox touched on earlier: despite individuals in Australia and New Zealand having an increased life expectancy, the aged population will not necessarily be healthier. In fact, the ageing population will live with more morbidity, particularly the conditions and
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Part 6 Contemporary health issues
TABLE 33.2 Causes of death: Australia 2015 Darker coloured regions have higher population density
RANK
Auckland Hamilton
Wellington
MALES
FEMALES
1
Coronary heart disease
Coronary heart disease
2
Lung cancer
Dementia and Alzheimer’s disease
3
Dementia and Alzheimer’s disease
Cerebrovascular diseases
4
Cerebrovascular diseases
Chronic lower respiratory diseases
5
Chronic lower respiratory diseases
Lung cancer
6
Prostate cancer
Breast cancer
7
Blood and lymph cancer
Diabetes mellitus
8
Diabetes mellitus
Colorectal cancer
9
Colorectal cancer
Heart failure
Suicide
Kidney disease
10 Christchurch
Dunedin
FIGURE 33.2
Geographical distribution of the New Zealand population. Most of the New Zealand population is located in the northern island. The darker green regions represent the most heavily populated areas.
TABLE 33.1 Australians’ projected life expectancy (in years) LIFE EXPECTANCY AT BIRTH
2015
2025
2035
2045
2055
Males
91.5
92.6
93.6
94.4
95.1
Females
93.6
94.5
95.3
96.0
96.6
diseases of arthritis, cancer, hypertension, coronary heart disease, osteoporosis, dementia, obesity and type 2 diabetes. The prevalence of disease is already higher in the aged population and this trend is expected to continue.8 Therefore, the aged population will be even more reliant on the healthcare system.
Hospitalisations
The bedrock of our healthcare system is our hospitals. In 2014–15, there were about 10.2 million admissions and 29
million days of patient care at 698 public and 624 private hospitals in Australia.12 The aged population require more hospitalisations than younger Australians — although those aged 65 and over make up 13% of the population, they made up the 41% of the hospitalisations and almost half of the patient days in hospitals. Women were admitted to hospital more frequently than men, particularly those in the younger and child-bearing age group between 15 and 44 years. Obese Australians were hospitalised for cardiovascular disease more frequently than those who were not obese.13 In New Zealand, there were around 2 million admissions in public and private hospitals in 2013–14.14,15 Bed occupancy and hospital admission rates increased with age. Thirty-eight per cent of hospitalisations were for patients 65 years and over. In a pattern similar to the Australian statistics, females in the age group 15 to 44 years were hospitalised more frequently than males.
Mortality
In Australia, there were approximately 159 052 deaths in 2015.16 The leading underlying cause of death was coronary heart disease (including angina, blocked arteries of the heart and heart attacks; see Table 33.2) which was responsible for 19 777 deaths, 12.4% of all deaths registered in 2015.17 Dementia and Alzheimer’s disease were the second leading cause of death, followed by cerebrovascular diseases which include stroke, haemorrhages, infarctions and blocked arteries of the brain in 2015. The number of deaths due to dementia has increased by 193% over the past decade from 6550 in 2006 to 12 625 in 2015. There were 31 168 deaths in New Zealand in 2014.18 As in Australia, coronary heart disease accounted for more deaths than any other disease, and was followed by cerebrovascular disease and lung cancer (Table 33.3).
CHAPTER 33 Introduction to contemporary health issues
TABLE 33.3 Causes of death: New Zealand 2014
TABLE 33.4 Causes of death by age group (top three causes): Australia
RANK
MALES
FEMALES
Coronary heart diseases
Coronary heart diseases
2
External causes (e.g. accidents and selfharm)
Cerebrovascular diseases
3
Dementia and Alzheimer’s disease
Dementia and Alzheimer’s disease
4
Cerebrovascular diseases
Chronic lower respiratory diseases
5
Lung cancer
Lung cancer
6
Chronic lower respiratory diseases
Other forms of heart disease^
7
Other forms of heart disease^
External causes (e.g. accidents and self-harm)
8
Prostate cancer
Colorectal cancer
9
Colorectal cancer
Breast cancer
10
Diabetes mellitus
Diabetes mellitus
1
AGE GROUP
MALES
FEMALES
< 1 year
Perinatal conditions and congenital anomalies
Perinatal conditions and congenital anomalies
Sudden infant death syndrome (SIDS)
Sudden infant death syndrome (SIDS)
Other ill-defined causes
Other ill-defined causes
Land transport accidents
Land transport accidents
1–14 years
Accidental drowning Perinatal conditions and congenital and submersion anomalies Perinatal conditions Brain cancer and congenital anomalies 15–24 years
^Other heart diseases include pericardial diseases, valvular disorders, myocarditis, cardiomyopathy, conduction disorders, cardiac arrest and heart failure.
25–44 years
Fig. 33.3 shows the death rate per 100 000 people by gender and age group. Males have a higher death rate than females at all ages and death rates increases exponentially with age. Diseases which prematurely cause death in developing countries do not cause significant mortality in Western countries. For example, rates of infant mortality from infections are very high in developing countries but are low in Western countries. While individual causes of death provide evidence about the health of a nation, to obtain a more accurate depiction of the mortality of a nation, we need to examine the causes of death for various age groups. For instance, coronary heart disease is common in the aged population, cancer is more prevalent as individuals become older, injury, self-harm and poisoning are the major causes of death in the younger population, and perinatal conditions and congenital anomalies are the most common causes of infant mortality (see Table 33.4). F O CUS O N L E A R N IN G
1 Describe the likely changes in the populations of Australia and New Zealand in the next 50 years. 2 Examine the effect of an ageing population on hospitalisations and the average length of hospital stay. 3 Discuss the major causes of death in Australia and New Zealand and why they differ from the major causes in developing countries.
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Suicide
Suicide
Land transport accidents
Land transport accidents
Accidental poisoning
Accidental poisoning
Suicide
Suicide
Accidental poisoning
Breast cancer
Land transport accidents 45–64 years
Coronary heart disease Lung cancer Suicide
65–74 years
Coronary heart disease Lung cancer Chronic obstructive pulmonary disease (COPD)
75–84 years
85+ years
Coronary heart disease
Accidental poisoning
Breast cancer Lung cancer Coronary heart disease Lung cancer Coronary heart disease Breast cancer
Coronary heart disease
Lung cancer
Cerebrovascular disease
Cerebrovascular disease
Dementia and Alzheimer disease
Coronary heart disease
Coronary heart disease
Dementia and Alzheimer disease Cerebrovascular disease
Dementia and Alzheimer disease Cerebrovascular disease
1038
Part 6 Contemporary health issues
Australia
A 90 years and over 85−89 years 80−84 years 75−79 years 70−74 years 65−69 years 60−64 years 55−59 years 50−54 years 45−49 years 40−44 years 35−39 years 30−34 years 25−29 years 20−24 years 15−19 years 10−14 years 5−9 years 0−4 years 250
200
150
100
50
0
50
Females
B
100
150
200
250
200
250
Males
New Zealand
90 years and over 85−89 years 80−84 years 75−79 years 70−74 years 65−69 years 60−64 years 55−59 years 50−54 years 45−49 years 40−44 years 35−39 years 30−34 years 25−29 years 20−24 years 15−19 years 10−14 years 5−9 years 0−4 years 250
200
150
100
50 Females
FIGURE 33.3
Death rate per 100 000 according to age and sex. Most deaths occur in the older population. A Australia. B New Zealand.
0
50 Males
100
150
CHAPTER 33 Introduction to contemporary health issues
Chronic diseases
and improvements in the treatment of the diseases. See Chapter 23 for more detail about the various conditions which make up cardiovascular disease. As the population ages, there is an increasing number of people living with and dying from cancer and dementia. The good news is that some cancers are on the decline. For instance, cervical cancer is likely to continue to decline, primarily due to improvements in early screening, and the mass introduction of the vaccine Gardasil, which provides protection against human papillomaviruses thought to be responsible for 80% of cervical cancers in Australia. The rates and types of cancers in the Australian and New Zealand populations are discussed more thoroughly in Chapter 37. In 2011, it was estimated that more than a quarter of a million Australians had dementia. Estimates suggest that by 2030, more than half a million Australian will have dementia and by 2050, more than 950 000.22 See Chapter 9 for a more detailed discussion of dementia and Alzheimer’s disease. Another major chronic disease that is likely to be encountered by healthcare professionals is diabetes mellitus. Rates of obesity are strongly related to the development of type 2 diabetes. It has been estimated that by 2050 approximately 14% of Australians (1 in 7) will have type 2 diabetes.23 Therefore, individuals with type 2 diabetes will be very prevalent in the hospital patient population and associated healthcare services. Chapter 36 explores type 2 diabetes in detail. Table 33.5 lists the risk factors for selected chronic disease. Physical inactivity and diet are discussed below.
Patients in acute-care hospitals in Australia and New Zealand are considerably different to those of 20 years ago. Patients now have more complex health problems, and are more likely to be older and require specialist care. Furthermore, they are statistically more at risk of developing problems during their hospital stay, such as infections, deep vein thromboses and cardiac events. Chronic diseases are the leading cause of illness, disability and death in Australia.19,20 A measure called ‘burden of disease and injury’ has been developed to better quantify the impact of disease on the population and compare the various conditions associated with illness, disability and premature death.21 In 2011, in Australia the conditions that caused the greatest burden were cancer, cardiovascular disease, mental health and substance use disorders, musculoskeletal disorders, and injuries. In New Zealand, neuropsychiatric disorders were the leading cause of health loss followed by cancer, cardiovascular diseases and musculoskeletal disorders.20 The burden of disease and injury changes according to age. For example, mental and substance use disorders were the main cause of disease burden in Australians 15 to 49 years, while cancer caused the most burden for those aged 50 to 79, and cardiovascular disease for those 80 years and older.21 Cardiovascular disease remains one of the most significant contributors to disability and death in older people. In more recent years the death rate has decreased, mainly due to reduction of risk factors such as smoking (decreased now to 12% of Australians; see Chapter 37),
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TABLE 33.5 Risk factors for chronic disease DISEASE
TOBACCO USE
PHYSICAL INACTIVITY
Coronary heart disease
✓
✓
✓a
✓
✓
✓
Stroke
✓
✓
✓
✓
✓
✓
Type 2 diabetes
✓
✓
✓a
✓
✓
✓
Osteoporosis
✓
✓
✓
Cancer
✓
✓
✓
Chronic kidney disease
✓
✓
Arthritis
✓f
✓g
COPD
✓
Asthma
✓
Depression a
ALCOHOL MISUSE
DIETARY RISKS
✓ c
OBESITY
HIGH BLOOD PRESSURE
b
✓d
✓e ✓
✓
Dietary risks relate to high intake of saturated fat b Dietary risks relate to insufficient calcium and vitamin D c Associated with liver and oral cancers d Dietary risks relate to high intakes of processed (preserved) meat and a high intake of red meat is associated with colorectal cancer e Associated with breast cancer in post-menopausal women f Associated with rheumatoid arthritis g Associated with osteoarthritis
ABNORMAL BLOOD LIPIDS
Part 6 Contemporary health issues
Mental health Until this point, we have explored the pathophysiology of common diseases and disorders which mainly have a physical origin. However, mental illness is known to have an enormous impact on contemporary health in Australia and New Zealand. Estimates from the 2007 National Survey of Mental Health and Wellbeing (SMHWB) suggest that more than 7 million Australians will experience a common mental disorder (such as depression, anxiety, or a substance use disorder) during their lifetime.24 Each year, 20% of the population, or 3 million Australians, aged 16–85 years are estimated to experience symptoms of a mental disorder. The second National Survey of People Living with Psychotic Illness, conducted in March 2010, estimated that almost 64 000 people in Australia had a psychotic illness and were in contact with public specialised mental health services each year. Psychotic illnesses are less common, but usually more severe, forms of mental illness than those covered in the SMHWB. Schizophrenia is the most common psychotic illness.25 When looking at access to mental health services, about 1.8 million Australians (8% of the population) received public or private mental health services in 2009–10. Around half a million people received mental health services from general practitioners.26 Over $8 billion, or $344 per Australian, was spent on mental health-related services in 2013–14 with state and territory expenditure on specialised mental health services accounting for most of this ($4.9 billion).27 The aetiology of mental health is complex. There are many theories about the pathophysiology of these disorders, and while many have limitations, these theories have greatly enhanced our ability to treat people with pharmacological agents. It has been shown that some mental illnesses are likely to have a strong genetic component; however, the effect of the environment is also strongly implicated. In recent years, advancements in neuroimaging have assisted in understanding the pathogenesis of mental illness. Chapter 39 is entirely devoted to our current understanding of the neurobiology of mental illness.
Indigenous health The Indigenous populations in Australia and New Zealand have poorer health outcomes than the non-Indigenous populations. Compared with their non-Indigenous counterparts, Indigenous Australians and New Zealanders are extremely disadvantaged, in terms of morbidity, mortality and life expectancy. Life expectancy for Indigenous Australians is much lower than for the non-Indigenous. Indigenous males born in 2010–12 can expect to live to 69.1 years, 10.6 years less than expected for non-Indigenous males.28 Indigenous females born in the same time period can expect to live
to 73.7 years, 9.5 years less than non-Indigenous females. In 2011–12, age-specific death rates were higher for Indigenous people than for non-Indigenous people across all age-groups, but the rate ratios were highest in the young and middle adult years. The infant mortality rate is also considerably higher than that for non-Indigenous people (6 per 1000 live births compared to 4 per 100 000 live births). Indigenous Australians rate their health as considerably lower than that of non-Indigenous Australians (see Fig. 33.4). 29 Indigenous Australians are also almost four times as likely to die with chronic kidney disease as a cause of death than non-Indigenous Australians.28 These are just a few examples of the poor health status of the Indigenous Australian population. In Chapter 40, we focus on diseases and conditions that are common to Indigenous Australians and the factors associated with these pathophysiological states. The health of the Māori population in New Zealand is poor compared with that of the non-Māori. For example, the life expectancy in 2012–14 for Māori males was 73.0 years, more than 7 years less than that for non-Māori males, 80.3 years. Similarly, the life expectancy for Māori females was 77.1, which is more than 7 years less than that for non-Māori females, 83.9 years.30 There is also a higher infant mortality rate in Māori compared with non-Māori in New Zealand (6.8 deaths per 1000 live births versus 4.5 deaths per 1000 live births). Māori also experience higher prevalence and mortality for a number of chronic diseases including cardiovascular disease, cancer, diabetes and asthma.31 These examples are elaborated further in Chapter 41, where the health of Maori is explored in greater detail.
60 50 Per cent
1040
40 30 20 10 0
Excellent/very good Good Fair/poor Self-assessed health status
Aboriginal and Torres Strait lslander peoples Non-Indigenous Australians
FIGURE 33.4
Self-reported health ratings by Indigenous and non-Indigenous Australians. More non-Indigenous Australians rate their health as excellent/ very good, while more Indigenous Australians rate their health as fair/poor.
F O CUS O N L E A R N IN G
1 Discuss which diseases are likely to be major causes of morbidity and mortality in the future. 2 Describe reasons why the health status of the Indigenous populations in Australian and New Zealand are poor.
Contemporary lifestyle While we are now living longer, an increasing number of older people are living with chronic illness. Unfortunately, in our society ageing is associated with an increasing prevalence of chronic diseases such as diabetes mellitus, depression, hypertension, coronary heart disease, arthritis, osteoporosis, cancer and neurological deterioration like dementia. In this section we look at some of the conditions that impact on the development of these chronic diseases. A range of genetic, social, economic and environmental factors are recognised as increasing the risk of developing a particular health condition. Specific lifestyle and related factors which have been identified as negatively impacting health include: • poor diet and nutrition • lack of physical activity • being overweight or obese • smoking and excessive alcohol consumption. Dietary factors, lack of physical activity, and overweight and obesity are discussed in the next sections, as these impact on chronic diseases that affect multiple body systems. Smoking is discussed in Chapter 25 in relation to its effects on the lungs, and alcohol is discussed in Chapter 27 in relation to alcoholic liver disease. However, it must be remembered that in addition to the effects of alcohol on the liver, alcohol also provides energy which can be in excess of body requirements, and as such it contributes to overweight and obesity.
Stress
One aspect of contemporary lifestyle that has been shown to influence the development of disease and our response to disease is the impact of stress. Stress can be both physical and psychological. The stimuli for stress are referred to as stressors and they can vary, both in their manifestation and how they affect an individual. For instance, exercise can be considered a physical stressor. Over time, with repeated sessions and in prescribed amounts, exercise can have a positive effect on an individual and lead to significant increases in cardiorespiratory fitness. However, exercise can also cause depression of the immune system, especially in the period immediately after the exercise session.32 Moreover, prolonged endurance-type exercise in environmental conditions with an elevated air temperature may lead to
CHAPTER 33 Introduction to contemporary health issues
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heat stroke, which in turn can lead to death.33 Therefore stress can be both beneficial and detrimental. The outcome depends on many factors, but it should be remembered that individuals respond differently to apparently similar stress situations. It also should be remembered that excess exercise is not common in our populations, as indeed insufficient physical activity is a common health risk. Physical stressors, such as pain and exercise, are the most obvious examples of stress. However, psychological stressors can also impact negatively on an individual. It has been suggested that psychological stress occurs when the environmental demands that the individual perceives are greater than the individual’s adaptive capability.34 Whichever way the stress is perceived, the main physiological response is activation of the sympathetic nervous system with a release of the hormones cortisol, adrenaline and noradrenaline. This effect is termed the hypothalamic–pituitary–adrenal axis, because it involves all of these glands. The release of hormones from these glands has a wide-ranging effect, and in prolonged activation can lead to dysfunction of organ systems, such as the cardiovascular, respiratory, hepatic and immune systems. In addition, psychological stress can influence or cause the development and progression of disease, and psychological stress is a major risk factor in our populations. Many diseases have been implicated with stress, including autoimmune disorders, cancers, osteoporosis, dementia, cardiovascular disease and diabetes mellitus. The development of autoimmune disorders is likely to be multifactorial, with genetic, hormonal and immunological factors influencing the pathogenesis. However, in up to 50% of all autoimmune disorders the onset of disease has been attributed to unknown trigger factors. It has been suggested that either physical or psychological stress may be the unknown trigger in some instances and that this may influence the development of autoimmune diseases such as rheumatoid arthritis.35 The likely link arises from stressors triggering the neuroendocrine hormones, causing immune dysfunction by changing cytokine production. This can lead to autoimmune disorder manifestation. Stress, the development of stress and the impacts on disease pathogenesis are discussed in detail in Chapter 34.
Dietary factors
Overweight and obesity are caused when energy intake from diet and drinking is greater than energy expended from physical activity and essential bodily functions such as metabolism.8 Recent surveys have shown that more than one-third of Australian and New Zealanders adults are overweight and a further 30% are obese, meaning that overall, approximately two-thirds of our populations are carrying excess weight.36,37 The long-term, regular consumption of fast food has been linked to weight gain through overconsumption of high energy density foods and large portion sizes.38 Australian studies have found
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that fast foods are high in energy, total and saturated fat and sodium, and that the average fast food meal can provide approximately half of an adult’s daily energy requirement. In addition, it has been estimated that almost one-third of the average energy intake is now derived from takeaway food, demonstrating a fundamental shift in dietary habits away from food being prepared in the home.39 Evidence shows that takeaway and fast-food consumption is linked to weight gain and insulin resistance, which often lead to obesity and the development of type 2 diabetes.40 While being higher in overall energy, fast foods also have fewer micronutrients, such as vitamins and minerals, and may cause nutritional deficiencies.41 Individuals from lower socioeconomic groups have been shown to consume more fast foods than individuals from higher socioeconomic groups.42 The prevalence of overweight and obesity is highest in inner, outer and remote regions, and among those in lower socioeconomic groups. As well as the types of food that Australians and New Zealanders are consuming, the frequency and amounts of food being consumed have changed. For instance, Australian children are now consuming more ‘extra’ food, eating more meals than required each day. Such foods are often high in energy, fat and sugar, are referred to as ‘energy dense’ foods and have been shown to make up almost half of their daily energy intake.43 The other major concern is the marketing strategy of ‘upsizing’ that has occurred in the fast-food industry. Although this has been driven by large multinational companies, a survey of Australian fast-food outlets has shown that for each percentage increase in cost, there is a doubling of the energy value of the food items, comprising mainly fats and sugars.44 This is particularly of concern for individuals aged 15–24 years, as they are the greatest consumers of fast food.40,44 Thus overconsumption of food is a major problem in contemporary society. Dietary guidelines provide simple effective information about what the population should be eating, including the types of foods and the portions. A broad outline of the Australian dietary guidelines is shown in Box 33.1. In Chapter 38 we consider the relative importance of genetic factors and the environment or lifestyle factors in disease development. Dietary factors are a significant part of contemporary lifestyles in this context.
Physical activity
The other area of significance to modern lifestyles is the amount of physical activity that the general population undertakes. We are not simply referring to formal sport here, but rather to the overall decrease in physical activity that has occurred due to the use of modern conveniences. Think of the multitude of devices that lower the amount of physical activity we undertake daily: cars, escalators, lifts, television remote controls, the internet (including online purchasing, email, social media), washing machines, microwaves, home delivery of groceries, domestic services
BOX 33.1
adults
Dietary guidelines for Australian
To achieve and maintain a healthy weight, be physically active and choose amounts of nutritious food and drinks to meet your energy needs Enjoy a wide variety of nutritious foods from these five food groups every day: • Plenty of vegetables of different types and colours, and legumes/beans • Fruit • Grain (cereal) foods, mostly wholegrain and/or high cereal fibre varieties, such as breads, cereals, rice, pasta, noodles, polenta, couscous, oats, quinoa and barley • Lean meats and poultry, fish, eggs, tofu, nuts and seeds, and legumes/beans • Milk, yoghurt, cheese and/or their alternatives, mostly reduced fat And drink plenty of water. Limit intake of foods and drinks containing saturated fat, added salt, added sugars and alcohol Encourage, support and promote breastfeeding Care for your food; prepare and store it safely
(e.g. cleaning, ironing, washing), fast-food shops and mobile phones. Although many of these devices have increased productivity and accessibility for the majority of the population and are therefore seen as great advances, they have undoubtedly also contributed to a decline in physical activity in the general population. The national physical activity guidelines for Australians recommend approximately 30 minutes of moderate-intensity exercise most days of the week (see Box 33.2). In Australia and New Zealand large national surveys have been carried out asking participants to report their exercise activity levels over a specified period, usually the previous 1–2 weeks. Accordingly, these statistics are based on a snapshot of physical activity, rather than longitudinal analysis. In Australia, more than 50% of adults (18–64 years old) participated in sufficient physical activity in the last week. Thirty per cent were insufficiently active and 15% were inactive (had no exercise in the last week).36 New Zealand has similar levels of physical activity, with 48% classified as physically active and 15% as physically inactive.37 Around 70% of Australian children and young people aged 5–17 years watch 2 or more hours of screen-based entertainment per day and so are participating in activities that do not require increased energy expenditure.45 The prevalence of physical inactivity increases with age; this is consistent in both Australia and New Zealand (see Fig. 33.5). The number of new bicycles sold has increased over the last decade; in fact, new bicycle sales outnumbered new motor vehicle sales. While this would seem encouraging,
CHAPTER 33 Introduction to contemporary health issues
Physical activity and sedentary behaviour guidelines
BOX 33.2
Physical activity • Any physical activity is better than none at all. Even if you currently do no physical activity, you can build up gradually to the recommended amount by commencing with a small amount each day. • Try to be active on most days of the week. • Accumulate 150 to 300 minutes of moderate intensity physical activity or 75 to 150 minutes of vigorous intensity physical activity each week. This can be an equivalent combination of both moderate and vigorous activities. • Do muscle strengthening activities on at least 2 days each week. Sedentary behaviour • Minimise the amount of time you spend sitting down. • Break up long periods of sitting as often as possible.
Percentage of population
80
Males
70
Females
60 50 40 30 20 10 0
15–24 25–34 35–44 45–54 55–64 65–74 75 plus Age group
FIGURE 33.5
Percentage of Australians undertaking no exercise in the previous week. This graph indicates that approximately half of all adults do not engage regularly in any exercise. Also, as the population ages, the level of physical activity declines.
it should be emphasised that just because bicycle sales are high, this does not translate into increased levels of physical activity. Although many people are taking steps to increase their physical activity levels, adherence to physical activity programs is generally weak.46 A number of factors contribute to this poor adherence, including the person’s age, gender, type of exercise, obesity and external motivators. Unfortunately, the positive aspects of regular physical activity are far outweighed by inactivity in the population.45 When coupling these facts with the changes taking place in eating habits, it will be seen that energy intake (eating) is more than energy expenditure (physical activity) for a large percentage of the population, hence the large numbers of overweight and obese individuals.
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FOCU S ON L EA RN IN G
1 Describe how stress can contribute to the development of disease. 2 Discuss how changes in nutrition and eating habits have changed in Australia and New Zealand over the last three decades. 3 Discuss how changes in contemporary lifestyle have contributed to a reduction in physical activity levels.
Obesity By far the greatest impact that contemporary lifestyle has had on health status is the increased prevalence of overweight and obese individuals in the population. A simple yet precise explanation for the cause of overweight and obesity, which is a more extreme category of overweight, is that energy intake exceeds energy expenditure and causes an energy imbalance over time,8 leading to the development of obesity (see Fig. 33.6). In 2014–15, 35.0% of Australians aged 18 years and over were overweight and a further 27.9% obese. Only approximately 35.0% were of healthy weight and 1.6% were underweight.36 Similar proportions of New Zealand adults were overweight and obese.47 More males were overweight or obese compared with females (70.8% vs 56.3%). Worryingly, the number of overweight and obese adults in Australia has doubled since the 1980s.48 Children are not spared from the issue, with 27.4% of children classified as either overweight or obese,36 which is a significant increase since the 1970s.49 Australians living in rural or remote areas are more likely to be overweight or obese (see Fig. 33.7). The number of people who are overweight or obese is likely to continue to increase. It has been estimated that almost 7 million Australians will be classified as obese by 2025 (see Fig. 33.8).50 The prevalence of diseases associated with obesity will also continue to increase. Already in Australia some 300 000 excess hospitalisations due to cardiovascular-related conditions have been attributed to obesity.51 The high rates of obesity and overweight may be related to people’s perceptions of their body mass. Evidence is emerging that people do not consider themselves to be overweight or obese, despite calculations clearly showing that they are in the overweight or obese range. In fact, within the population who are either overweight or obese, almost half of men and about one-fifth of women consider their weight to be in the acceptable range.52,53 One reason for this may be the incremental increase in people’s weight over time: individuals often acquire excess body mass over months or years so their weight gain may pass unnoticed. It also may be that with the majority of our population being overweight or obese, an individual may perceive their body size as being similar to the size of other people, and therefore not realise that they are overweight.
Part 6 Contemporary health issues
%
1044
80 70 60 50 40 30 20 10 0
Major cities Inner regional Outer regional and of Australia Australia remoteness remote Australia areas Males Females
Large fries
2L
FIGURE 33.6
The relationship between dietary factors and physical activity and the development of obesity. Low fruit and vegetable intake and low levels of physical activity, combined with increased meal size and fast food consumption, contributes to the development of obesity.
To place it in pathophysiological terms, the building of excess body mass can be viewed as altered homeostasis. We can use a simple example to demonstrate this effect. If an individual has a normal blood glucose level but then ingests a high concentration of simple sugars, such as found in carbonated soft drinks, their blood glucose level will rise. If the individual does not readily use the glucose for energy requirements, the increase in blood glucose level will quickly be reduced with the release of insulin. In contrast, an overweight or obese individual gains more weight incrementally. In response to an intake of energy excess to the body’s needs at a particular meal,
FIGURE 33.7
Geographical distribution of overweight and obese adults in Australia. There are higher rates of obesity in regional and remote locations.
there is no correction such as a reduction in food intake at the next meal or an increase in energy expenditure, and so this excess energy is converted to fat for storage. As a result, over time these small increases accumulate, and the individual will eventually have a significant increase in body mass. The individual can be considered in a state of altered homeostasis, as no correction is readily available in the short term, and as a result, the obesity may lead to significant health problems. Fig. 33.9 illustrates this example. Another consideration for overweight and obese individuals is the estimated reduction in their life expectancy. A recent meta-analysis of 189 studies of almost 4 million adults, including Australians and New Zealanders, found that being overweight or obese is associated with an increased risk of premature death, which is second only to smoking. The risk of premature death (before age 70) among those who are overweight or obese is increased by 10.5% for men and 3.6% for women.54 Studies have shown that if a younger adult is obese, the likelihood of premature death increases, although this is more strongly correlated with the severely obese.54–56 As the current obese population ages, the extent of the presumed reduction in life expectancy will become more apparent. It should be noted that this needs to be balanced against the advancements in medical technology and healthcare, which are projected to continue to improve in the future. The last area that links the contemporary health issue of obesity with chronic disease is its impact on the pathogenesis of chronic diseases. We now have clear evidence linking obesity with disease development and progression.54,57 Based on the rates of obesity in the current population, it is estimated that obesity causes 20 to 25% of type 2 diabetes mellitus, cardiovascular disease, colorectal and breast cancer.50 In fact, there are strong links between obesity and a variety of diseases, with causal links with the diseases listed in Fig. 33.10.
CHAPTER 33 Introduction to contemporary health issues 9.0
Males
Females
8.0
Prevalence (million people)
7.0 6.0 5.0 4.0 4.0 3.8
1045
4.2
4.4
4.5
4.7
4.9
5.1 5.2
5.8 5.4 5.6
6.0 6.2
6.4
6.9 6.6 6.7
7.1
7.3
7.6
3.0 2.0 1.0
28
27
20
26
20
25
20
24
20
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21
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14
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13
20
12
20
11
20
10
20
09
20
20
20
08
0
Year
FIGURE 33.8
The projected increase in the prevalence of obesity in Australia until 2028. Projections demonstrate that obesity is expected to affect more Australians into future years.
FIGURE 33.9
Altered homeostasis leading to overweight and obesity. A An acute alteration in blood glucose level is counteracted by the release of insulin to restore the blood glucose level to normal levels. This is an example of a negative feedback response and usually occurs in seconds to minutes, and importantly, homeostasis is now restored. B The individual starts with normal body mass, but incremental changes in physical activity level and energy intake (type of food and portion sizes) can lead to increases in body mass. Over time, usually months to years, this imbalance in energy intake and expenditure can lead to overweight or obesity. This can be considered a semi-permanent homeostatic imbalance. If the individual can lose weight and return to a normal body mass, homeostatic balance will be restored.
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Part 6 Contemporary health issues
Genes
Environment Obesity
Arthritis
Heart disease
Diabetes Cancers
Kidney disease
Depression
FIGURE 33.10
The relationship between factors contributing to obesity and the known links to disease. Obesity is known to increase the risk of main diseases that affect our populations.
F OC US O N L E ARN IN G
1 Discuss reasons for the high numbers of overweight and obese individuals in the population. 2 Discuss the links between obesity and disease progression.
Health promotion initiatives The Australian Chronic Disease Prevention Alliance (ACDPA) is an alliance of five non-government health organisations which are working together in the primary prevention of chronic disease, with particular emphasis on the shared risk factors of poor nutrition, physical inactivity, overweight and obesity and their social determinants.58 The members of the ACDPA are: • Cancer Council Australia • Diabetes Australia • Kidney Health Australia • National Heart Foundation of Australia • The National Stroke Foundation. The aims of the alliance are to: • develop evidence-based recommendations and initiatives that will contribute to the prevention of chronic disease and to provide leadership and a strong unified advocacy voice for the prevention of chronic disease • make evidence-based recommendations on priorities for action in the prevention of chronic disease to government • develop initiatives contributing to the prevention of chronic disease, which may be best achieved through the collaborative work of ACDPA members, while complementing the activities of member organisations • work cooperatively with government and members of parliament at all levels, including the Australian
Department of Health and Ageing, and State/Territory Departments of Health in the development and implementation of programs for the prevention of chronic disease • work cooperatively with other organisations, including Aboriginal and Torres Strait Islander health organisations, which are active in the field of chronic disease prevention, as appropriate.49 The New Zealand government has a similar approach and has published a wide range of objectives to improve the overall health of New Zealanders. The objectives are to: • reduce smoking • improve nutrition • reduce obesity • increase the level of physical activity • reduce the rate of suicides and suicide attempts • minimise the harm caused by alcohol and illicit and other drug use to individuals and the community • reduce the incidence and impact of cancer • reduce the incidence and impact of cardiovascular disease • reduce the incidence and impact of diabetes • improve oral health • reduce violence in interpersonal relationships, families, schools and communities • improve the health status of people with severe mental illness • ensure access to appropriate child healthcare services, including well child and family healthcare and immunisation. In addition, there are now physical activity guidelines to help New Zealanders aged 65 years and over live longer, healthier, and more independent lives. These include: • spending more time being physically active and less time sitting down • any activity is better than nothing, and it all adds up • daily activities such as walking to the shops, vacuuming or gardening, all count • aiming for at least 30 minutes of activity, 5 days a week, that increases breathing and heart rates is ideal — such as brisk walking, cycling, swimming, or playing with grandchildren.
FOCU S ON L EA RN IN G
1 Describe some of the health initiatives that strive to increase the overall health status of the population.
CHAPTER 33 Introduction to contemporary health issues
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chapter SUMMARY Australia and New Zealand: demographics
Contemporary lifestyle
• The populations of Australia and New Zealand are small compared with most other countries: Australia and New Zealand are the 53rd and 127th most populous countries in the world, respectively. • Australia’s population is projected to increase to between 37 and 48 million by 2050. • Life expectancy in Australia is one of the highest in the world; New Zealand is not far behind in life expectancy rates. • The aged population is projected to increase dramatically in the next 40 years, which will significantly impact on health services. • In 2014–15, there were about 10.2 million admissions to hospital in Australia and in 2013–14, there were around 2 million admissions to hospital in New Zealand. • Each year, approximately 159 000 Australians and 30 000 New Zealanders die. There are more male deaths than female deaths. • Coronary heart disease remains the greatest single cause of death in both countries.
• Stress activates the sympathetic nervous system and causes a release of the hormones cortisol, adrenaline and noradrenaline, which can lead to organ dysfunction and the development and progression of disease. • The dietary habits of contemporary lifestyles have changed over the last 30 years. Takeaway and fast foods are consumed regularly in Australian and New Zealand households, and there is strong evidence linking this to weight gain. • For a large percentage of the Australian and New Zealand populations, physical activity levels have declined below the recommended 30 minutes of exercise most days of the week.
Chronic diseases • While there has been a decline in cardiovascular disease and cancer deaths over the last 20 years, these diseases remain the leading causes of death in Australia and New Zealand. • The major diseases that contribute to mortality and morbidity and are likely to be encountered by healthcare professionals are obesity and diabetes mellitus.
Indigenous health • The Indigenous population is an extremely disadvantaged group, in terms of both morbidity and mortality. For almost all health statistics, the Indigenous population fares poorly compared with their nonIndigenous counterparts.
Obesity • Approximately 63% of the Australian population are either overweight or obese. • More males are classified as overweight or obese compared to females. • Approximately 27% of children aged 5–17 are overweight or obese. • Rates of overweight and obesity do not appear to be confined to the urban populations of Australia and New Zealand. • Almost 7 million Australians are expected to be classified as obese by 2025.
Health promotion initiatives • The Australian and New Zealand governments have identified a range of national health priorities, including preventing and managing diseases and conditions that cause significant morbidity to the community. • The Australian and New Zealand governments have initiated multiple programs to improve the health of their populations, essentially in response to contemporary health issues.
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CASE STUDY
A DULT Mary is a 24-year-old Aboriginal Australian about to give birth to her third child. She lives with her partner, aged 32 years, and her extended family in a remote area of Western Australia that has a grocery store and a fuel station. The nearest access to medical care is a medical centre over 5 kilometres away, where a weekly antenatal clinic is held. She has been diagnosed with gestational diabetes, which was also apparent with her two previous pregnancies. A general practitioner visits the medical centre twice a week but Mary will have to attend the nearest hospital (which is 30 kilometres away) to give birth.
1 2 3 4 5
What is the life expectancy of an Aboriginal Australian compared to a non-Aboriginal individual? Discuss the incidence of diabetes in the Aboriginal population. Compare the infant mortality rate for Aboriginal babies to those of non-Aboriginal. Highlight the problems Mary may encounter due to limited provisions at the grocery store. Outline the challenges that may arise for Mary following the birth of her baby due to limited access to healthcare.
CASE STUDY
A GEING Max is 75 years old. He lives in the country and is married to Jess (who is 73 years old), has four children and seven grandchildren. He has never smoked, drinks two beers every Friday evening with his mates at the local hotel, eats a nutritionally balanced diet and is a normal weight for his height. He worked in a timber mill for all his working life and was physically active, playing sport regularly until recently. His eldest son, John, aged 54, has just been diagnosed with coronary heart disease with an 8-year history of type 2 diabetes mellitus. John is obese. His siblings are overweight but have not been diagnosed with any diseases.
1 2
3 4
5
Explain why John may have type 2 diabetes and coronary heart disease but his father does not. John has developed coronary heart disease at a relatively young age. Discuss the influence of genetic and environmental factors on ‘Western diseases’. Outline the diseases that are likely to affect Max and Jess and which may contribute to their deaths. Describe the changes in contemporary lifestyle that may have contributed to Max and Jess’s children’s weight and medical problems. Discuss the possibility that Max and Jess’s grandchildren may have a lower life expectancy than their grandparents and parents.
REVIEW QUESTIONS 1 Describe the population demographics of either Australia or New Zealand. 2 Describe how the ageing population will change the demographics of Australia. 3 Outline how many people die each year in Australia and New Zealand and list the 5 most common reasons. 4 Name 5 conditions that contribute most to the burden of disease in Australian or New Zealand. 5 Discuss why the average length of stay in hospital is decreasing. 6 Describe how stressors in contemporary lifestyles have contributed to disease.
7 Provide reasons for dietary changes in both the child and the adult populations in the last 30 years. 8 List the 4 recommendations associated with physical activity to achieve good health. 9 Explain why obesity and overweight rates are high in the Australian and New Zealand populations. 10 List measures the governments of Australia and New Zealand are undertaking to improve the health of their populations.
Key terms adaptation, 1052 alarm stage, 1051 allostasis, 1060 allostatic overload, 1060 burnout, 1065 catecholamine, 1053 chronic inflammation, 1061 circadian rhythm, 1067 coping, 1066 cortisol awakening response, 1067 exhaustion stage, 1051 general adaptation syndrome, 1051 resilience, 1063 resistance stage, 1051 stress, 1050 stressors, 1051 TH2 shift, 1059
CHAPTER
Stress and chronic disease
34
Sarah List
Chapter outline Introduction, 1050 The general adaptation syndrome, 1051 Stressors, 1051 Physical stress, 1051 Psychological stress, 1051 Contemporary stressors, 1051 The detection of stress, 1052 The alarm stage, 1052 The resistance stage, 1052 The exhaustion stage, 1052 Physiological processes of the stress response, 1052 The sympathetic nervous system, 1053 The hypothalamic–pituitary–adrenal axis, 1054 Physiological effects of the stress response, 1055 Increased cardiac output and breathing rate, 1055 Elevated blood pressure, 1056
Increased blood glucose and lipid levels, 1057 Altered immune response, 1058 Suppression of pain, 1060 Benefits of the stress response, 1060 Health alterations with chronic stress, 1060 Stress, inflammation and chronic disease, 1061 Modulation of the stress response, 1063 Psychological influences on stress, 1063 Personality characteristics and stress, 1066 Sex hormone influences on stress, 1066 Strategies for coping with stress, 1066 Stress and sleep, 1067 Hormonal fluctuations with circadian rhythm, 1067 Sleep and circadian regulation of stress hormones, 1068 Sleep, stress and immunity, 1069 Shift work and disease, 1069 Ageing and stress, 1071
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Part 6 Contemporary health issues
Introduction Stress can be broadly defined as the body’s psychological and physiological response to what is perceived as a threat. When we are exposed to a stressor, a physical or psychological agent that we perceive (rightly or wrongly) as a danger, our body undergoes a bundle of adaptive behavioural, physiological, and cellular responses to prepare us to confront the threat referred to as the stress response. Therefore, stress is an adaptive response, one that is important in protecting us from danger. This acute stress response is normal and is not typically associated with any long-term health or cognitive problems. Chronic stress, on the other hand, is associated with a number of health problems due, in part, to effects on the immune system and resistance to disease. Walter B. Cannon used the term stress in both a physiological and a psychological sense as early as 1914.1 He applied the engineering concept of stress and strain in a physiological context and believed that emotional stimuli were also capable of causing stress. In 1946 Hans Selye popularised these same findings, viewing stress as a biological phenomenon.2 The concept that stress can influence immunity and resistance to disease has been investigated since the 1950s. In the 1970s, studies found that life changes or emotions, occurring over a prolonged period of time, were associated with decreased immune function. In more recent times, studies have investigated the interactions among social, psychological and biological
factors and their role in causing and prolonging the course of disease. What is emerging from wide areas of research is that stress is a complex response that involves relationships among the central nervous system, autonomic nervous system, endocrine system and immune system. One specific example of stress, particularly in those doing shift work, is the relationship between inconsistent sleep patterns and disturbances in physiological processes. In this sense, the altered sleep patterns form a type of stress. Sleep is a normal cyclic process that restores the body’s energy and maintains normal functioning; it is so essential to both physiological and psychological function that sleep deprivation causes a wide range of clinical manifestations. Stress may cause or exacerbate several diseases, including those that are leading causes of death in Australia and New Zealand: cardiovascular disease, cancer and type 2 diabetes. Stress is also directly related to symptoms and outcomes in a number of diseases and conditions, including irritable bowel syndrome, gastric ulcers, asthma, autoimmune disorders, delayed wound healing, reproductive dysfunction, depression and some cancers (see Table 34.1). It has been suggested that chronic inflammation, which can be stimulated by stress, is important in the functional decline that leads to disability and untimely death.3 The mental interpretation of stress is also linked to physiological processes in the body. This chapter describes definitions of stress, the general stress response and its benefits and adverse consequences.
TABLE 34.1 Examples of stress-related diseases and conditions TARGET ORGAN OR SYSTEM
DISEASE OR CONDITION
TARGET ORGAN OR SYSTEM
DISEASE OR CONDITION
Cardiovascular system
Coronary heart disease
Gastrointestinal system
Ulcer
Hypertension
Irritable bowel syndrome
Stroke
Diarrhoea
Disturbances of heart rhythm
Nausea and vomiting Ulcerative colitis
Muscle
Tension headaches
Urinary system
Diuresis
Muscle contraction
Genital system
Impotence
Skin
Eczema
Backache Connective tissues
Rheumatoid arthritis (autoimmune disease)
Neurodermatitis Acne
Pulmonary system
Immune system
Asthma (hypersensitivity reaction) Endocrine system
Type 2 diabetes
Hay fever (hypersensitivity reaction)
Amenorrhoea
Immunosuppression or deficiency Central nervous system
Fatigue and lethargy
Autoimmune diseases
Overeating Depression Insomnia
The general adaptation syndrome Selye’s early research revealed that the body’s physiological responses to stress were the same, regardless of the type of original stress, such as cold, surgical injury or noxious stimulus (toxic chemicals).2 He called these stimuli stressors. Because many diverse agents caused the same responses, Selye named this the general adaptation syndrome — a generalised set of physiological processes that occur regardless of the initial cause of the stress. The stress response can be considered a response to a disturbance of homeostasis brought about by the stress. As well as the generalised stress response, some additional responses specific to the stress may also occur. For example, exposure to cold causes the general adaptation syndrome as well as shivering in an effort to maintain core temperature. Three successive stages of the general adaptation response are: 1 the alarm stage, or reaction, in which the central nervous system is aroused and the body’s defences are mobilised (namely, the ‘fight or flight’ response) 2 the resistance stage, or adaptation, during which hormones extend and enhance the ‘fight or flight’ response 3 the exhaustion stage, in which continuous stress causes the progressive breakdown of compensatory mechanisms and homeostasis. The stage of exhaustion marks the onset of certain diseases. These stages are discussed in more detail later in the chapter in the section ‘The detection of stress’.
Stressors Physical stress
The stress response is primarily a protective mechanism to deal with immediate, physical threats. For example, if you come across a crocodile while on holidays, your body will respond involuntarily to the threat, preparing to fight or flee. Most of your body’s energy will be routed to your skeletal muscles in order to respond appropriately to the croc. In more primitive times, when this type of threat was a more common one, the stress response served us well as a species. We are still exposed to physical stress, for example, an injury or a trauma, a disease, a physical threat or even heavy exercise. Of particular relevance in the healthcare setting is the physical stress of surgical procedures, which will activate the general adaptation syndrome. Other examples of physical stress are a dog growling and lunging towards you, having to run towards the closing doors on a train or attempting to shift heavy furniture that you can barely move. Intense levels of exercise can also initiate the stress response, such as exercising to exhaustion or exercising in a particularly difficult environment like cold water.
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Psychological stress
The other main type of stress is psychological stress, which encompasses those types of triggers that are not a physical threat to the body. These psychological stressors can be considered mental stressors (such as a work deadline or an examination) or emotional stressors (such as bullying, break-ups, death of a friend or family member). Even the memory of a stressful event can act as a stressor. For these types of stressors, the perception of the threat is individualised. For example, having to speak in public may be a stress for many people, but of little concern to others. Another example is if someone has abused a particular person: the appearance of the abuser will cause a stress response in the victim, but not in someone else. In this way, the cerebral cortex and other regions of the brain involved in interpretation of the sensory stimulus and memory information (such as the memory of being abused) can actually process the stimulus, thereby determining whether the situation is a stress, and signal to the hypothalamus accordingly. A person’s resilience to stress, their ability to cope with stressors, is dependent on a number of factors, including genetic factors, approaches to coping with stress and, importantly, their early life experience. Individuals who are less resilient to day-to-day stress are more likely to develop long-term stress-related health problems. Interestingly, the stress response is associated not only with negative triggers, but also positive situations. For example, a surfer who walks onto the beach and sees a big swell would be extremely pleased and experience excitement and anticipation, which lead to the stress response. The sight of the swell might cause fear in a non-surfer — but surprisingly, the same set of general physiological processes would occur in both the excited and the fearful person. Similarly, a family reunion may bring excitement to some and dread to others, but either way the same stress response occurs — although someone with no strong feelings about the reunion would not have a stress response. The interpretation of the situation in the brain is important in deciding whether to stimulate the general adaptation response. People are not disturbed by the actual situation itself, but by the ways that they appraise and react to the situation. In general, a person experiences stress when the demand exceeds their coping abilities — their ability to control the situation is an important factor in how it is interpreted by the brain.
Contemporary stressors
Most of the common stressors in modern-day Australia and New Zealand are psychological stressors, derived from mental stress — for example, time stress is particularly common, as is handling deadlines at work, and even recreational activities such as playing computer games can cause adrenaline release due to their intensity. Other stressors have increased in the light of the ongoing economic uncertainty as a result of the global financial crisis of 2008–2009, as issues of housing affordability and finding
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and maintaining employment have become more widespread. Rapidly changing technology can be a stressor for older adults, most of who did not grow up using computers and related technology in the classroom. So-called technological stress, or technostress, is a dysregulation of adaptation caused by an inability to cope with new technologies. Emotional stresses are also common as we become more time-poor and are faced with guilt and disappointment at ‘not having enough time’ to fit in everything, such as spending enough time with family and friends. These stressors are so commonplace that phrases such as ‘I don’t have enough time to …’ or ‘I’m so stressed …’ are now a normal part of conversation. The types of responses that are usually required for mental and emotional stresses are not of a physical nature. The way we respond to our mental and emotional stressors can be termed ‘feed and faze out’4 — that is, we are most likely to react to the stress by eating or finding an activity that we perceive as reducing the stress. The term emotional eating is used to describe a common response to stress: eating. Interestingly, eating further enhances elevated blood glucose and lipid levels, leading to an exacerbation of the physiological response — which is exaggerated even further if the food chosen is high in glucose and lipids. People use different means of ‘fazing out’; some of these activities are relatively benign, such as sitting down and reading a book or watching television. However, in some cases, lack of resilience in the face of mental and emotional stress is also linked with an increased risk of developing drug or alcohol addiction. In these cases, use of drugs or alcohol may temporarily relieve the perception of stress, leading individuals to use these substances more regularly.
The detection of stress A physical or psychological stressor is first perceived or detected as sensory information by the cerebral cortex. After the signals are processed and interpreted as a stressor by association regions of the brain, the hypothalamus is quickly alerted (see Fig. 34.1). The hypothalamus is then responsible for coordinating the stress response, resulting in the nonspecific physiological responses of the general adaptation syndrome. Importantly, a physical injury, a physiological disease or an emotional trauma will all directly activate the stress response at the hypothalamus without any interpretation of the stimulus being required. For example, inflammation as a result of an infection activates the stress response, as does a surgical wound to internal organs.
The alarm stage
The alarm stage begins when a stressor activates the hypothalamus and sympathetic nervous system (SNS). This sympathetic response is a general one, a concept known as ‘mass discharge’, whereby the neurons throughout this system all send signals to their target organs throughout the body at the same time (see Fig. 34.1). In addition, the adrenal gland is stimulated to release hormones (adrenaline
and noradrenaline) that enhance and extend the effects of the sympathetic nervous system. In parallel with the SNS response, the hypothalamus stimulates the anterior pituitary gland, which in turn triggers the release of stress hormones from the adrenal cortex. Stress induces other hypothalamic endocrine pathways as well, resulting in the production and release of thyroid hormones, aldosterone, growth hormones and antidiuretic hormone among others (see Chapter 10). The overall effect of these changes is to prepare the body to respond appropriately to the stressor.
The resistance stage
If the stress continues for a longer period of time, the body progresses into the resistance or adaptation phase. Towards the end of the resistance stage, the sympathetic nervous system and levels of circulating hormones return to normal, as the body has adapted and so returns to a state of homeostasis. If the stress persists, adaptation may actually occur during this phase, so that there is a perception change in the individual — that is, the individual no longer sees the original stress as being so negative. For example, when someone first moves into a home beside a train line, they may notice the train noise, but over time they may no longer notice the noise because they have adapted to the stress of the noisy living conditions.
The exhaustion stage
If the stress continues after the resistance reaction, the body moves into a state of exhaustion, which is strongly linked to the development of chronic disease. Exhaustion occurs if stress continues and adaptation is not successful, which can ultimately cause impairment of the immune response, heart failure and kidney failure. FOCU S ON L EA RN IN G
1 Describe the 3 stages of the general adaptation syndrome. Discuss how the stress response progresses through these stages with time. 2 Compare physical and psychological types of stressors.
Physiological processes of the stress response The two general branches of the stress response are coordinated by the systems responsible for the regulation of all body processes: the nervous system and the endocrine system. The hypothalamus is the control centre for the initiation of a number of steps that bring about a range of body responses, thereby ensuring that the body is physically and mentally prepared to respond to the stress. This includes: (1) activating the sympathetic nervous system; and (2) activating the hypothalamic–pituitary–adrenal axis.
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may be either or
Physical trauma, injury, disease
Visual, auditory, olfactory, oral, pain, mental and psychological factors information goes for processing Interpretation by areas such as cerebral cortex, limbic system, thalamus
signals to
CONCEPT MAP
sensory information inputs
signals to
Hypothalamus initiates the activates the
Stress response
Endocrine system
Sympathetic nervous system direct to target organs by Release of noradrenaline (and adrenaline) by nerves
to adrenal gland, causing Release of adrenaline (and noradrenaline) by adrenal gland
leads to
leads to Adrenergic effects at target organs including Increased cardiac output Increased breathing rate
activates the
causing
Activation of hypothalamic– pituitary axis
results in Release of several pituitary hormones stimulates secretion of Cortisol, growth hormone, thyroid hormone, antidiuretic hormone
FIGURE 34.1
Sensory information, including that coming from the special senses, is interpreted before reaching the hypothalamus. Although a large amount of sensory information is interpreted by the individual based on personality, life experiences, memory, emotion and other factors before being considered as a stress, a physical injury directly activates the hypothalamic stress response.
The sympathetic nervous system
The sympathetic nervous system mediates many of the characteristic responses to stress, hence the descriptive term ‘fight or flight’, in which the body prepares to defend itself from or to run away from a threat (see Chapter 6 to review the sympathetic nervous system — see also Table 34.2).
Most of the direct effects from the sympathetic nervous system are controlled by catecholamine neurotransmitters (mainly noradrenaline, and also adrenaline). Important effects of sympathetic activation include an increased heart rate, increased blood pressure and increased cardiac output. This is matched with bronchodilation and an increased
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TABLE 34.2 Physiological effects of the catecholamines ORGAN/CELL
EFFECTS
Brain
Vasodilation, increased blood flow Increased glucose usage
Cardiovascular system
Increased rate and force of contraction Peripheral vasoconstriction Increased blood coagulation
Pulmonary system
Bronchodilation Increased ventilation
Muscle
Vasodilation, increased blood flow Increased breakdown and release of glucose from stores Decreased glucose usage (use of fats as fuel) Increased contraction
Liver
Increased glucose production Increased breakdown and release of glucose from stores
Adipose tissue
Increased breakdown and release of lipids from stores Decreased glucose uptake and utilisation (decreases insulin release)
Skin
Vasoconstriction Sweating
Eye
Pupil dilation
Gastrointestinal and genitourinary tracts
Decreased smooth muscle contraction, sphincter constriction Decreased secretions Vasoconstriction
Lymphoid tissue
Acute and chronic stress inhibits several components of cellular immunity, particularly decreasing natural killer cells*
Macrophages
Inhibit and stimulate macrophage activity; depends on availability of type 1/proinflammatory cytokines, the presence or absence of antigenic stressors and peripheral corticotrophin-releasing hormone (CRH)
*Natural killer cells appear to be the most ‘sensitive’ cells to the suppressive effect of stress and thus have become an important index of stress-induced suppression of cellular immunity.
breathing rate. Extensive vasoconstriction limits blood flow to areas such as the skin and abdominal organs, thereby increasing venous return to further enhance cardiac output. Vasodilation occurs at the skeletal muscles. This is important because the person will need to utilise their muscles in ‘fight or flight’ and therefore an increase in muscle blood flow is required. Blood coagulation is enhanced, which is important in preventing blood loss from any injuries that may occur and is needed for the stress of haemorrhage. There is an overall decrease in digestive function, including decreased motility, constriction of the sphincters and decreased secretions. Blood glucose levels are increased by stimulating the secretion of glucagon and inhibiting the release of insulin. Pupillary dilation allows more light into the eyes and increases visual acuity. Reproductive and growth functions are inhibited during stress. The sympathetic nervous system also activates the adrenal medulla to secrete adrenaline and also some noradrenaline
into the blood stream, where they act as hormones. There is a slight delay compared with the immediate response at the target cell by direct sympathetic innervation. The release of these hormones from the adrenal medulla enhances and elongates the immediate neural responses; either way, the catecholamines have the same effect whether from the neural or the endocrine system. (In this chapter, when referring to the sympathetic nervous system response, both the direct neural effects and the extended hormonal effects are considered together.)
The hypothalamic–pituitary–adrenal axis
There is a functional relationship between the hypothalamus, pituitary gland and adrenal gland, known generally as the hypothalamic–pituitary–adrenal axis (see Chapter 10). In response to stress, the hypothalamus releases
CHAPTER 34 Stress and chronic disease
corticotrophin-releasing hormone (CRH) which stimulates the anterior pituitary gland to release adrenocorticotrophic hormone (ACTH). ACTH then acts on the adrenal cortex, inducing the release of glucocorticoids such as cortisol. Stress induces other hypothalamic endocrine pathways as well, resulting in the production and release of thyroid hormones, aldosterone, growth hormones and antidiuretic hormone (ADH) among others (see Chapter 10). Each of these contributes to the overall stress response. In general terms, cortisol is considered one of the most important molecules of the stress response, and it increases blood glucose and blood lipid levels (see Table 34.3), providing the raw materials for energy production. Cortisol also interacts with the immune system (see ‘Altered immune response’ below). Aldosterone causes increased reabsorption (retention) of sodium and water, while ADH hormone also causes water retention. Thyroid hormone increases the heart rate and breathing rate and increases levels of glucose and lipids in the blood. Growth hormone increases blood glucose levels. All of these physiological events benefit the body in the short term in reacting to the stressful stimuli; however,
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if they continue to be released, their effects can considerably alter homeostasis and the body will become prone to the harmful effects of stress.
Physiological effects of the stress response The generalised response to stress by the sympathetic nervous system and the hormones stimulated by the hypothalamic–pituitary–adrenal axis lead to a number of physiological processes, including an increased heart rate and cardiac output, increased breathing rate, elevated blood pressure, elevated blood levels of glucose and lipids, altered immunity and suppression of pain.
Increased cardiac output and breathing rate
The sympathetic nervous system increases the heart rate and causes widespread vasoconstriction, which in turn
TABLE 34.3 Physiological effects of cortisol FUNCTIONS AFFECTED
PHYSIOLOGICAL EFFECTS
Carbohydrate and lipid metabolism
Diminishes peripheral uptake and utilisation of glucose; promotes glucose production in liver to increase blood glucose levels; promotes breakdown of lipids in adipose tissue to increase blood lipid levels
Protein metabolism
Decreases protein production (including immunoglobulin production) in muscle, lymphoid tissue, adipose tissue, skin and bone; increases plasma level of amino acids
Anti-inflammatory effects (systemic effects)
High levels or long-term secretion of cortisol suppress the inflammatory response and inhibit proinflammatory activity of many growth factors and cytokines; however, over time some patients treated with cortisol may develop tolerance to glucocorticoids causing an increased susceptibility to both inflammatory and autoimmune disease
Pro-inflammatory effects (possible local effects)
Cortisol levels released during the stress response may transiently increase pro-inflammatory effects
Lipid metabolism
Lipolysis in the extremities and lipogenesis in the face and trunk
Immune effects
Treatment levels of glucocorticoids are immunosuppressive, thus they are valuable agents used in numerous diseases; cellular immunity is particularly affected by these larger doses of glucocorticoids with suppression of TH1 function or cellular immunity. Stress can cause a different pattern of immune response; these non-therapeutic levels can suppress cellular (TH1) and increase humoral (TH2) immunity; several factors influence this complex physiology and include long-term adaptations, reproductive hormones (i.e. overall, androgens suppress and oestrogens stimulate the immune responses), defects of the hypothalamic–pituitary–adrenal axis, histamine-generated responses and acute versus chronic stress; thus stress seems to cause an increase in TH2 cells systemically whereas locally, under certain conditions, it can induce pro-inflammatory activities and by these mechanisms may influence the onset or course of infections, autoimmune/inflammatory diseases, allergies and cancers
Digestive function
Promotes gastric secretion
Urinary function
Enhances excretion of calcium
Muscle function
Maintains normal contractility and maximal work output for skeletal and cardiac muscle
Bone function
Decreases bone formation
Cardiovascular system
Maintains normal blood pressure; permits increased responsiveness of arterioles to the constrictive action of adrenergic stimulation; optimises myocardial performance
Central nervous system function
Modulates perceptual and emotional functioning, essential for normal arousal and initiation of daytime activity
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in the lungs, and thereby contributes to increases in oxygenation.
CONCEPT MAP
increases venous return, thereby increasing cardiac output. Adrenaline also acts to enhance myocardial contractility, which further increases cardiac output. Thyroid hormone also contributes to increased heart rate and enhances the effects of adrenaline and noradrenaline on the heart. Overall, therefore, cardiac function is increased. This occurs in conjunction with an increased breathing rate, mediated by the sympathetic nervous system, which causes bronchodilation to maximise airway diameter during the stress response. This enables the individual to increase the amount of air available for gas exchange
Elevated blood pressure
Sympathetic nervous system activity causes vasoconstriction of many blood vessels, which contributes to elevated blood pressure (see Fig. 34.2). Vasoconstriction at the kidneys is an important means of redirecting blood flow to other organs; however, in response, the kidneys secrete renin to activate the renin–angiotensin–aldosterone system (see
Hypothalamus activates the activates Sympathetic nervous Stress response system enhances effects of adrenaline causes and noradrenaline Cortisol ↓ Renal blood flow
kidney releases
causes the
Renin
Hypothalamus
release of stimulates adrenal gland to Corticotrophinproduce releasing hormone
causes conversion of
results in Vasoconstriction
stimulates the anterior pituitary
Angiotensin I
Adrenocorticotrophin hormone
activates to causes
stimulates adrenal cortex release of
Angiotensin II
stimulates posterior pituitary to release
stimulates kidney to release Aldosterone causes Fluid retention
causing
Antidiuretic hormone
results in results in
Increased blood pressure
FIGURE 34.2
Stress response processes that lead to elevated blood pressure. The stress response activates various processes, including the renin-angiotensin-aldosterone pathway, activation of the sympathetic nervous system and release of antidiuretic hormone. Together, these contribute to increased blood pressure.
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activates the activates
causes the
Stress response
Sympathetic nervous system
Hypothalamus releases
releases
releases
Corticotrophinreleasing hormone
Thyrotrophinreleasing hormone
Growth hormonereleasing hormone
releases
Adrenaline and noradrenaline stimulates release of
Glucagon
stimulates anterior pituitary release of Adrenocorticotrophin hormone
stimulates anterior pituitary release of Thyroid-stimulating hormone
stimulates adrenal cortex release of
results in
Cortisol results in
CONCEPT MAP
Hypothalamus
stimulates anterior pituitary release of Growth hormone
stimulates thyroid gland
Thyroid hormone
results in
Increased blood glucose levels AND Increased blood lipid levels
causing causing
FIGURE 34.3
Stress response processes that lead to elevated blood glucose and blood lipid levels. The stress response activates various processes, including activation of the sympathetic nervous system and release of various hormones. These lead to an increase in blood glucose levels, as well as the mobilisation of fats, causing increased blood lipid levels.
Fig. 28.15). The effects of aldosterone include the reabsorption of sodium and water, which increases blood volume. Similarly, antidiuretic hormone causes reabsorption of water, which further increases blood volume. This increase in blood volume also leads to elevated blood pressure.
Increased blood glucose and lipid levels
Cortisol, glucagon, adrenaline, noradrenaline, thyroid hormone and growth hormone all contribute to a rise in
blood glucose and blood lipid levels (see Fig. 34.3). Body stores of glucose, lipids and proteins are broken down and released into the blood. Consequently, stress may cause a substantial rise in blood glucose and blood lipid levels. Glucose and lipids act as precursors in the production of cellular energy and the increase in their levels provide a ready energy source for skeletal muscles and other body systems. It is quite important to have an understanding of the effects of stress on increasing blood glucose levels. Those encountering stress, particularly physical stress in clinical
CONCEPT MAP
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A
B
Stress (e.g. injury/infection)
Hypothalamus
stimulates to continue
SNS response
Cortisol (when administered pharmacologically)
↓ Inflammatory response
↓ Number of leucocytes
↓ Monocytes and ↓ basophils
↓ Eosinophils
HPA response
enhances
inhibits
Pro-inflammatory cytokines
↓ Allergic response
Inflammatory response FIGURE 34.4
The effects of cortisol on innate immunity. A Stress causes the hypothalamus to activate the sympathetic nervous system (SNS), and the hypothalamic–pituitary axis (HPA); these have opposing effects on inflammation. B Therapeutic levels of cortisol, due to pharmacological treatment, inhibit the innate responses, thereby suppressing the inflammatory response and allergic reaction.
settings, such as illness, trauma, or surgery, can be prone to elevated blood glucose levels. Clinical settings also cause emotional stress for patients, which may be more substantial for some individuals. Together, these processes can be particularly relevant for patients with diabetes, as their blood glucose levels may be much higher than expected, requiring closer management.
Altered immune response
The impact of stress on the immune system has been actively studied for over 30 years. It is well established that long-term physical or psychological stress is associated with increased risk of infection and chronic health problems. The reason for this is that, in general, stress has a detrimental effect on immune function. The activity of many stress hormones, particularly cortisol, adrenaline, noradrenaline and growth hormone, can all modulate various functions of both the innate and adaptive immune defences, leading to a general immune dysregulation.
Stress and the innate defences
The effect of stress on the body’s first line defences is a complex one. There is extensive ‘cross-talk’ between the nervous, endocrine and immune systems. These body systems play major roles in the body’s ability to adapt to environmental changes and communication between them allows optimisation of their functional responses, allowing the body to adapt rapidly.5 One of the ways in which communication occurs is through the activity of both catecholamines and glucocorticoid hormones. For example,
catecholamines (adrenaline and noradrenaline) can be produced by the sympathetic nervous system, the adrenal medulla and white blood cells.6 While cortisol is produced primarily from the adrenal cortex, it is distributed to all body tissues, including the brain where it plays a role in regulating arousal, cognition, mood, sleep and metabolism. The relationship between stress and the body’s innate defences are best illustrated by looking at the body’s response to an acute injury or infection (see Fig. 34.4A). After a breach in the body’s surface barriers both the inflammatory and stress responses are rapidly activated (for a review of inflammation, see Chapter 13). One important aspect of the inflammatory response is the production and release of pro-inflammatory cytokines. These immune-signalling molecules help to stimulate both the innate and adaptive defences. The stress response modulates the inflammatory response by regulating levels of pro-inflammatory cytokines. The release of catecholamines by the sympathetic nervous system increases pro-inflammatory cytokines, initially enhancing the inflammatory response. Cortisol administered pharmacologically, on the other hand, inhibits inflammation (Fig. 34.4B). Cortisol can bind to glucocorticoid receptors on immune cells and inhibit the production of pro-inflammatory cytokines. However, inhibition depends on dose and cell or tissue type.7 This apparent conflict between the two branches of the stress system is very important in regulating the intensity of the inflammatory response and preventing excessive tissue damage that may occur due to an over-exuberant inflammatory response. This balance between the nervous, endocrine and immune systems is a delicate one and dysregulation of the system,
CHAPTER 34 Stress and chronic disease
CONCEPT MAP
Adrenaline and noradrenaline
Cortisol
Increased TH2 activity ← Decreased TH1 activity Increased humoral immunity ↑ Antibody response but
↑ Autoimmune disease
↓ Production of new antibodies ↑ Risk of new infections
Decreased cell-mediated immunity ↓ Number and function of lymphocytes ↓ Natural killer cell activity ↑ Risk of cancer
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↑ Risk of viruses
FIGURE 34.5
The effects of stress hormones on the adaptive immune system. There is a decrease in cell-mediated immunity (T lymphocytes and natural killer cells) and an increase in humoral immunity (beta lymphocytes and antibodies). Similar general effects on adaptive immunity are seen with physiological levels of cortisol secreted during stress, as well as with therapeutic levels of cortisol administered as treatments.
through either excessive stress response or long-term stress, can lead to immune dysfunction and an increased risk of developing a stress-related disease.
and directly activate peripheral sensory neurons.8 This inflammatory signal stimulates the alarm stage in the hypothalamus.
Stress and the adaptive defences
A delicate balance
The effects of stress on the other branch of the immune system, adaptive immunity, are more complex. At levels reached during stress cortisol and noradrenaline/adrenaline decrease cellular immunity by inhibiting TH1 cells and increase the extracellular (humoral) responses by enhancing TH2 cells (see Fig. 34.5). Supporting this model, it has been found that examination stress in medical students causes a general decrease in T lymphocytes, the primary cell type used by the cellular branch of the adaptive defences.7 Consequently, stress results in immunosuppression and an increased risk of infection (due to decreased cellular immunity) at the same time as there is a heightened antibody response. This decrease in TH1 activity and increase in TH2 activity is called the TH2 shift.
Immune system signalling to the hypothalamus
Cytokines released by immune cells have significant influence on neuroendocrine function and thus the immune system alerts other systems of threatening stimuli, such as infection, tissue damage and tumour cells, which may disrupt homeostasis. In other words, the immune system can itself act as a stressor. The release of pro-inflammatory cytokines such as interleukin-1β, tumour necrosis factor β and interleukin-6, which are released in response to pathogen infection, tissue damage or cancer, can act as neuromodulators
This balance between the nervous, endocrine and immune systems is a delicate one (Fig. 34.6). Dysregulation of Stress and/or circadian rhythms
Nervous system
Endocrine system
Immune system
FIGURE 34.6
Interaction between the nervous, endocrine and immune systems. Stress and the circadian rhythms lead to complex interactions between these body systems.
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this balance, through either excessive stress response or long-term stress, can lead to immune dysfunction and an increased risk of developing a stress-related disease. For example, either chronic activation, or dysfunction, of the hypothalamic–pituitary–adrenal gland relationship — possible results of chronic stress — can actually lead to excessive inflammation (often in the absence of any threat) in various body tissues. This chronic low-grade inflammation can contribute to the development of a number of diseases including osteoporosis, metabolic syndrome, depression and cardiovascular disease.9
Suppression of pain
Beta (β)-endorphins (endogenous opiates) are released into the blood as part of the response to stressful stimuli, including traumatic injury and an acute intense stress situation such as severe physical injury. In inflamed tissue, immune cell-derived endorphins activate endorphin receptors on peripheral sensory nerves leading to pain relief or analgesia (see Chapter 7). This may contribute to some people not experiencing the intense pain that would be anticipated in some circumstances of physical injury (via the stress response).10–14
Effects of cortisol used as a therapeutic agent
Due to its powerful anti-inflammatory effects, cortisol and other glucocorticoid substances are used therapeutically in clinical practice as anti-inflammatory and immunosuppressive agents. For example, inhalable cortisol can be administered as a long-term preventative therapy for asthma, where it acts to reduce airway inflammation. When administered to patients, the amount of cortisol used is much higher than the physiological amount secreted by the body during stress. However, there are significant side effects of glucocorticoid therapy, particularly when administered systemically, because the drug activates many physiological stress responses in the absence of a stressor. Long-term glucocorticoid therapy is associated with immunodeficiency, hyperglycaemia, insulin resistance, adrenal insufficiency and other problems. It appears that this higher level has the opposite effect on innate immunity, such that the inflammatory response and the allergic response are lessened (see Fig. 34.4B). The effects of therapeutic doses of cortisol on the adaptive immune response, in general terms, appear similar to that seen with physiological levels. However, some of the detailed processes may actually differ and are complex. Overall, treatment levels of cortisol are immunosuppressive across most of the immune system functions.
Benefits of the stress response The stress response is necessary in mobilising body stores, such as glucose and ATP, and shunting blood to the working
FOCU S ON L EA RN IN G
1 Discuss the role of the sympathetic nervous system and hypothalamic–pituitary–adrenal axis in the stress response. 2 List some important physiological effects of the stress response. Explain how stress contributes to these factors. 3 Compare the effects of cortisol produced during stress and used pharmacologically.
skeletal muscles, heart, lungs and brain, giving them access to oxygen and the nutrients necessary to protect and keep the body safe. These physiological changes equip the body to respond to a physical challenge or threat by either fight (defending itself) or flight (escaping). The key features of the stress response are sufficient blood pressure and blood flow and adequate levels of glucose and lipids in the blood as fuels delivered to the organs. The stress response enables these physiological processes to be maximised, thus preparing the body for a physical response. This is particularly beneficial in the short term. The term eustress describes a stress that causes this response when it is of benefit to the body, such as during exercise or a task that provides a challenge to the individual. For example, during exercise the stress response is vital to allow adequate glucose, lipids, oxygen, blood flow, cardiac output and respiratory rate to support the exercise activity.
Health alterations with chronic stress The exhaustion stage of the general adaptation syndrome occurs if stress persists for an extended period of time and adaptation is not successful. In progressing to exhaustion, the stress is defined as distress, meaning the long-term effects of the stress are having a negative impact on the health of the individual, leading to pathophysiological processes. While all aspects of the physiological stress response may contribute to the pathophysiology, it is cortisol that is associated with most of these undesirable effects. Exhaustion is also referred to as allostatic overload. Allostasis is considered an adaptive physiological response to stressful events. Chronic or disregulated allostasis (long-term or chronic exaggerated responses to stress) can lead to disease. Allostatic load is the individualised cumulative amounts of stressors that exist in our lives and that influence our physiological responses. Allostatic load includes our genetic make-up, lifestyle (including damaging health behaviours), daily events, and sometimes, dramatic events such as disasters.15 Over time this load exacts a toll on our bodies. Because the brain is a key player in deciding what is stressful, it is influential in determining when we have reached allostatic overload. Moreover, these responses are individualised — that is, what would be considered normal for one person may be considered extremely stressful for another.16 In response to acute and
Stress, inflammation and chronic disease
Several conditions with various pathophysiological characteristics appear to have a common origin relating to chronic inflammation. These conditions include
A
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Stress activates Hypothalamus activates
leads to
Sympathetic nervous system
Cortisol
causes Vasoconstriction at the stomach
causes
CONCEPT MAP
chronic stress some regions of the brain may respond by undergoing structural remodelling that can alter behavioural and physiological responses, such as cognitive impairment and depression.16 The key system involved in allostatic overload is excess production of cortisol, but catecholamine and pro-inflammatory cytokines also play a role. For example, extended periods of high levels of cortisol cause increased gastric secretions, which contribute to the risk of developing gastric ulcers. Although Helicobacter pylori is well known as a main cause of gastric ulcer formation, it appears that there is still a role for stress in the development of this condition. Stress can increase acid secretion and impair mucosal defences, facilitating the colonisation of the stomach by Helicobacter pylori and hence the development of ulcers.17 In addition, the effects of the sympathetic nervous system causing vasoconstriction to the digestive tract result in a decrease in blood flow and a decrease in the secretion of protective mucus, which also contributes to gastric ulcers (see Fig. 34.7). Cortisol causes the breakdown of lipids and proteins to increase blood glucose levels; however, the decreased amount of protein in the tissues can lead to complications including delayed wound healing (see Fig. 34.8). The immunosuppressive effects of glucocorticoids may also contribute to the impaired wound healing.18 In fact, psychological stress in the time after surgery can lessen the repair of a surgical wound, which highlights the importance of reducing stress in patients in order to promote their recovery.19 The breakdown of protein from bone, decreased calcium absorption from food and increased renal excretion of calcium, all of which occur with stress, lead to bone weakness and osteoporosis in cases of allostatic overload (see Fig. 34.9). The muscle weakness due to the breakdown of muscle protein can make individuals prone to falls and, combined with weak bones, this increases the likelihood of bone fracture. In addition, stress interferes with a wide variety of neurological functions. The stress response is linked with a disruption to the blood–brain barrier, so that additional substances from the blood may be allowed to cross into the brain and contribute to alterations in brain activities.20 Cortisol affects mood and behaviour and stress is associated with changes in cognition, appetite, sleep and sensory perception.21 There is also evidence that stress impairs memory processes associated with the hippocampus, an important region of the brain involved in memory — as well, there is evidence of the hippocampus undergoing atrophy (shrinkage) with chronic stress.22 The functioning of both the hippocampus and the hypothalamus is altered with chronic stress.23,24
CHAPTER 34 Stress and chronic disease
results in ↓ Secretion of mucus in stomach
↑ Gastric acid secretion in stomach leads to
leads to
Gastric ulcers
B
FIGURE 34.7
A The effects of stress on the development of gastric ulcers.
Stress leads to increased secretion of gastric acid, and loss of mucus secretion, which can lead to gastric ulcers. B Gastric ulcer. The ulcer has arisen due to the acidic environment eroding part of the stomach mucosa.
cardiovascular disease, type 2 diabetes, other diseases associated with ageing and some cancers. All are characterised by a prolonged presence of pro-inflammatory cytokines (which promote the inflammatory response by activating inflammatory mediators).25,26 Chronic stress and negative emotions are associated with dysfunctional immune regulation and production of increased levels of pro-inflammatory cytokines, providing a possible link
Part 6 Contemporary health issues
A
A
Stress
Stress
activates
activates the
Hypothalamus
Hypothalamus
to release Cortisol
leads to
causes
causes
causes
Cortisol
causes
causes
↑ Breakdown of proteins
↓ Production of proteins
leads to
↓ Intestinal calcium absorption
leads to
leads to
Decreased wound healing
↓ Blood calcium levels
B
↑ Renal calcium excretion
leads to
↑ Breakdown of bone (to release amino acids to blood) causing
stimulates
results in
Bone resorption/ breakdown
results in Bone weakness Osteoporosis
FIGURE 34.8
A The effects of stress on wound healing.
B
C
An overall decrease in production of proteins leads to impairments in wound healing. B Wound healing of a vascular ulcer. Impairments in wound healing can lead to significant ulceration of tissue.
between stress, immune function and disease.25,26 In fact, the individualised nature of the stress response is such that anticipatory stress and worry can elongate and enhance the adverse effects of stress on the cardiovascular, immune and other systems.27 The link between chronic disease, stress and inflammation is particularly relevant to Australian and New Zealand healthcare settings, as chronic diseases are particularly prevalent in our societies. The leading causes of death in Australia include ischaemic heart disease, stroke, type 2 diabetes and cancers (respiratory, colorectal, haematological, prostate, breast, pancreatic and skin).28 The list is similar in New Zealand, with ischaemic heart disease, cerebrovascular accidents and cancers (respiratory, colorectal, breast, prostate, stomach and cervical) all featuring as main causes of death.29 The stress response causes increased blood lipid levels, and hyperlipidaemia is strongly associated with the development of atherosclerotic processes in the heart leading to ischaemic heart disease, as well as in the brain leading to stroke. In addition, the increased blood volume leads to hypertension, a main contributor to cardiovascular disease
FIGURE 34.9
A Elevated levels of cortisol and the development of
osteoporosis. The increased release of cortisol leads to lowering of blood calcium levels, as well as promoting bone resorption. Compare normal bone, B, with bone from osteoporosis C. Note the substantial loss of bone tissue with osteoporosis.
(see Fig. 34.10). For further details on cardiovascular disease, refer to Chapter 23. The elevated blood glucose levels that occur for extended periods during chronic stress can contribute to insulin resistance and type 2 diabetes30 (see Fig. 34.11), as well as pre-diabetic conditions and metabolic syndrome. In addition, there is a connection between stress and the development of abdominal or visceral obesity (as lipids are broken down from the body periphery and deposited around the abdomen). Recent evidence suggests that chronic stress
CONCEPT MAP
CONCEPT MAP
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CONCEPT MAP
CHAPTER 34 Stress and chronic disease
A Stress response causes contributes release of to Adrenaline Hyperlipidaemia Aldosterone and noradrenaline contributes Hypertension causes to enhances contributes to
↓ Fibrinolysis results in
Atherosclerosis
↑ Platelet aggregation results in
↑ Blood coagulation
results in Coronary heart disease
B
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There are strong relationships among stress, the immune system and cancer. Indirect links between psychological stress and cancer are based on behaviour. For example, people under stress often develop certain behaviours, such as smoking, overeating, or drinking alcohol, which increase a person’s risk for cancer. Stress-induced immune changes affect many immune cell functions, including decreasing natural killer cell and T cell cytotoxicity. In addition, there is a relationship between infection and the development of cancer: approximately 15–20% of cancers are attributed to infection.32 For example, hepatitis C is strongly linked with liver cancer, human papillomavirus is related to cervical cancer and Helicobacter pylori is related to stomach cancer. Because the infection activates inflammation, cancer is actually described as an inflammatory disease in these cases.33–35 In addition, the inflammatory bowel disease ulcerative colitis is a risk factor for the development of colorectal cancer. Although the relationships among infection, inflammation and cancer may appear simple, in fact the detailed mechanisms by which these processes occur are quite complex and are still being discovered (see Chapter 37 for detailed discussion on cancer). What is clear is that stress can adversely influence many disease processes, particularly those with an inflammatory process. Impairments of immune function may have dire health consequences for stressed individuals, including increased risk of infection and cancer.
Modulation of the stress response Psychological influences on stress FIGURE 34.10
A The relationship between stress and coronary heart
disease. The stress response promotes the development of both atherosclerosis and blood coagulation. B Angiographic image before placement of a sirolimuseluting stent. The left anterior descending artery contains a tight stenosis (arrow).
leads to the production of the inflammatory cytokine interleukin 1-beta (IL-1β) in visceral adipose tissue. Excess production of IL-1β is associated with a failure of abdominal adipose tissue to function properly. As a result, the body attempts to compensate by producing more adipose tissue in the abdomen, leading to an increase in the ratio of abdominal fat to non-abdominal fat.31 This chronic condition is associated with lower quality of life and has a strong relationship with the development and worsening of both diabetes and cardiovascular disease. (Obesity and diabetes are discussed in Chapters 35 and 36).
Many stressors do not necessarily cause a physiological stress response if psychological factors are minimised. Stress itself is not an independent entity, but rather a system of interdependent processes moderated by the nature, intensity and duration of the stressor and the perception, appraisal and coping abilities and resources of the affected individual, all of which in turn mediate the psychological and physiological responses to stress. Resilience is the ability of most individuals to maintain normal physiological and psychological function when exposed to stress, preventing the development of stress-related disease. Levels of resilience vary between individuals, with a number of factors playing a role. Resilience varies from person to person, with a number of factors mediating how resilient a person is in the face of stress. Genetic factors and early life experience play important innate roles and lifestyle factors, such as use of drugs or alcohol, exercise, and diet, play important environmental roles in resilience.36 In psychological distress, the individual feels a general state of unpleasantness after life events that manifests as physiological, emotional, cognitive and behavioural changes. Periods of depression and emotional upheaval are often associated with adverse life events and place the affected individual at risk for immunological deficits, increasing
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CONCEPT MAP
A
Stress response utilises hormones
Glucagon Cortisol Thyroid hormone Growth hormone
leads to Increased blood glucose levels manifests as
uses
Cortisol
activates the
Sympathetic nervous system leads to
leads to
Visceral obesity contributes to
Increased blood lipid levels manifests as
manifests as
Metabolic syndrome and type 2 diabetes
B
FIGURE 34.11
A The relationship between stress and type 2 diabetes.
Stress can lead to increases in blood glucose and blood lipid levels, increased visceral adiposity and sympathetic nervous system activation. Together, these can contribute to metabolic syndrome and type 2 diabetes. B Blood glucose monitoring for a patient with type 2 diabetes. Diabetes management requires frequent blood glucose monitoring.
the risk of ill-health.5 Examples of triggering circumstances include bereavement, academic pressures and marital conflict. Stressful life events and mood have been reported as important factors preceding the onset or exacerbation of symptoms in acquired immune deficiency syndrome (AIDS) infection, diabetes and multiple sclerosis.33–35 In addition, interaction with healthcare providers in a clinical setting,
the diagnosis of a major illness and various clinical procedures (e.g. blood sampling, injections, examinations, surgical procedures) may represent significant negative events for many individuals (see Fig. 34.12). These additional stressors may interfere with the efficacy of the medical intervention. Identifying and reducing stress in the clinical setting have particular applicability for both preventing disease and managing illness.
CHAPTER 34 Stress and chronic disease
A
POTENTIAL EFFECTS IN HEALTHY INDIVIDUALS
c fe
co pi
Ef
ng
Stressful life event
ng
In eff ec
pi co
tiv e
e t iv
Significant stress response Distress/illness
B
Transient effect Return to steady state
POTENTIAL EFFECTS IN SYMPTOMATIC INDIVIDUALS
In
ng
pi
eff ec
co
tiv
e
e
tiv
co
pi
ec Eff
ng
Stressful life event
Exacerbation of illness
C
Little or no effect on symptoms
POTENTIAL EFFECTS DURING MEDICAL INTERVENTION Symptoms +
–
Diagnosis
If perceived as stressor
Treatment
+ = Stimulation – = Inhibition
FIGURE 34.12
Health outcome determination in stressful life situations is moderated by numerous factors. Whether a life-challenged individual experiences distress or illness depends on the subject’s appraisal of the event and the coping strategies used during the stressful period. Models A and B reflect possible outcomes in stressed healthy and symptomatic individuals. Model C illustrates the dynamic clinical setting in which the diagnosis of a serious illness and subsequent medical interventions may be perceived as stressful challenges and have potentially detrimental influences on physical outcome.
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RESEARCH IN F CUS Stress, fatigue and burnout Burnout is a stress-related state that is characterised by mental and physical fatigue. We’ve all experienced burnout at some point in our lives — that feeling of simply not being able to do any more, often accompanied by a feeling of failure or incompetence. Think about the last time you crammed for an exam in the wee hours of the morning before the exam. Burnout is simply the physiological and psychological consequence of spending too much time in the exhaustion stage of the generalised adaptation response. In most cases, we move away from the task, have a good night’s sleep and recover. However, burnout in the workplace represents a significant problem. Workplace burnout is associated with a combination of high psychological demands and relatively poor resources. Healthcare workers are among the most prone to work-related burnout. High levels of burnout were found in a population of haemodialysis nurses, particularly in those stressed about the risk of acquiring an infectious disease through their work. Thus, the chronic stress that leads to burnout may predispose healthcare workers to stress-related health complications. The fatigue that is associated with burnout represents another potentially lethal outcome of work or task-related stress, particularly in the context of operators of heavy machinery. The stress associated with shift work or work in an unfamiliar or hostile environment, which is the norm for military personnel, mining workers and long-haul drivers, can lead to a state of fatigue in which the operator is no longer competent to operate machinery. This is evidenced by countless industrial accidents that have been linked to fatigue, including high profile disasters at the Three Mile Island nuclear plant, the Bhopal chemical plant and on board the Exxon Valdez. The development of objective biological measures of fatigue and/or sleepiness to assess operator state is desirable for a number of industries to prevent both major and minor accidents. To be useful in industry, biomarkers need to be sensitive to changes in state, easily collected in the field in a non-invasive manner and closely linked to subjective and other objective markers of fatigue. Currently, there is a lack of validated biomarkers of acute fatigue. This is an active area of research in Australia and New Zealand, with universitybased researchers at Monash University and the University of South Australia collaborating with the Australian Defence Science and Technology Organisation, the New Zealand Defence Force, the Australian Transport Safety Bureau as well as the mining industry to develop novel biological markers and other objective ways to assess fatigue in individuals who may be at risk for burnout.
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Personality characteristics and stress
Personality characteristics are associated with individual differences in the interpretation of stressors. Many of these are genetically predisposed or are due to early life experience and determine how reactive an individual will be to a psychological stressor; in other words, how well they will cope with stress.37 Other mediating factors that may influence stress susceptibility, resilience or ability to cope include age, socioeconomic status, gender, social support, religious or spiritual factors, and current health status. Coping is the process of managing stressful challenges that tax the individual’s resources.38 Adverse consequences of stress may be minimised by coping styles, as the stress signal reaching the hypothalamus will be less intense. Coping styles associated with altered immunity include repression (unconscious forgetting of periods of intense stress), denial, escape–avoidance and concealment. Repression has been associated with lower monocyte counts, higher eosinophil counts, higher serum glucose, inhibited T-cell response and more self-reported medication reactions in medical outpatients.39,40 In addition, higher Epstein-Barr virus antibody titres have been observed in students who exhibit repression.41 Another study found increased markers of accelerated human immunodeficiency virus (HIV) infection in men who concealed their homosexual identity42 and therefore were living with the stress of keeping a major secret. Evidence suggests that effective intervention may result in greater stress resilience and improved psychological and physiological outcomes.43 For example, women with recurrent metastatic breast cancer who were provided weekly group counselling in addition to routine medical treatment lived an average of 19 months longer than control subjects.13 On the other hand, those who had major stressors in their lives had increased incidence (or relapse) of their breast cancer.44These important findings highlight the serious and adverse effects of stress on health. The importance of social support for seriously ill individuals has focused attention on the health of caregivers. Significant stress manifested as depression, anxiety and fatigue has been noted in family caregivers of those with cancer, Alzheimer’s disease and burn trauma. Patients and caregivers exhibited suppression of various measures of immune function, with improved function associated with better perceived social support.38 Therefore, the improved ability to cope with the stress has had a positive outcome on the stressed individual.
Sex hormone influences on stress
Gender-based coping differences may be attributed, in part, to the sex hormones, with females more likely both to seek and to offer social support, a behaviour with an oxytocin/ oestrogen association.45 Oxytocin is a pituitary hormone with stress-decreasing properties: this has been shown in animal experiments, where elevations in oxytocin were associated with reduced hypothalamic–pituitary–adrenal axis activation and reduced anxiety.46 Oxytocin in some
tissues works in concert with oestrogen; these two hormones have a calming effect during stressful situations.47 The oxytocin-mediated calming of the stress response may promote the ‘tend and befriend’ response, more commonly experienced by women because oestrogen is a co-mediator.45 Also, oestrogen is thought to mediate the more robust immunological profiles of females,48 resulting in enhanced resistance to infection but risk for autoimmune diseases. Testosterone and cortisol are both steroid hormones. However, in one major sense, their actions oppose one another. Cortisol release stimulates an increase in blood glucose by breaking down glycogen, fats from adipose tissue and, in extreme cases, protein from skeletal muscle. One of the roles of testosterone, on the other hand, is to stimulate protein production, particularly in the skeletal muscles. Stimulation of the hypothalamus by stress leads to repression of testosterone secretion, thus shifting the body’s energy metabolism to a catabolic state — the breakdown of larger macromolecules for the production of glucose. Testosterone levels decrease after stressful stimuli such as anaesthesia and surgery.49 In addition, psychological stressors decrease testosterone levels, and individuals with respiratory failure, burns and congestive heart failure show a marked reduction in plasma testosterone.50 Decreased levels of testosterone occur during ageing and are associated with a lower cortisol responsiveness to stress-induced inflammation, suggesting a decreased physiological response to chronic stress in older men.51 In fact, this balance between catabolic hormones, such as cortisol and thyroid hormone, and anabolic hormones, such as testosterone, has been suggested to be a major factor in the development of frailty and cognitive decline in older adults. In older men, in particular, the decline in testosterone levels is accompanied by an increase in cortisol and thyroid hormone levels. The anabolic hormones are thought to play a role in protection of the nervous system by preventing neuronal loss. Elevated levels of the stress hormones, in contrast, may induce neuronal damage or death leading to cognitive decline.52 As testosterone decreases in response to such varied physical stresses, it has been suggested that testosterone may impair the ability to respond to stress. In acute, severe physical stress situations, males may be at a disadvantage because the presence of testosterone has not declined quickly enough. Males have a higher risk for morbidity after injury and testosterone exhibits immunosuppressive activity.50 Thus, different effects of stress on males and females may be partly explained by gender-related hormonal profiles that influence the characteristics, quality and outcomes of the stress response.
Strategies for coping with stress
Interventions to prevent or manage stress-related psychological or physical problems include both short- and long-term coping strategies. Educational components are specific to the individual’s problems. Exercise is one of the useful tools for minimising the adverse effects of stress, as discussed above. A number of relaxation techniques have
CONCEPT MAP
CHAPTER 34 Stress and chronic disease
Stress
Relaxation interpreted by
interpreted by
Cerebral cortex (thought) sends information to Limbic system signals the Hypothalamus/pituitary initiates Autonomic nervous system Endocrine system results in results in ↑ Heart rate ↑ Ventilation ↑ Muscle tone ↑ Metabolic rate ↓ Immune function
↓ Heart rate ↓ Ventilation ↓ Muscle tone ↓ Metabolic rate ↑ Immune function
FIGURE 34.13
A simplified chart showing the cyclic mind–body and body– mind influences of stress and relaxation, and on health. As our body experiences the physical responses to stress and relaxation, our central nervous system remembers them, causing a continuation of the cycle and resulting in long-term positive or negative physical consequences.
been shown to lower the physiological stress response (see Fig. 34.13) including meditation, imagery, massage, yoga, breathing exercises and biofeedback. In particular, numerous peer-reviewed studies have been run analysing the effects of mindfulness meditation and yoga on stress. Both techniques have been shown to result in significant decreases in psychological stress symptoms. The effects of yoga and mindfulness meditation on physiological and biochemical markers of stress have also been assessed, with inconclusive results.53,54 Nonetheless, these and related relaxation techniques offer a number of advantages over pharmacological therapies. These approaches may be used on an individual or support-group basis. Incorporating these approaches into clinical training facilitates their use in the clinical arena. Future research should focus on the efficacy of such approaches with various populations.
Physical activity
Perhaps the most effective activity for minimising the impact of stress and improving resilience is physical exercise. There is extensive research on the benefits of exercise in the context of stress.55 Even though physical exercise leads to an acute stress response, regular exercise seems to normalise the stress response by reducing reactivity to stressors.56 In fact, those who are more physically fit actually have a less heightened stress response,57 which shows the benefits for
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the body in minimising the undesirable effects of chronic stress. Regular exercise, therefore, has been shown to improve stress-related health problems. For example, with exercise there is a substantial improvement in glucose tolerance, which improves diabetes and related conditions, potentially by lowering cortisol levels.58 Hyperlipidaemia improves and abdominal fat decreases with exercise.59 Furthermore, the effects of chronic stress within the brain are effectively counteracted by moderate exercise.60 However, the overall amount of physical activity that we undertake is quite low. In Australia, 34% of people lead sedentary lives and a further 31% undertake only low levels of exercise, meaning that 65% of people over the age of 15 do not undertake the recommended moderate exercise levels.61 The data are more positive in New Zealand, with only 49.5% of the population not undertaking regular physical activity62 — but this figure is still high.
FOCU S ON L EA RN IN G
1 Outline the benefits of the stress response. 2 Discuss how stress and exercise are related. 3 Explain why stress-related diseases occur. 4 Discuss how the immune system participates in stressrelated disease. 5 Explain how the stress response can be altered.
Stress and sleep Many factors undergo regular daily patterns, such as body temperature and the secretion patterns of some hormones. In this section we explore how some hormones involved in the stress response are secreted in patterns associated with the circadian rhythm, the roughly 24-hour cycle that governs a number of our physiological processes. We also consider the impact of changes to our normal circadian rhythm and how these changes may influence disease.
Hormonal fluctuations with circadian rhythm
Two key hormonal systems associated with circadian fluctuations are cortisol and growth hormone. Cortisol secretion, stimulated by the hypothalamus and anterior pituitary (hypothalamic–pituitary–adrenal axis), is subject to a regular circadian rhythm, with a daily peak in cortisol secretion shortly before waking followed by a rapid decrease for 2–3 hours after awakening. This early morning peak is commonly referred to as the cortisol awakening response (Fig. 34.14). Cortisol levels are steady or decline slowly over the remainder of the day, with the lowest daily levels around midnight.63 It is likely that the surge of cortisol just prior to waking assists in elevating blood glucose levels, due to the lengthy time since eating prior to sleep. The
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0.8
Cortisol (µg/dL)
0.6
0.4
0.2
0.0 0
5
10
15
Time since waking (h) FIGURE 34.14
The cortisol awakening response. Cortisol levels are highest just before waking and decline quickly within the first hour after waking. Graph shows salivary cortisol levels (ug/dL) over the course of a typical day in 35 healthy middle-aged men.
Sleep and circadian regulation of stress hormones
Normal sleep patterns are essential to maintaining circadian regulation of stress hormones and other physiological
Circadian rhythms
Stress
influence
influences
Hypothalamic–pituitary–adrenal axis and it then Controls reactions to stress and regulated body processes secretes Cortisol causing Altered immune response FIGURE 34.15
Stress and altered circadian rhythms can lead to altered immunity. Alterations in the circadian rhythms and the effects of stress influence the hypothalamic–pituitary–adrenal axis, which in turn modifies secretion of cortisol to alter the immune system responses.
CONCEPT MAP
effects of cortisol cause a morning breakdown of proteins to increase blood glucose. One of the benefits of eating breakfast is that it can help to counteract the effects of cortisol on protein breakdown, as glucose becomes available from the food. The secretion of growth hormone surges during the middle of the night. The increase of this hormone during the first few hours of sleep may be to enable the maintenance of growth and restorative processes, at a time when the body’s overall demands for oxygen and nutrients are low. Although circadian rhythms set up the regular, cyclical patterns of hormonal secretion in the healthy individual who has regular sleep patterns, these rhythms can be altered by the stress response.64 This means that periods of stress cause surges in the hormones at times of the day that do not necessarily match the regular circadian patterns. Abnormalities in the circadian pattern of cortisol secretion, for example, have been associated with a number of pathologies including HIV-AIDS, breast cancer, and has been found to be predictive of early mortality.65 The interactions between the circadian rhythm, stress and the hypothalamic response to stress can alter cortisol secretion and the immune system function (see Fig. 34.15).
processes. Sleep is a state of partial unconsciousness during which many of the brain’s higher functions are shut down or repressed, but more basic processes continue (control of heart rate, blood pressure and respiration: the process of sleep is discussed in Chapter 6). Sleep is essential for the maintenance of normal homeostasis and chronic sleep restriction is a health hazard linked to impaired immune function, insulin resistance and obesity. Interestingly, experimental data points to links between shortened sleep and the altered glucose metabolism common in individuals under long-term stress.66 There are inextricable links between sleep patterns and the stress response. For example, if you sleep much less than normal for one night, you often find yourself irritable, unable to focus and more reactive to stress than you would be on a typical day. On the other hand, the reason you may not have gotten enough sleep on the previous night may be due to life stressors — concern about an upcoming exam, family problems or perhaps a heavy night on the town. Excess stress can be both a cause and a result of sleep loss. This is due to alterations in the normal circadian rhythms of cortisol secretion.
CHAPTER 34 Stress and chronic disease
associated with sleep disturbances and reduced natural killer cell numbers. Irregular or inadequate levels of sleep can interrupt the body’s normal circadian rhythms. Insufficient sleep may link to weight gain (see Fig. 34.16), which is a substantial issue in our society. Glucose tolerance and balance in the morning appear to be related to growth hormone secretion through the night and to the overall levels and fluctuations of blood glucose and insulin levels that occur during sleep.70,71 This suggests that insufficient sleep may lead to impaired tolerance to glucose — which is a main contributing factor to type 2 diabetes. SLEEP LOSS
– – – – – –
Cortisol and sleep
The relatively low overnight levels of cortisol are required to maintain normal sleep patterns. Minor fluctuations in cortisol secretion overnight are required for cycling between various sleep stages overnight and play an important role in overall sleep quality.65,66 Acute stress causes an increase in cortisol production and release, as well as increased sympathetic nervous system activity, which increases alertness and can make it difficult to relax and fall asleep. Chronic stress can lead to chronic elevation of cortisol levels, making regular sleep even more difficult. Of more concern is a state of adrenal fatigue, in which the adrenal cortex no longer responds to ACTH, leading to chronically low levels of cortisol. Because cortisol plays a role in regulating blood glucose levels, lower than normal night-time levels of cortisol do not adequately sustain blood glucose levels. Low blood glucose can trigger waking, causing disrupted sleep during the night.
Sleep, stress and immunity
The relationships between regular sleep patterns and the immune system are complex, but are mediated in large part by stress. The pineal gland regulates the immune response and mediates the apparent effects of circadian rhythm on immunity (the role of the pineal gland in sleep is discussed in Chapter 6). When melatonin production in the pineal gland is blocked (by continuous light or by pharmacological means), the immune response is suppressed; whereas administration of melatonin reverses these effects.67 This may affect immune changes found with sleep disturbances and altered circadian rhythms,68 which are common among acutely ill and stressed patients. Stress-induced sleep loss also directly inhibits the innate immune responses.69 A study undertaken on recently bereaved individuals found that greater frequency of escape–avoidance behaviour was
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Altered glucose metabolism. Increased appetite. Unhealthy food choices. More time to eat. Reduced energy expenditure? Reduced physical activity?
ENERGY EXPENDITURE ENERGY INTAKE ENERGY BALANCE FIGURE 34.16
Relationship between sleep loss and weight gain. A schematic representation of potential pathways through which sleep loss may lead to a positive energy balance in which energy intake is greater than energy expenditure.
Shift work and disease
We have considered some of the benefits of maintaining adequate patterns of sleep and some of the problems associated with sleep disturbance. Many people do not maintain regular sleep patterns and in this section we explore some of the issues that may arise from irregular sleep. Of particular concern to healthcare workers is the impact of shift work on circadian rhythms and stress. In the healthcare industry (and other industries) where staff are required to work irregular shifts throughout the day and night, workers are forced to adjust their normal sleep–wake cycles in order to meet the demands of changing work rosters. This can lead to sleep disturbances, fatigue and problems with cognitive function, and resistance to illness and disease may be altered.
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Secretion of the hormones melatonin and cortisol remain similar to their regular pattern during the first few days of shift work, but the pattern of growth hormone secretion appears to be affected more quickly. Over time, in those whose employment is based on shift work, there are decreased secretions of cortisol, with increased growth hormone.72 It can take 2 weeks of adaptation before the new circadian rhythm is reset64 — at this point, the shift worker may have been rotated to a different shift roster and so the process of adjusting needs to start all over again. Shift work is associated with a decreased ability to perform tasks as well as gastrointestinal disturbance,73 insomnia and sleepiness at undesirable times74 — this is known as shift-work sleep disorder. There is some evidence of an increased risk of cancer (breast, colon and prostate)75 in those who work night shifts. In addition, melatonin secretion is decreased in those who work night shifts, which may be related to an increased risk of endometrial cancer75 — however, this risk has been shown to occur in obese people and not those of normal weight, which indicates the complex nature of this system. There is also evidence to indicate that shift work may be associated with chronic disease such as coronary heart disease, metabolic syndrome and infection, but it is unclear why this is so and whether it is a result of the shift work itself or other lifestyle factors — including stress.76 Complicating the issue further is evidence that factors such as gender, age and weight are more significant than the influence of shift work on health complaints,77 as well as the finding that breast cancer risk is not linked to shift work.78 One theory that has been proposed over the last few decades is that the use of lighting at night may be a factor in some undesirable health effects, perhaps by causing a reduction in the amount of melatonin produced.75,78,79 A number of behavioural approaches have been proposed to help manage the health issues associated with shift work. One of these involves use of light therapy to ‘re-set’ the body clock (see ‘Research in Focus: Light therapy for shift
work’ below). The actual relationship between the altered hormonal and circadian patterns that occur with insufficient sleep and the medical alterations of shift workers is quite complex and is still being determined.70
FOCU S ON L EA RN IN G
1 Discuss the hormonal patterns associated with the circadian rhythm. 2 Explain how disturbed sleep patterns relate to disease. 3 List factors that change with ageing and the stress response.
RESEARCH IN F CUS Light therapy for shift work A number of therapies have been proposed for treating the stress associated with shift work. These include pharmacological interventions, such as melatonin and caffeine, as well as non-pharmacological interventions. One of the more promising non-pharmacological options is timedlight exposure. This type of treatment involves exposure to brief bursts of bright light at particular times and is thought to reprogram the body’s circadian clock and to alleviate some of the stress associated with shift work. It has been found that short daily exposure to intense blue light is able to regulate melatonin production and to advance the circadian rhythm. In other words, when changing shifts, workers could use blue light exposure upon waking on the first morning of the new shift. The exposure to blue light would help to reprogram to body’s circadian clock and to alleviate some of the physiological stress associated with the sudden change in circadian rhythm.
One of the most significant factors that determine a person’s ability to cope with stress, or their resilience, is early life experience. Exposure of children to severe stress can have a broad range of effects that can last throughout their life. These include development impacts on the brain and body that include effects on cognitive function, behaviour and an increased risk for a number of physiological and psychological disorders.81 For example, schizophrenia is thought to result from an interaction between genetic factors that predispose individuals to the disease and early exposure to severe stress.82 Early exposure to severe stress generally makes
children more reactive and less resilient to stressors as adults.83 Physiologically, severe stress in early life leads to alterations of the hypothalamic–pituitary–adrenal function, and excessive release of cortisol in the face of relatively minor stressors. This dysregulation in children can lead to early puberty, reduced adult height and changes to adult body composition. More importantly in the context of healthcare, it can also lead to early-onset diabetes, metabolic syndrome and type 2 diabetes.84 The most vulnerable periods of development for exposure to severe acute or chronic stress are before
PAEDIATRICS
Paediatrics and stress
CHAPTER 34 Stress and chronic disease
birth, childhood and adolescence. The types of stressors that can impact upon future health vary and depend in large part on genetic factors.37 Certainly, traumatic events such as physical or sexual abuse have significant lifelong effects on the stress response. But even less severe stressors, such as a cold or uncaring family or chaos in the home environment are associated with
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emotional problems, depression, posttraumatic stress disorder, increased risk for obesity and cardiovascular disease.85,86 Even maternal stress during pregnancy results in long-term physiological and psychological effects on children, notably the development of an anxious or nervous temperament and increased stress reactivity.87
Ageing and stress reserve and coping. In addition, the process of ageing itself can trigger a psychological stress for some people.80 The elderly are also more likely to become bereaved due to the death of spouses and family members or to be thrust into a caregiver role for a spouse or be exposed to healthcare-associated stresses, thus increasing their allostatic load. As a result, older adults tend to be at a higher risk for developing stress-related health problems.
chapter SUMMARY The general adaptation syndrome • Stress is defined as the state of affairs arising when a person relates to (i.e. interacts or transacts with) situations in a certain way. How the individual appraises and reacts to situations is important. • Selye identified structural changes in response to varied noxious stimuli (stressors) and believed that the three changes were caused by a nonspecific physiological response to any long-term stressor. He called this response the general adaptation syndrome. • The general adaptation syndrome occurs in three stages: (1) the alarm stage, (2) the resistance stage, and (3) the exhaustion stage. Diseases of adaptation develop if the stage of resistance or adaptation does not restore homeostasis.
Stressors • Physical stressors directly activate the hypothalamus, while other stressors require integration of sensory information to determine whether the situation is a stress; if so, then the hypothalamus will become
activated. The stress response is initiated when a stressor is present in the body or perceived by the mind. • Psychological stressors can be anticipatory and triggered by anticipation of an upcoming stressor or can be reactive to a stressor. Both of these psychological stressors are capable of eliciting a physiological stress response. • In most circumstances of stress, a physical response is not necessary, as the stressors are psychological. Furthermore, physical activity is quite low even when the body is not stressed.
The detection of stress • Stress is detected by the hypothalamus. While physical trauma activates the hypothalamus, other sensory information is interpreted by the hypothalamus, to determine whether it is a stress. • In the alarm stage, the sympathetic nervous system becomes activated to undergo a mass discharge of activity. Hormones are released via the hypothalamic– pituitary axis. Continued
AGEING
With ageing, a set of neurohormonal and immune alterations, as well as tissue and cellular changes, may develop. These changes include a rise in the blood concentration of adrenaline and noradrenaline (catecholamines), antidiuretic hormone and cortisol. There is also a pattern of chronic inflammation and increased blood coagulation. These stress-related alterations of ageing can influence the course of developing stress reactions and lower adaptive
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• The resistance stage reflects a slowing down of the responses from the alarm stage, as the body has adapted to stress. • If the stress continues, exhaustion may ensue; this can lead to chronic disease.
Physiological processes of the stress response • The stress response involves the nervous system (sympathetic branch of the autonomic nervous system) and the endocrine system (hypothalamic–pituitary– adrenal axis).
Physiological effects of the stress response • In general, the sympathetic nervous system releases adrenaline and noradrenaline (catecholamines), which prepare the body to act by: increasing cardiac output and increasing blood flow to the heart, brain and skeletal muscles by dilating vessels that supply these organs; bronchodilation, which increases delivery of oxygen to the bloodstream; and increasing mental alertness. • The hypothalamus stimulates the pituitary gland to secrete adrenocorticotrophic hormone, which in turn stimulates the adrenal cortex to secrete cortisol: cortisol mobilises glucose, lipids and amino acids. Cortisol at low levels consistent with stress can increase humoral immunity, activate pro-inflammatory mediators and decrease cellular immunity. Cortisol at high levels (e.g. therapeutic levels) decreases both humoral and cellular immunity and is anti-inflammatory. • The hypothalamus also stimulates the release of antidiuretic hormone, aldosterone and growth hormone from the pituitary gland as part of the stress response. • Other hormones are affected by the stress response; these include increased circulating levels of βendorphins, prolactin and oxytocin. Testosterone decreases during the stress response.
Benefits of the stress response • The stress response prepares the body for physical activity and allows for increased mental processing, speed of reactions and effectiveness of the skeletal muscles, heart and lungs.
Health alterations with chronic stress • The long-term effects of stress can have detrimental effects on health. For example, gastric ulcers, poor
wound healing, osteoporosis, impaired memory, cardiovascular disease, type 2 diabetes and cancer are all associated with stress.
Modulation of the stress response • Psychological distress is linked with poor health outcomes. • Personality characteristics are associated with individual differences in appraisal and response to stressors. Coping styles associated with altered immunity include repression, denial, escape–avoidance and concealment. • Gender differences in the stress response include the calming effect of oestrogen in females and a decrease in testosterone after stress in males. • Effective strategies for managing stress include relaxation techniques, yoga and breathing exercises, which can modify the stress response reaching the hypothalamus.
Stress and sleep • Fluctuations in growth hormone and cortisol occur normally over a 24-hour cycle. Disturbances in sleep patterns can alter the cycle of hormone secretion, which is related to development of disease. Shift work may be associated with some adverse health effects, including decreases in concentration and the development of some cancers, although research into this is continuing. • High stress levels are both a cause and a result of poor sleeping patterns or sleep loss.
Ageing and stress • Ageing itself is a psychological stress for some people. • Changes in the stress response associated with ageing are potentially damaging.
Paediatrics and stress • Early life exposure to stress can have long-term effects on a child’s ability to cope. • Early life stress is associated with a number of stressrelated disorders later in life.
CHAPTER 34 Stress and chronic disease
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CASE STUDY
ADULT Stephen owns a small business in the swimming pool industry and had to take some time away from work recently to undergo knee surgery. Although Stephen was concerned about having to be away from his business at a time when the weather was warm and work was busy, his surgery was necessary so he booked into hospital. After the surgery, Stephen stayed in hospital overnight but found it very difficult to sleep due to the noise of the staff and other patients. On returning home, pain and discomfort from his knee kept waking him up through the night. In the days after surgery, Stephen undertook short periods of work, managing the accounts and taking orders, and was regularly on the phone to his staff. The knee surgery was a success, but after 2 weeks Stephen noticed that his wound had developed an infection,
so he saw his doctor immediately. The infection was obviously clearing after a few days of antibiotic therapy. 1 Describe how Stephen’s physical stress of surgical trauma would have been detected by his brain. Does this physical stress require interpretation by the cerebral cortex? 2 Describe how the mental stress that Stephen experienced regarding keeping his business running was detected by his brain. Does this mental stress require interpretation by the cerebral cortex? 3 Compare the features of the stress response to the two different stress types, namely physical and psychological. 4 Explain how Stephen’s stress in the days after his knee surgery may have contributed to the wound infection. 5 Broadly describe how Stephen’s broken sleep patterns could have altered some of his body processes.
CASE STUDY
AGEING Russell is 71 years old, and has recently experienced significant grief as his wife passed away 6 months ago. Although he feels like he is getting through the pain, he is significantly affected by her death. He and his wife used to do the grocery shopping together, as he would push the trolley while she would put the food in it. Now, he finds that he has to walk up and down the aisles slowly, never being quite sure of what will be coming next. His wife used to do all the cooking while he set the table, but now he has to do the cooking, and it still feels strange setting the table with just one plate. He feels like cooking is just too much work, with all that preparation and cleaning up,
for just one meal. He is otherwise fairly healthy, with his only medication being to prevent blood coagulation. 1 Which stage of the general adaptation syndrome do you think Russell is in at the moment? Explain. 2 Outline the main functions of cortisol in the stress response. 3 List the main diseases that Russell is at increased risk of developing now that he experiences this stress. 4 Which hormones are likely to be raised for someone Russell’s age who is experiencing stress? 5 Why is it so important that Russell continue to take his medication to prevent blood coagulation?
REVIEW QUESTIONS 1 Explain what the stages of the general adaptation syndrome represent. Discuss how someone might progress through those stages if facing a chronic stress. 2 List the features of the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis that cause the physiological changes of the stress response. 3 Explain how aldosterone and antidiuretic hormone contribute to the stress response. 4 Discuss how cortisol influences the immune system and explain how this is different when the cortisol is administered as a drug treatment. 5 Outline the ways in which exercise is beneficial for minimising the effects of stress.
6 Describe how stress is related to poor wound healing and explain what stress does to neurological function. 7 Compare the stress-related mechanisms for the development of hypertension and type 2 diabetes. 8 Explain how relaxation activities can be useful in limiting the impact of stress. 9 Outline the part(s) of the brain that control (a) sleep and (b) waking. 10 Describe the hormonal regulation of cortisol and the impact of dysregulation of cortisol on sleep and disease.
Key terms adipose cells, 1083 body mass index (BMI), 1076 central obesity, 1077 leptin, 1084 obesity, 1076 obesogenic, 1075 obstructive sleep apnoea, 1084 omentum, 1083 overweight, 1076 peripheral obesity, 1077 satiety, 1084 subcutaneous fat, 1083 visceral fat, 1083 waist circumference, 1077 waist/hip ratio, 1077
CHAPTER
35
Obesity Elizabeth Anne Cayanan
Chapter outline Introduction, 1075 The progression to overweight and obesity, 1075 Evaluation of body size, 1076 Body mass index, 1076 Waist circumference, 1077 Body composition, 1078 Obesity, 1078 The extent of the issue, 1078
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Risk factors for the development of obesity, 1079 Health complications associated with obesity, 1084 Metabolic syndrome, 1092 Evaluation of metabolic syndrome, 1092 Chronic complications associated with metabolic syndrome, 1093
CHAPTER 35 Obesity
Introduction In this chapter, we consider a chronic health complication that is rapidly increasing in prevalence in our society, and has substantial associated health risks: overweight and obesity. While Australia and New Zealand do not classify obesity as a disease, the effects of overweight and obesity are one of the leading health concerns, and have a major contribution to morbidity and mortality (see Fig. 35.1). In the next section, we discuss the classifications of body size into overweight and obese. Overweight and obesity have become the norm for the Australian population, with more people being overweight and obese than those of healthy weight. Obesity is defined as an excessive storage of energy as fat, which has adverse effects on health. Obesity is an important risk factor for the development of coronary heart disease, which was discussed fully in Chapter 23. It is also a significant risk factor for the development of type 2 diabetes which is discussed in Chapter 36. Metabolic syndrome may be considered an intermediate condition between obesity and other conditions such as diabetes and coronary heart disease, as the presence of abdominal obesity and other characteristics of this syndrome are also risk factors for these conditions. Importantly, the consequences of obesity can underpin the progression of comorbidities, and can also extend beyond physical ailment into the psychosocial and economic aspects of life.
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The progression to overweight and obesity Obesity is a chronic condition, which generally develops when energy intake exceeds energy expenditure. In this context, energy is measured in kilojoules (where 1 kilojoule = 0.24 calories), and this can be used for measuring either food intake or energy expenditure. Energy that is not needed by the body is stored in adipose tissue. The digestive system is particularly efficient at digesting and absorbing most of the available nutrients from foods, including energy. Excesses of energy contained in dietary fat, protein and carbohydrate, as well as alcohol, may all be stored as adipose tissue. This is particularly useful in preparing for times of famine when intake of nutrients is low, as body stores can then be released and used. However, given the contemporary environment in Australia and New Zealand, where there is often an abundance of energy-dense foods and drinks available, these excess stores are rarely required. Therefore, while adequate amounts of energy and fats are essential for survival, overweight and obesity develop when the amount of stored adipose tissue is more than is necessary for normal body function. Modern Western society promotes an obesogenic environment, which means that there is a tendency towards the development of obesity, and individuals are rarely in Overweight can lead to Obesity
Risk factors • age • family history • dietary factors • cigarette smoking • genetic influences • sedentary lifestyle • stress
and Metabolic syndrome which can develop into Type 2 diabetes
can lead to
Coronary artery disease
which are major contributors to Morbidity and mortality
FIGURE 35.1
The relationship between the development of increased body size and metabolic syndrome, coronary artery disease and diabetes. These conditions can impact upon each other, and have substantial effects on morbidity and mortality.
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Part 6 Contemporary health issues
a state of famine. To the contrary, there is an expectation that food be readily available on demand. This is coupled with a 24-hour lifestyle, meaning that the working day is typically longer, and technology has migrated to the home setting to foster after-hours work and sedentary recreational activities. People are continually connected to the world at large, and the outcome is less physical activity, less sleep and a greater physical and emotional burden on health. Such challenges work against our physiological efficiency for energy storage, promoting obesity and hindering effective weight loss. As weight increases from a healthy range, the individual is considered as overweight — further increases in body fat result in obesity. The distinction between being overweight and obese is based on body mass index and lie on a continuum (see below). In this chapter, we focus more on obesity, as this signals the largest body size and it is associated with the highest risk of serious illnesses and mortality. However, it should be noted that although being overweight does not attract consequences as severe as obesity, it still increases an individual’s likelihood of chronic diseases, and for many individuals, overweight is a sign to act now to prevent the development of obesity.
Evaluation of body size Body mass index and waist circumference are the most widely used methods for measuring or estimating body fat mass, and in most cases they provide sufficient information for clinical assessment of body size. Hence in this chapter we concentrate on these two methods. However, several other methods are available, including CT and MRI techniques, dual energy x-ray absorptiometry (DEXA), bioimpedance analysis, underwater weighing and other anthropometric measurements such as skin-fold thickness and waist-to-hip ratios. Each of these techniques has limitations and benefits according to the individual for which they are used. For instance, CT and MRI techniques offer a relatively accurate means of assessing visceral fat but are not readily accessible in clinical settings and can be time consuming to analyse. Underwater weighing and DEXA scans are broadly accepted as an accurate means of assessing body composition, although not all facilities that manage obesity have access to such equipment. Skinfold measures are more reliable in lean or healthy individuals, and indeed should not be used in an obese cohort. Body mass index and waist circumference provide a sufficient platform for monitoring obesity in a clinical setting, and are readily accessible to both clinician and patient.
Body mass index
Body mass index (BMI) defines overweight and obesity. It is calculated by measuring the weight in kilograms (kg) and the height in metres (m). This technique was first observed in the 19th century by a Belgian mathematician who noticed weight was proportional to height squared in those with a ‘normal frame’. To obtain the BMI, the weight
is divided by the height value squared (height multiplied by height). Thus: BMI =
weight (kg) height2 (m2 )
So, for someone who weighs 65 kg and is 1.7 m tall, the calculation is: 65 (kg) 1.72 (m2 ) BMI = 22.5 BMI =
Those who have a BMI of 25 and over are overweight; those who have a BMI of 30 and above are obese, which is then divided into different categories of obesity (see Table 35.1). As weight increases, the risk of comorbidities increases substantially. Obesity refers to excess body fat, and BMI defines the degree of obesity experienced by the individual. However, BMI is based only on body weight, regardless of its composition. So, an individual who has a large amount of muscle bulk can have a heavier weight, but without storing excess fat they would not actually be at any increased health risk. In that case, a high BMI would not necessarily be a cause for concern. BMI values are age independent and the same for both sexes. The health risks associated with increasing BMI are continuous; however, the interpretation of risk may vary for different populations. Despite the limitations of BMI that we will discuss here, it does correlate well with the percentage of body fat in populations. Once BMI reaches 35, the graphical relationship with body fat is no longer reliable at the population level.1 As mentioned, BMI does not distinguish between weight due to muscle and weight due to fat. Therefore, the BMI calculation of a muscular athlete may suggest that the
TABLE 35.1 Classification of weight by BMI* CLASSIFICATION
BMI
RISK OF COMORBIDITIES
Underweight
< 18.50
Low (but risk of other clinical problems increased)
Normal range
18.50–24.99
Average
Overweight
≥ 25.00
Pre-obese
25.00–29.99
Increased
Obese class I
30.00–34.99
Moderate
Obese class II
35.00–39.99
Severe
Obese class III
≥ 40.00
Very severe
*These BMI values are age-independent and the same for both sexes. However, BMI may not correspond to the same degree of fatness in different populations due, in part, to differences in body proportions. The table shows a simplistic relationship between BMI and the risk of comorbidity, which can be affected by a range of factors, including the nature of the diet, ethnic group and activity level. The risks associated with increasing BMI are continuous and graded and begin at a BMI above 25. The interpretation of BMI gradings in relation to risk may differ for different populations. Both BMI and a measure of fat distribution (waist circumference or waist:hip ratio (WHR)) are important in calculating the risk of obesity comorbidities.
CHAPTER 35 Obesity
individual is overweight or obese, rather than reflecting muscle bulk. At the opposite end of the scale, the elderly have less muscle bulk, as well as being shorter. As a result, their BMI calculation may actually underestimate their condition of overweight. Also, people with a very long leg length, such as some Aboriginal Australians who are very tall and lean, may have quite low BMIs, and therefore the healthy BMI range for these people is lowered to 17–22. Individual level diagnosis of excess adiposity via BMI may be flawed, particularly when BMI values are in the overweight and not obese range (below 30 kg/m1), and hence patients will have undiagnosed excess adiposity.2 Furthermore, cases of normal weight obesity, which refers to those people with a normal BMI but high body fat content, experience a higher prevalence of metabolic syndrome and other cardiovascular risk factors.3 The fact that BMI does not consistently correlate with body fat means this method of obesity assessment should not be used in isolation, and indeed the BMI should be interpreted with caution. Despite these limitations, epidemiologic studies show a correlation between a high BMI value and morbidity, disability and mortality and a high correlation coefficient between body fat and BMI.2
Waist circumference
Another commonly used indication of body size is waist circumference. Waist circumference remains the currently preferred measure of body size, because it more directly indicates the amount of fat stored around the abdomen (visceral fat). The waist measurement is measured midway between the lower rib margin and the iliac crest with the person in the standing position, without heavy outer garments and with emptied pockets. For some overweight individuals, this can be difficult to locate, and hence the narrowest point is measured. The measurement is taken at the end of a normal exhalation and the value is recorded in centimetres. Waist measurements are categorised into increased risk and substantially increased risk for males and females (see Table 35.2). The specific location of the measurement may be less relevant in some individuals, as the relationship between waist circumference and morbidity and mortality remains the important focus.4 Obesity usually presents with two different forms of adipose tissue distribution (see Table 35.3). Central obesity (also known as visceral, intraabdominal, android or masculine obesity) occurs when the distribution of body
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fat is localised around the abdomen and upper body, resulting in an apple shape. Measurement of the waist circumference is a good indication of the amount of central obesity, and hence the waist circumference will be higher with central obesity. Peripheral obesity (also known as gluteal-femoral, gynoid, or feminine obesity) occurs when the distribution of body fat is below the waist around the thighs and buttocks, resulting in a pear shape (see Fig. 35.2). Males who are overweight and obese are usually characterised by central obesity, with the excess fat stored around the waist. Younger women tend to have less centrally located fat than men, as most of their stores are usually below the waistline. However, after menopause, the female distribution becomes more central. In the sections below, we further discuss why central obesity is a particular health concern, which supports the use of the waist circumference as the preferred measure of body size. Combining the BMI calculation with the waist circumference gives a better overall perspective of an individual’s status (see Table 35.4). For example, a male with a BMI in the overweight category is at further risk of major health complications if he also has a waist circumference greater than 102 cm. Therefore, healthcare professionals should always consider both BMI and waist circumference when providing information to individuals, as body shape may influence the individual’s overall risk. Waist/hip ratio is calculated as the ratio of waist to hip circumference. This measure has been popularly considered
TABLE 35.3 Comparison of fat distribution in obese individuals CENTRAL OBESITY
PERIPHERAL OBESITY
Apple-shaped
Pear-shaped
Visceral and abdominal fat stores
Hips and buttocks fat stores
Higher risk of obesity-related complications
Lower risk of obesity-related complications
TABLE 35.4 Combined BMI and waist circumference measurements for increased risk of type 2 diabetes WAIST CIRCUMFERENCE
Men
TABLE 35.2 Waist circumference and risk of health complications
94–102 cm
102+ cm
Women
CLASSIFICATION
BMI (kg/m2)
WAIST CIRCUMFERENCE (cm)
Underweight
< 18.5
—
—
Men
Women
Healthy weight
18.5–24.9
—
Increased
Increased
≥ 94
≥ 80
Overweight
25–29.9
Increased
High
Substantially increased
≥ 102
≥ 88
Obesity
≥ 30
High
Very high
RISK OF METABOLIC COMPLICATIONS
80–88 cm
88+ cm
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measurements such as weight and waist circumference provide valid alternatives to define excess body fat. Body fat can be estimated based on BMI, where these calculated estimates are comparable to skinfold measurements or bioelectrical impedance: Body fat per cent = 1.2 (BMI) + 0.23 (age ) − 10.8 (gender ) − 5.4 ( the value for gender is 1 for men and 0 for women).
It is also necessary to remember that lipids have a range of essential structural and functional roles in the body and therefore it is important to have some fat in the diet to maintain a healthy body weight with a normal level of body fat. It is excessive stores of fats as associated with disease that are of concern in this chapter. FOCU S ON L EA RN IN G
1 Explain how to calculate BMI and indicate the different BMIs for overweight and obesity. 2 Discuss the potential uses and limitations of the BMI calculation. 3 Discuss the use of the waist circumference measurement as an indication of body size.
FIGURE 35.2
A Central obesity. B Peripheral obesity.
In central obesity, excess body weight tends to be stored around the abdomen, while in peripheral obesity, it is mainly stored in the buttocks, hips and thighs.
as a marker of fat distribution for the last century. While some experts believe it to be more strongly correlated to mortality than waist circumference, the ratios are difficult to interpret.5 For example, a high ratio may be indicative of either a high waist circumference or a small hip circumference.
Body composition
Approximately 20–25% of body weight in a normal weight person is fat. The percentage of body fat increases with age in both sexes, with women generally having a higher percentage than men.6 Adult men with a healthy weight have approximately 15–20% body fat, and in women this percentage is higher at 25–30%. These differences can be explained in part by the influence of gonadal steroids on body composition and appetite. There are no cut-off points for body composition with regards to morbidity and mortality risk, although excess body fat has been defined as exceeding 25% in men and 35% in women. The proportion of body fat also increases with increasing body size and can exceed 45% of body weight in those who are obese class III (BMI > 40). It is difficult to obtain precise measures of body fat in clinical settings and so anthropometric
Obesity The extent of the issue
In 2014 worldwide, 1.9 billion adults were overweight and of these, 600 million were obese. This equates to 39% of adults being overweight and 13% being obese worldwide. There is an increasing prevalence of obesity in underdeveloped parts of the world resulting from cheap, energy-dense foods. It is estimated that around 224 million school-age children are overweight, making this generation the first predicted to have a shorter life span than their parents. In addition, 41 million children under the age of 5 were overweight or obese in 2014.7 The rates of obesity have been increasing over recent decades (see Fig. 35.3A). In Australia in 2017, 36% of the adult population were overweight only (i.e. over their ideal weight, but not obese), and a further 28% were obese, meaning 64% of the population were above ideal weight (Fig. 35.3B).8 The situation is almost identical in New Zealand, as 66% of the population are overweight, which includes 34% being only overweight and 32% being obese.9 In Australia, slightly more men are overweight and obese than women (71% and 56%, respectively). Obesity is one of the Australian National Health Priority Areas, as it is a huge cost to the health system — it is the second highest cause of the burden of disease, second only to tobacco use.10 Data from the Australian Diabetes, Obesity and Lifestyle (AusDiab) study showed the total direct cost for overweight and obesity in 2005 was $21 billion ($6.5 billion for overweight and $14.5 billion for obesity); with indirect costs of $35.6 billion per year.11
CHAPTER 35 Obesity
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B 70 60
A 60
50 Males
Percentage
Percentage
80
Females
40 20 0
Obese Overweight
40 30 20 10
1990
1995
2001 Year
2005
2008
0
2014–15 Australia
2017 New Zealand
FIGURE 35.3
The prevalence of overweight and obesity in Australia and New Zealand. A Changes in the percentage of overweight and obese men and women in Australia. B Percentage of the population who are overweight and obese in Australia and New Zealand.
There is a higher proportion of obesity in Indigenous Australians compared with non-Indigenous Australians: in 2017, 69% of adult Indigenous Australians were overweight, with 29% being overweight only and a further 40% obese.8 Depending on their degree of ‘Westernisation’, Aboriginal Australians may have a much higher or lower prevalence of obesity than the non-Indigenous population. In addition, a high proportion of Māori are overweight, with a total of 78% of the Māori population being overweight in 2017, consisting of 28% being overweight only and a further 50% being obese.9
Risk factors for the development of obesity
Weight increases when the energy consumed exceeds physical activity, and hence energy consumed is greater than the energy requirements — this excess energy is stored as adipose tissue. However, concluding that overweight or obesity is driven by merely physical inactivity or ingestion of large amounts of food or drink is an oversimplification. Equally, treating these behaviours in isolation without consideration for the broader driving factors can result in poor patient outcomes. The complex interplay of numerous influences on energy intake and expenditure can originate either within or external to the individual (see Fig. 35.4). These can drive the imbalance between energy intake and consumption, and these encompass a range of lifestyle and environmental factors, genetics and metabolic or endocrine disorders. These factors must be simultaneously addressed to promote successful obesity reduction. Less than 20% of individuals who have attempted to lose weight, achieve and maintain a 10% reduction over a year.12 Individuals tend to regain more than one-third of
the lost weight within 3 to 5 years,13,14 which remains a challenge for patients and health professionals.
Steady state weight
Feedback loops between the brain and the periphery control weight regulation, as long-term signals are related to energy stores and short-term signals are related to nutrient availability. The body then adjusts energy balance based on these signals to match the long- and short-term needs. In general, the response promotes a positive energy imbalance, the replenishment of energy stores and an increase in nutrient availability. Our stable steady state body weight is affected by homeostatic, behavioural and environmental influences. These interact with each other to establish a steady state weight, at which the individual stabilises, and they are also influenced by genetics. Changing any one of these pressures will change the individuals’ steady state weight. The homeostatic system must change in response to these pressures during the development of obesity, during weight loss and weight regain.15 Individuals can avoid ongoing weight loss or weight gain through the adaptation of the homeostatic system, despite ongoing changes in the environmental and behavioural influences. In this way, biology becomes a driving force for weight regain after weight loss. The modern environment has become more obesogenic to favour behavioural choices that increase energy intake.16 As a result, energy is stored and metabolism is forced to adapt to prevent perpetual weight gain. These biological adaptations re-establish a balance with the obesogenic pressures to achieve a new (higher) steady state weight.15 It is interesting to note that some people become obese and others don’t, despite similar obesogenic pressures. This may be somewhat explained by mouse models where rodents can be divided as obese resistant or obese prone. Despite
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Part 6 Contemporary health issues
Inside the person
Outside the person
Increased intake
Increased intake
Emotional eating Heightened hunger response Delayed satiety (sense of fullness) Impaired glucose tolerance Mood disturbances Smoking cessation
Larger portion sizes Lack of nutrition education Increased availability of energydense, nutrient poor options Food advertising
Energy storage Fat stores
BMI
Adipocytes
Decreased expenditure Exercise avoidance Mood disturbances Physical disabilites Pain sensitivity Age-related changes such as menopause Conditions of hormonal imbalance
Decreased expenditure Increased screen time Labour-saving devices Decreased opportunity for physical activity Consistent temperature (indoor heating/cooling)
FIGURE 35.4
Potential contributors to obesity Various factors, within and external to an individual, can contribute to increased energy intake and decreased energy expenditure.
access to identical food types and physical activity, the obese resistant mice sense the nutrient overload, increase fat oxidation, elevate expended energy and re-establish energy balance.17,18 In contrast, the obese prone mice continue to eat to excess until expenditure increases from their accumulated mass to re-establish energy balance. In humans, the highly palatable and rewarding components of the diet drives a desire of the brain to eat more, further challenging the homeostatic system.19,20 Restricting food intake can provide weight loss; however, satisfactory amounts of weight loss usually does not occur without restricted intake. When an individual balances at a lower steady state weight due to homeostatic adaptation, they often experience a ‘plateau’ in their weight loss.15 They must then step up their environmental and behavioural strategies to resume weight loss. The problem lies in most individuals perceiving the changes for weight loss as a temporary change, or not using
sustainable methods so the biological adaptations start to drive weight regain.21,22
Lifestyle factors
Lifestyle factors which contribute to obesity include food intake and habits, physical activity, stress, smoking and socioeconomic status. UNHEALTHY DIET
As noted, the contemporary diet in Australia and New Zealand allows ready access to energy-dense foods. Such foods are high in fats and simple sugars, but low in important nutrients such as vitamins, minerals and proteins, to render them a cost-effective option for rapid food production. Processed foods and takeaway fast foods have become increasingly prevalent in our community within the last 20 years and are typically energy dense. The majority
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of obesity does not solely occur as a result of fast food intake. Generally, poor dietary patterns, meal skipping and overconsumption at infrequent times are the driving cause of weight gain, in addition to large portion sizes. Other generally unhealthy dietary habits include lower diet quality, such as insufficient consumption of fruits, vegetables, grains and fibre. Low-starch vegetables unfortunately rarely feature as a staple ingredient within meals, and meals are often carbohydrate-dense. It is important to note that in remote communities, particularly within the Indigenous population, the scarceness of fresh food and irregular meal times adds to the burden of making healthy lifestyle choices. Despite broad public health advertising campaigns regarding fruit and vegetable intake, almost half of all Australians do not eat sufficient servings of fruit and more than 90% do not consume sufficient vegetables (the recommendation is two fruits and five vegetables per day).23 The guidelines for healthy eating in Australia recommend limiting intake of foods high in saturated fat such as biscuits, cakes, pastries, pies, processed meats, commercial burgers, pizza, fried foods, potato chips, crisps and other snacks.24 The Australian Dietary Guidelines suggest that 20–35% of total energy intake should be from fat, 45–65% from carbohydrates and 15–25% from protein. Although no specific macronutrient may be solely responsible for the development of obesity, the proportion of macronutrients in the diet does influence energy and nutrient intake, which may impinge on weight management and health outcomes.
lifestyle than seen in previous generations, and the likelihood is that such trends will continue to drive an obesogenic environment, which increases the tendency towards obesity. Despite the clear reduction in physical activity in modern society, an interesting study assessed total energy expenditure in Hadza hunter-gatherer tribes of Tanzania. It reported there was no difference between the nomadic, hunter-gatherers compared to Western populations,27 so it is likely it is the combination of physical inactivity and high-energy diets typical of modern civilisation that contributes greatly to obesity. Australian physical activity guidelines are based on the adequate level of physical activity for weight maintenance and the key message is to be active on most, preferably all, days every week. Individuals are encouraged to accumulate 150 to 300 minutes of moderate intensity physical activity or 75 to 150 minutes of vigorous intensity physical activity, or an equivalent combination of both moderate and vigorous activities, each week. In addition, people should do muscle strengthening activities on at least 2 days each week.28 This recommendation is for all people, to assist in maintaining weight and overall good health. For those individuals requiring weight loss, Australia bases the recommendation on the American College of Sports Medicine Guidelines which recommend greater than 250 minutes of cardiorespiratory exercise per week.29 The importance of physical activity cannot be overestimated, and evidence consistently supports a combination of dietary and exercise changes to support long-term weight loss maintenance.
PHYSICAL INACTIVITY
Stress may be either a cause or a result of obesity. It is most likely that stress causes physiological and physical changes, including emotional eating and altered cortisol secretion, to worsen developing obesity (see Chapter 34 for more about stress). Stress resulting from various factors including relationship, employment or personal issues, can influence obesity. It is important that the direct impact of stress on eating be considered in an individual’s trajectory towards obesity. This includes skipping meals and subsequently gorging later in the day. Ongoing stress must be effectively managed in order to improve the eating patterns. Stress is also a factor for those in particular age groups, including adolescence, menopause and the ageing. These periods are associated with significant changes in metabolism and energy utilisation, factors which can induce weight gain. This is why these transitional periods are often considered to be obesogenic, and many individuals struggle to maintain a steady state weight when hormonal and stress-related signals drive greater energy intake. For example, menopause is associated with weight gain independent of age, as a result of oestrogen deficiency associated with hyperphagia (increased eating) and increased body weight, especially visceral adiposity.30–34 Stress can also have a significant impact on sleep and periods of stress can cause insomnia in some individuals. Changes in sleep patterns alter metabolism and long-term sleep restriction is also considered to be a driver of weight gain.35
Physical inactivity was identified as the fourth leading risk factor for non-communicable diseases, and accounted for more than 3 million preventable deaths worldwide in 2009.25 The advancement in technologies in recent decades has significantly impacted upon physical labour, and resulted in decreased overall energy expenditure, with changes in transport also decreasing physical activity. Together, the overall decrease in physical activity in recent decades is detrimental for human body function, as most systems do not develop and function in an optimum way unless stimulated by frequent physical activity.26 Low levels of physical activity are now commonplace for a range of reasons related to the modernity of social contexts. Many workplaces have become sedentary as a result of computerisation where historically physical labour was more commonplace. Sedentary recreational activities such as television, computer games, and overall screen-time mean an increased amount of our recreation time is spent sitting down. The cost of living has driven many people to live further away from their place of work in suburbia or rural areas, which has contributed to more people driving rather than using physical modes of transport such as walking or cycling. We also depend heavily on labour-saving devices such as remote controls for televisions and garage doors, which all reduce the potential for energy expenditure. Together these components make for a more sedentary
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SMOKING
Nicotine seems to reduce appetite in the short term, which explains why smokers tend to have lower body weight than non-smokers, and why smoking cessation is often followed by weight gain.36 Contrary to this, heavy smokers tend to have greater body weight than light or non-smokers which likely reflects a cluster of risk behaviours that drive obesity.37–39 While much attention has been directed towards smoking cessation and its tremendous health benefits, evidence suggests those who quit smoking may undergo considerable weight gain (approximately 5–6 kg within a year).40 Clinicians should consider supporting those quitting smoking with adequate direction and follow-up to aid weight maintenance or weight loss in order to prevent the likely weight gain following smoking cessation. SOCIOECONOMIC FACTORS
Socioeconomic status and education levels can impact substantially on lifestyle choices such as food selection, physical activity and understanding the importance of maintaining a healthy weight. Furthermore, those in rural areas generally have less access to wide varieties of healthy food, exercise options, and support and medical care. Where health clinics are available, health delivery is often overstretched, leaving little time for formal health-promotion activities.41
RESEARCH IN F Obesity and the gut
CUS
The gut microbiota has been linked with various chronic diseases including obesity. Humans are in fact ‘supraorganisms’, composed of human and microbial cells and thus carry two sets of genes — those encoded in our genome and those encoded in our microbiota. Our genome contains about 23 000 genes, while the microbiome can contain upwards of 3 million genes, making it a unique identity. Interestingly, obese individuals with less bacterial variety have more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial-rich individuals. Those with less bacterial variety also gain more weight over time and as such, the gut microbiome can be used to identify subsets of individuals who may be at a greater risk for progressing to obesityrelated comorbidities. Recent evidence from animal and human models suggests faecal microbiota transfer could also be used as a therapeutic intervention against obesity, where the obese phenotype can be transmitted by gut microbiota transplantation. Microbial analyses after Rouxen-Y gastric bypass showed the overabundance of Proteobacteria in the distal gut microbiome, a distinctly different finding from the changes seen in patients who lost weight without Roux-en-Y gastric bypass. Future research will explore the impact of various obesity treatments upon the gut microbiome.
Genetic factors
Genes have a significant role in the pathogenesis of obesity, and over 300 genes have been identified that could influence obesity. There are different patterns of genetics and obesity — monogenic, syndromic and polygenic. Monogenic obesity is rare and has a severe and early-onset associated with endocrine disorders. It is related to mutations in genes related to leptin (discussed below) and the melanocortin axis which is involved in food intake regulation. Syndromic obesity corresponds to obesity associated with other genetic syndromes. These patients present clinically as severely obese and in addition, have mental retardation and certain developmental abnormalities (most commonly Prader-Willi syndrome or Bardet-Biedl syndromes). Polygenic obesity is more common, and in such cases, each susceptible gene has a slight effect on weight where the cumulative contribution of these genes becomes significant, particularly when this occurs in conjunction with an obesogenic lifestyle. In Chapter 38, we further explore the complex relationships between genetics and environmental influences on health.
Metabolic disorders
Metabolic abnormalities associated with obesity include increased production of cortisol (Cushing’s syndrome), polycystic ovarian syndrome, hypothyroidism and hypothalamic injury. Diagnosis and adequate treatment of these metabolic disorders is important in preventing weight gain. Insulin is often indicated as the hormone promoting weight gain in these conditions, and the nature of its interaction with obesity will be further explored in this chapter and the next. PATHOPHYSIOLOGY
Visceral obesity
Visceral obesity is associated with an increased risk of metabolic alterations including hyperlipidaemia, cardiovascular disease and insulin resistance, alongside the development of type 2 diabetes.42 Visceral fat is that which is stored around the abdominal organs, and is also referred to as central fat or central obesity. Abdominal fat is associated with specific changes in hormones that are involved in blood glucose regulation (see Box 35.1), which are consistent with the development of diabetes. For this reason, the waist circumference is an important measurement of body size, as it indicates the amount of visceral fat which is stored.
Effects of increased intraabdominal fat on glycaemic hormones
BOX 35.1
• • • •
Insulin resistance Increased insulin secretion Increased cortisol Decreased growth hormone
CHAPTER 35 Obesity
In those of healthy weight, 90% of body fat is subcutaneous (fat stored below the skin but outside of the visceral cavity) while the remaining 10% is visceral (lying beneath the abdominal wall). The omentum also stores visceral fat, and this is described as an apron-like flap of tissue lying below the abdominal muscles and over the top of the intestines. Visceral fat deposits lead to metabolic alterations, being a significant determinant of obesity-related metabolic complications, regardless of total adiposity. This is thought to be due to the venous draining of these adipocytes by the portal vein system. Furthermore, visceral adipocytes have hyperlypolytic activity which is associated with impaired free fatty acid metabolism because these adipocytes are resistant to insulin. This flux of free fatty acids towards the liver favours secretion of triglyceride rich lipoproteins, hyperinsulinaemia, and increases hepatic glucose production to contribute to glucose intolerance and type 2 diabetes (Fig. 35.5; see also Chapter 36). Therefore, visceral fat is metabolically active as it interacts with hormones, and may directly influence the liver. Stores of subcutaneous fat are usually referred to as being ‘quieter’ than visceral fat for these reasons, as subcutaneous fat is less involved with other body systems and contributes less to complications arising from obesity. According to the National Health and Medical Research Council: ‘Waist circumference appears to be the best clinical determinant of truncal (relating to the body trunk) obesity and hence metabolic risk.’43
secretes
Adipose cells
Adipose cells (adipocytes or fat cells) were previously thought to be relatively inactive, their only function being the storage of large droplets of fats — up to 90% of the cell volume is occupied by stored fat. However, we now know that adipose tissue is an endocrine organ, and adipose cells actually secrete molecules such as hormones and cytokines that are collectively known as adipocytokines (see Box 35.2). Adipose cells secrete at least 20 different substances that behave like hormones, in that they can bind to receptors on target cells to influence other body processes.44 In this way, adipose cells have a real and powerful effect on the body. Adipocytokines participate in the neuroendocrine regulation of food intake, lipid storage, metabolism, insulin sensitivity and female reproduction. Adipocytokines also influence the complement system, vascular homeostasis, blood pressure regulation and the inflammatory and immune responses. Adipose cells can also stimulate angiogenesis, to ensure that adequate blood supply is available for the increased amount of adipose stores — an increase of fat tissue will require increased blood circulation.44 Excessive increase in fat cell mass causes dysfunction in the regulation and interaction of adipocytokines and contributes to the complications and consequences of obesity. Adipose cells clearly have a diverse role and higher amounts of adipose tissue will result in a greater interaction with body processes.
Increased free fatty acids in systemic circulation
Increased risk of glucose intolerance and type 2 diabetes
results in
secretes Increased free fatty acids in portal circulation (to the liver) leads to Lipid deposition in the liver
re
su in lts
lts su re in
leads to
Increased secretion of: - glucose - insulin - triglycerides
results in
Increased risk of coronary heart disease e.g. atherosclerosis
FIGURE 35.5
Increased visceral fat increases the risk of type 2 diabetes and heart disease. The excess visceral fat secretes high levels of free fatty acids. In turn, these contribute to increased risk of both type 2 diabetes and coronary heart disease.
CONCEPT MAP
Visceral fat
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Examples of adipocytokines and hormones from adipose tissue
BOX 35.2
Adipocytokines Leptin: hunger/appetite suppression at hypothalamus; promotes insulin resistance and increases blood glucose levels Adiponectin: insulin sensitising for regulation of blood glucose; promotes anti-inflammatory vascular effects and reduces atherosclerosis Resistin: promotes insulin resistance and increases blood glucose levels Vistatin: mimics insulin and binds to insulin receptors Other hormones Tumour necrosis factor-alpha (TNF-α): a pro-inflammatory cytokine Angiotensinogen: increases blood pressure and blood volume Plasminogen activator inhibitor-1 (PAI-1): promotes clot formation by inhibiting plasminogen and urokinase Interleukins 6 and 8: pro-inflammatory cytokines
Taste Cerebral Smell cortex Sight stimulates Emotions the inhibits inhibits Hypothalamus inhibits Leptin Nutrients Insulin
GI hormones Neural signals
Adipose GI tract mass Energy absorbed
Energy ingested
to increase Food intake
FIGURE 35.6
Conscious thought about food by the cerebral cortex stimulates the hypothalamus. The hypothalamus regulates food intake. The digestive tract also sends signals to the hypothalamus. The hormone ghrelin is released by the stomach in the hours after a meal to increase appetite. When food is present in the stomach, stretch receptors send signals back to the hypothalamus, and gastrointestinal (GI) hormones are released to inhibit further food intake. The hormone leptin, which is released by adipose cells, inhibits appetite at the hypothalamus.
Control of appetite
Neuroendocrine regulation of appetite, eating behaviour, energy metabolism and body fat mass is controlled by a dynamic circuit of signalling molecules from the periphery acting on the hypothalamus45 (see Fig. 35.6). An imbalance
in this system is usually associated with excessive energy intake in relation to a decrease in exercise, with the consequence of weight gain and obesity. Appetite and body weight are controlled by many different hormones and signalling systems. These include insulin from the pancreas, ghrelin from the stomach, peptide YY from the intestines and leptin, adiponectin and resistin from adipose tissue. These hormones circulate in the blood at concentrations proportional to body fat mass and serve as peripheral signals to the hypothalamus where appetite and metabolism are regulated. Obesity is associated with increased circulating plasma levels of leptin, insulin, ghrelin and peptide YY and decreased levels of adiponectin. Interaction of these hormones with neuropeptides at the level of the hypothalamus may be an important determinant of excessive fat mass. One of the functions of leptin is to act on the hypothalamus to suppress appetite and function to regulate body weight within a fairly narrow range. Leptin secretion increases as adipose cells increase; however, high leptin levels are ineffective at decreasing appetite and energy expenditure, a condition known as leptin resistance (due to reduced leptin sensitivity). Leptin resistance disrupts hypothalamic satiety (the feeling of fullness), and can promote overeating, which may be a factor in the development of obesity46 (see Fig. 35.7). Decreases in adiponectin are also associated with insulin resistance, coronary heart disease, and hypertension, and may contribute to the complications of obesity.47
Health complications associated with obesity
Obesity is linked to increased morbidity and mortality which is associated with many significant health complications, including type 2 diabetes, coronary heart disease and some cancers (such as colorectal, breast in postmenopausal women, endometrial, prostate, kidney and oesophagus). The health crisis of diabetes is so extensive that we will explore it in more detail in the next chapter. Obesity is also a risk factor for stroke, hepatobiliary disease (gallstones and non-alcoholic fatty liver disease) and osteoarthritis. Pulmonary function can be compromised by a large amount of adipose tissue putting excess pressure on the chest cage, and obstructive sleep apnoea can occur as a consequence. The main disorders that are exacerbated by obesity are shown in Box 35.3.
Cardiovascular disease
Obesity is a significant risk factor for the development of cardiovascular disease (discussed in Chapter 23), and higher body weight corresponds to higher risks of complications and mortality. Obesity exerts its effects on the heart and circulation, both directly, and also by complicating other risk factors such as hypertension and diabetes. Dyslipidaemia is indicated by increased triglycerides, increased low-density lipoproteins (LDL) (‘bad cholesterol’) and lowered HDL (‘good cholesterol’) — this is related to the development of
CHAPTER 35 Obesity
Normal body weight
Obesity
Normal fat cell mass
Increase in fat cell mass
means that Leptin level normal affecting the Hypothalamus and leads to Decreased appetite and food intake Increased metabolism Increased sympathetic activity
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means that Leptin level increased excessively which adversely affects the resulting in Leptin resistance and other hormone action: Increased appetite and food intake Decreased metabolism Sustained sympathetic activity
FIGURE 35.7
Leptin theory of obesity. The hypothalamus controls appetite, fat cell mass and energy expenditure by responding to circulating levels of leptin and other hormones. Regulation of normal body weight is presented in the green boxes, and changes occurring with obesity are presented in the pink boxes.
BOX 35.3
Disorders exacerbated by obesity
• Cardiovascular disease (heart disease, dyslipidaemia, hypertension, stroke) • Diabetes (type 2 diabetes, pre-diabetes) • Cancers (colorectal, endometrial, breast, liver, kidney, pancreas, prostate, oesophagus, ovary) • Respiratory problems (sleep apnoea, hypoxaemia) • Gallbladder disease (gallstones, gallbladder cancer) • Musculoskeletal disorders (osteoarthritis) • Infertility • Psychological problems
coronary disease, and is common in obese individuals where there is a direct correlation between fat tissue and cholesterol. Furthermore, obesity is linked to abnormalities of the coagulation system, increasing the likelihood of developing thrombosis and myocardial infarction. The amount of fat surrounding the heart (epicardial fat) may be a contributor to cardiovascular disease in the obese — epicardial fat has smaller adipose cells, which behave in a slightly different way to other adipose stores, as they release fatty acids at high rates and are slow to decrease during weight loss.48 There is a strong relationship between the amount of epicardial fat and both the amount of abdominal fat and the presence of coronary atherosclerosis.49
Central obesity is associated with a number of cardiac structural changes, including right and left ventricular dilation and hypertrophy, left atrial dilation, and fatty infiltration of the conducting system. Several haemodynamic and metabolic abnormalities have been implicated in the development of hypertension in diabetes. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, insulin resistance, endothelial dysfunction and renal function abnormalities. One of the major mechanisms leading to the development of obesity-induced hypertension appears to be leptin-mediated effects on blood vessels and the kidneys. Leptin is a circulating peptide hormone that is primarily secreted by adipose cells. Although obesity is generally associated with resistance to the weight-reducing actions of leptin, the resultant increased levels of this peptide cause an increase in sympathetic nervous system activity and adversely lead to sodium retention. Further studies aimed at achieving better understanding of leptin signalling in the hypothalamus and in the renal and vascular systems may lead to new treatments for obesity-related hypertension.
Type 2 diabetes
A number of risk factors are common to obesity and diabetes, such as an unhealthy diet, physical inactivity, smoking and dyslipidaemia. It therefore comes as no surprise to learn that obesity and diabetes often, but not always, develop together. In many people, an increased waist circumference is the first major step in the process of
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developing diabetes. The risks of developing diabetes are significantly increased in the presence of increasing obesity (Table 35.4). Modifying risk factors associated with either diabetes or obesity will usually improve the other condition too. Type 2 diabetes is discussed in detail in Chapter 36. Diabetes attracts not only the inconvenience of a lifelong commitment to controlling and monitoring blood glucose levels, but also substantial health risks such as end-stage kidney disease and lower limb amputations. This can be a chronic debilitating disease that has substantial effects on the affected individual and the healthcare system.
Cancer
Being overweight or obese is a risk factor for cancer development, with there being evidence of increased risk of cancers due to increased body size, abdominal obesity, or adult weight gain.43,50 The types of cancers that have the strongest incidence in the obese can be broadly divided into those associated with hormones (reproductive organs) and those associated with the digestive system. These include endometrial, postmenopausal breast cancer, ovarian, and cancers of the colorectum, kidneys, gallbladder, liver, and pancreas. While some details of these risks remain unclear, a weight loss of even 0.5–1.0 kg is associated with a substantial decrease in mortality due to obesity-related cancers.51 The mechanisms that underpin sex differences and differences across ethnicities in terms of obesity-related cancer risk are not clear.52
Respiratory disorders
Obesity is associated with an array of respiratory disorders ranging from asthma to obstructive sleep apnoea, all of which are driven by different mechanisms. Respiratory function is impaired in obese individuals due to increased adipose tissue around the chest and abdomen, which makes expansion of the thoracic cage more difficult. This is worsened when lying down, as the abdominal fat tends to push towards the thoracic cavity, thereby making expansion of the lungs more difficult. This makes obese individuals more likely to experience hypoxaemia. As many as 45% of obese individuals are thought to experience obstructive sleep apnoea.53 Obstructive sleep apnoea is characterised by frequent episodes of hypopnoea (shallow breathing) and apnoea (complete breathing cessation) during sleep. Furthermore, obesity is the major modifiable risk factor for obstructive sleep apnoea. Patients with this condition report waking gasping for air, and as a result, experience excessive daytime sleepiness. Excess weight around the neck can constrict the upper airways — this is a particularly unnerving symptom, as patients wake up suddenly, gasping for breath (see Chapter 25 for more details). Obesity is a predisposing risk factor for developing asthma, but the underlying mechanism remains unclear. Furthermore, obesity impacts on asthma control, rendering medications less effective. Weight loss is associated with a universal improvement in asthma and should be a part of patient management.54
Gallbladder and liver disease
Cholelithiasis (gallstones) is three to four times more prevalent in obese individuals compared with non-obese people. This is due to increased hepatic secretion of cholesterol, which solidifies or precipitates as cholesterol gallstones. The risk is also increased in those with visceral adiposity who do not have an overall increase in the BMI. The liver is an important storage site for excesses of nutrients, including excess energy stored as fat. This makes the liver prone to becoming infiltrated with excess fat during obesity. As a result, non-alcoholic fatty liver disease is common (see Chapter 27), and the majority of patients with non-alcoholic steatohepatitis are overweight or obese, and also have insulin resistance which contributes to the underlying dysregulated energy metabolism.55 The associated lipotoxicity identified in these patients is responsible for various changes in the liver, that can lead to cell injury, apoptosis, and ultimately liver fibrosis and cirrhosis.56
Osteoarthritis
Osteoarthritis is characterised by pain and dysfunction of the joints. Osteoarthritis of the joints bearing most of the body weight (namely, the knees and ankles) is increased in obese individuals. Exercise in this group is particularly problematic unless carefully constructed to consider patient limitations. Excessive inflammation and mechanical stresses make low impact or non-weightbearing options such as swimming or cycling more sustainable options alongside specific gentle strengthening exercises.
Mortality
It is not surprising that with the profound effects that obesity has on the body systems, individuals who are obese have a higher mortality rate than those of normal weight. While there is considerable variability in the methods used to assess obesity and mortality, reported estimates range from 5–15% of mortality being attributable to obesity.57 In 2003, high body mass index contributed to 5.5% of the total burden of disease and injury in Australia, ranking as the second risk factor with the most attributable burden. High body mass index was responsible for 52% of diabetes burden, 38% of chronic kidney disease burden, 23% of coronary heart disease burden and 17% of stroke burden.58 In recent years, life expectancy has been increasing, largely due to a decrease in cardiovascular risks such as cholesterol, hypertension and smoking. However, the recent surge in the incidence of obesity has led to a lowering of life expectancy.59 In fact, one estimate is that obese individuals have a life expectancy 7 years shorter than those of a healthy weight.60 Having a lower life expectancy in an era of great modern medicine and research is of grave concern. Efforts to improve education about and modification of risk factors of obesity, cardiovascular disease and diabetes are necessary in order to develop healthier communities. This requires making changes in patients’ attitudes and their perceived ability to improve their own condition while equipping
CHAPTER 35 Obesity
them with the knowledge and tools to improve their health. This is the challenge for healthcare professionals. MANAGEMENT OF OBESITY
Obesity is a chronic disease that requires various approaches to treatment according to patient health status and psychological readiness; these can include individually tailored weight-reduction diets, exercise programs and correction of metabolic abnormalities. Self-motivation and support systems are critical aspects of treatment. Additional treatments, such as psychotherapy, behavioural modification, medications and bariatric surgery (surgery directed at weight loss, such as gastric banding), may also be prescribed and when successful, can significantly reduce weight and comorbidities.61,62 Achieving weight loss of even 5 to 10% of body weight (which is up to 30% reduction in visceral fat) will see improvements across a range of health complications and importantly a lowering of cardiovascular risk factors, as well as better control of blood glucose levels (see Box 35.4). Individuals who are obese do not come to the condition through the same avenue; therefore it is false to assume one approach is going to work for all patients. The prescription and strategies for treating obesity are as good as the clinician’s ability to collect information from the individual. Knowing someone’s behaviours, their historical weight trajectory and what has changed in their life over time will likely explain their weight gain, and help in how to go about managing weight. Knowing the features of an individual’s lifestyle allows clinicians to match the weight loss approach for the most likely potentially successful strategy. Effective treatment needs to identify how much of the problem is attitude, and also how much is the challenge that comes with being of the specific size of the obese individual. Unravelling the exact causes of obesity will likely lead to more specific prevention and management strategies.
Dietary factors
Overweight and obesity may be prevented by making individual choices that are aligned with a healthy lifestyle. This means: • choosing foods that are lower in fat, and changing from consumption of saturated fats to unsaturated fats — it is
Benefits of moderate weight loss (10% of body weight)
BOX 35.4
• Improved glycaemic control (lowering of fasting blood glucose levels) • Reduced cardiovascular risk factors (lowering of blood pressure and cholesterol, decreased tendency towards coagulation) • Improved lung function (less breathlessness, less sleep apnoea) • Alleviates osteoarthritis
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FOCU S ON L EA RN IN G
1 List the modifiable and non-modifiable risks factors associated with the development of overweight and obesity. 2 Discuss why visceral obesity is a particular health concern. 3 Explain the function of adipose cells. 4 Briefly explain the factors involved in the control of appetite. 5 Discuss the main health complications associated with being overweight or obese.
important that total energy intake is reduced, as simply reducing dietary fat without also reducing overall energy intake is not effective in achieving weight loss for the overweight and obese • limiting consumption of sugars and simple carbohydrates, especially via processed or refined foods, and limiting those foods which have a high glycaemic index (discussed in Chapter 36). • increasing consumption of fruits, vegetables, as well as some increased consumption of whole grains, legumes and nuts, whilst considering their carbohydrate content. A weight loss of even 5–10% of original body weight is defined as ‘modest weight loss’ and will result in benefits to the patient’s health.63,64 Some realistic weight loss goals are listed in Table 35.5, although these are dependent on individual circumstances. A realistic and achievable rate of weight loss is 0.5–1.0 kg per week and to achieve a weight loss in this range, an energy deficit of approximately 2000 kilojoules per day is adequate, which is known as a reduced energy diet. This reduced energy diet approach allows patients to make educated decisions about appropriate food choices and encourages them to focus on low-energy and healthier alternatives. It does not promote radical changes; in contrast, it favours sustainable and realistic adjustments while incorporating generally healthier options. Allowing patients to have flexibility in their food selection enables them to develop the skills necessary to maintain a healthy weight in the long term. These dietary changes are often easily applied to other members of the family and therefore promote healthy eating among household members. More prescriptive diets may be necessary for some patients according to their degree of obesity. A low-energy
TABLE 35.5 Realistic goals for weight loss DURATION
WEIGHT LOSS
WAIST CIRCUMFERENCE
Short term
1–4 kg/month
1–4 cm/month
Medium term
10% of initial weight
5% after 6 weeks
Long term
10–20% of initial weight
88 cm (females); 102 cm (males)
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diet provides a total of 4000–5000 kilojoules per day, while a very low-energy diet provides only 1700–3300 kilojoules per day — usually as liquid meals or shakes, which should also include some protein according to the patient’s ideal body weight. The very low-energy diet is particularly useful for those who have previously had little success with weight loss, or who have life-threatening risk factors that require urgent weight loss. These diets offer a means of rapid weight loss, and the use of shakes or prepackaged foods during these diets can make their prescriptive nature simple to follow. However, these programs are not a long-term sustainable solution. While using these diets, it is important to provide effective support and patient education, to ensure that patients learn the lifestyle changes necessary for long-term weight-loss maintenance. In particular, while on such programs, individuals do not benefit from learning about choosing and preparing healthier food choices (as they can if adopting the reduced energy diet). Hence, on ceasing the program, the previously consumed unhealthy foods are likely to be recommenced and any lost weight then regained, without adequate patient education and support.
RESEARCH IN F Fad diets
CUS
Fad diets are weight loss plans that promote quick results through temporary nutritional changes. There are a multitude of fad diets that come into popular attention and do not necessarily promote evidence based nutritional changes. These diets are often effective as they restrict specific macronutrients (i.e. the Atkins diet and ketogenic diet promote low carbohydrate intake and compensate with higher fat and protein foods). Some of these models of eating promote a worsening of cardio-metabolic profiles (such as triglyceride status) or suggest the use of detoxification or tonics to promote normal physiological functioning (neither of which are substantiated by evidence). Other dietary approaches which have recently been popular include interval fasting, which is fasting of a period of 16–48 hours, followed by normal eating (which brings a risk of binge eating), and the paleo diet, which includes meats, fruits and vegetables, but avoids grains, legumes and dairy (which brings a risk of insufficient fibre or dairy). Furthermore, many of these fad diets may have the benefit of promoting weight loss simply by means of the reduced energy intake, rather than there being any specific benefit of the dietary approach per se. Also, after the time on the diet is completed, any weight which has been lost is often regained.
Physical activity
‘Physical activity’ refers to body movements, and is not restricted to structured or formal exercise sessions. Combining exercise with dietary restraint is necessary for
effective weight loss.65 Frequent and moderate intensity physical activity are also recommended for maintaining health in those of a healthy weight.66 The benefits of exercise in consuming energy are two-fold, because on top of the amount of energy that is consumed by working muscles at the time of exercise, an episode of exercise can increase the metabolic rate for several hours afterwards, thereby continuing the higher consumption of energy after the exercise has ceased. Health benefits occur with moderate levels of physical activity, such as brisk walking for 30 minutes per day or by expending 4000 kilojoules of energy per week. Clinically significant weight loss can be achieved through at least 250 minutes of cardiorespiratory exercise per week.66 It is clear that more exercise leads to more weight loss; however, this must be in conjunction with decreases in dietary intake of energy. Those who are very obese may be somewhat limited in their exercise options due to mobility and joint issues. Appropriate choices include non-weight-bearing activities such as swimming, walking in water and cycling that offer lower joint impact. The principles of progressive overload should be applied, whereby patients are encouraged to gradually increase their exercise participation, in order to reduce the likelihood of injury and joint inflammation which can occur if commencing physical activity at an intensity too high at first.
Pharmacological agents
Pharmacological treatments should be considered after lifestyle approaches have proven unsuccessful; namely, the dietary, exercise and behavioural modifications. They may also be suitable for patients who have had some success with lifestyle modifications but need assistance to continue losing weight or to maintain weight loss. Medications are usually best targeted for those with a BMI of at least 30 or for those with a BMI greater than 27 with obesity-related comorbidities (such as hypertension, diabetes, obstructive sleep apnoea). While several anti-obesity agents have been withdrawn from the market due to concerning safety profiles, Australia currently lists liraglutide, orlistat, phentermine and fluoxetine as weight loss medications. In this section, we take a brief look at each of these medications. Liraglutide is a peptide that is similar to glucagon. It is given subcutaneously and may aid weight reduction (modest weight loss in studies). It works by slowing gastric emptying and increases the feeling of fullness. Liraglutide produced 5.2 kg weight loss after 1 year compared to placebo.67 It has not been shown to have a positive effect on the health complications associated with obesity. Compliance is often limited by gastrointestinal adverse effects. Orlistat works by preventing the absorption of dietary fat; however, it is a costly option that results in modest weight loss. It inhibits the action of the pancreatic lipase in the small intestine, which is responsible for the digestion of fats (see Chapter 26). As a result, fats cannot be digested and absorbed into the blood, and hence these exit the body
with the faeces. Orlistat produced 2.6 kg weight loss after 1 year compared to placebo.67 This treatment option may also be adequate in reducing other indicators associated with obesity, such as blood pressure and total cholesterol, although no improvements in mortality have been demonstrated. Common side effects due to the presence of excess fat in the faeces include diarrhoea, flatulence, abdominal pain and faecal incontinence. These side effects can be minimised by patients restricting their fat intake, which in turn can assist patients in adopting a healthier lifestyle by decreasing their intake of fatty foods. However, insufficient fat digestion may result in deficiency of fat-soluble vitamins over a period of time (vitamins A, D, E and K). Phentermine mimics some effects of the sympathetic nervous system, and therefore can be beneficial for weight loss due to increasing metabolic rate. It can also affect the hypothalamus, leading to decreased appetite. Phentermine produced 8.8 kg weight loss after 1 year compared to placebo.67 This medication has the potential for misuse, and it is not recommended for long-term weight reduction, despite its potential short-term role in behaviour modification, and is approved for 3 months’ use only. Fluoxetine and other selective serotonin reuptake inhibitors may aid weight loss in patients suffering depression; however, the effects appear to last only 6 months despite continued treatment. Until recently, sibutramine was another medication that was used to promote satiety (a feeling of fullness), thereby assisting patients to decrease their food intake. It stimulated the body’s basal metabolic rate, to assist in using energy and contribute to weight loss. However, there have been higher rates of cardiovascular events in obese and overweight patients compared to those using diet and exercise alone. Accordingly, it has been withdrawn from the market in Australia and elsewhere. Regardless of drug choice, if patients do not learn about appropriate food and lifestyle choices, they usually regain weight after drug treatment is ceased, if their patterns of food and physical activity do not support weight loss. Some inappropriate agents can cause weight loss too. Laxatives decrease the absorption of all foods within the gut, but they have a strong risk of electrolyte disturbances as well as damage to the intestines. Thyroxine increases the metabolic rate (see Chapter 11), but has an accompanying risk of arrhythmia and hypertension. Diuretics decrease overall weight by causing loss of body fluids, with the consequent risks of dehydration and electrolyte imbalance. These agents are not recommended for use in weight-loss programs.
Surgical treatment
Surgical treatment is usually reserved for those with a BMI greater than 40, or for those with a BMI greater than 35 with serious comorbidity risk factors. While usually explored after alternative therapeutic options have been attempted,
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surgery provides an effective treatment for weight loss and to aid the prevention of weight regain. Prior to surgery, it is important that patients be well educated about the potential results, and receive substantial support regarding the lifestyle changes required to ensure maximum weight loss success in the medium to long term. Surgical options include gastric restrictions, which decrease the functional size of the stomach, with the goal of limiting food intake. A ‘lap band’ procedure (laparoscopic adjustable gastric banding) involves laparoscopic insertion of a band towards the top part of the stomach, creating a small stomach pouch, and does not involve removal of any part of the stomach. This means the procedure is reversible, as the band can be adjusted to vary the degree of restriction. Alternatively, a sleeve gastrectomy procedure involves surgically removing the lateral side of the stomach which greatly reduces the expansion capacity of the stomach, and it changes from being a roundish organ to a longer, thinner shape, and hence this procedure is irreversible (see Fig. 35.8). A more substantive procedure is the Roux-en-Y bypass, in which most of the stomach is bypassed as well as the duodenum. A small pouch of the stomach is created, and attached directly to the jejunum of the small intestine. Together, these changes result in significant decreases in food intake and food absorption. Biliopancreatic diversion is a type of gastric malabsorption surgery usually reserved for the most obese patients. Liposuction involves removing localised deposits of fat, but is best used for those of normal weight who have excess fat deposits in certain areas and is therefore not a recommended treatment option for obesity. Patients undergoing bariatric surgery have a reduced risk of myocardial infarction, stroke, cardiovascular events and mortality compared with those who have not had surgery.68 Obesity must be treated as a chronic disease that requires longer-term patient follow-up, to determine the sustained effect of the treatment. Use of permanent surgical interventions must be supported with a range of allied health professionals to ensure the patient has the greatest likelihood of sustained success. Patients are also required to make lifelong changes to their approach to diet and physical activity, regardless of any other treatment used, and long-term support from health professionals is essential.
Complications of weight loss
In contrast to the range of health complications arising from carrying excess weight, the hazards associated with losing weight are few. Gallbladder disease may occur due to the release of cholesterol from storage in adipose cells; this can temporarily increase the concentration of cholesterol in the bile. An alteration in bone density may also occur, as the bone is remodelled while carrying less weight. However, those who are obese may already have low bone density, due to the effects of excess levels of leptin in obesity, which can lower bone density. This is an important and complex
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A Vertical banded
B
gastroplasty
Bypassed portion of the stomach
Oesophagus Stomach pouch
Gastric bypass (Roux-en-Y)
Band
Oesophagus
Duodenum
C Laparoscopically adjustable gastric banding
Stomach
D Gastric sleeve
Jejunum
Adjustable band Small remaining portion of stomach is ‘sleeve’ shaped
Large portion of the stomach is removed Stapler
FIGURE 35.8
Bariatric surgical treatment procedures. A Vertical banded gastroplasty. B Gastric bypass (Roux-en-Y). C Laparoscopically adjustable gastric banding. D Gastric sleeve.
interaction — weight-bearing exercise, a temporary process, stimulates increased bone mass by allowing the bone to remodel in response to the period of the weight-stimulation. However, carrying excess body weight as a full-time process does not achieve the same goal of stimulating increased bone mass, as the presence of excess leptin
prevents bones from remodelling with ideal bone mass. In the long term, bone density can be improved in these patients in a similar manner to that recommended for everyone — by undertaking weight-bearing activities and ensuring an adequate intake of calcium and vitamin D (see Chapter 21).
The Childhood Obesity Working Group of the International Obesity Task Force has published cut-off points for childhood BMIs at specific ages throughout childhood and adolescence, based on the adult reference BMIs of 25 for overweight and 30 for obesity.69 This links the growth patterns during childhood and adolescence through to body size in adulthood and
allows for appropriate early classification and diagnosis of overweight and obesity. The rate of increase in the percentage of children and adolescents who are becoming overweight and obese is alarmingly high. Approximately 25% of Australian children aged 2–17 were classified as overweight or obese
PAEDIATRICS
Paediatrics and obesity
CHAPTER 35 Obesity
in 2011–12.70 Furthermore, between 1995 and 2007–08 the percentage of obese children (those with BMI above 30) rose to 25%, and more recently has remained stable to 2011–12 (26%).70 Risk factors for the development of childhood obesity Overweight and obesity are often seen in families, and children with an overweight parent have a greater likelihood of developing obesity. This is probably due to a combination of poor lifestyle choices within the family, as genetics alone is usually linked to only 30% of weight variation. The causes for children developing obesity are similar to those listed for adults, such as sedentary recreational activities, increased consumption of energy-dense foods (such as high-fat foods and sugary soft drinks) and low levels of physical activity. Health professionals need to support parents in generating an action plan to address childhood obesity. Dietary changes with an emphasis on limited fat intake and smaller portions should be recommended.71 This should be alongside an increase in physical activity and reduction in sedentary behaviours. It is crucial that parents be engaged and support the behavioural change necessary as a family to ensure that weight loss is ongoing. Complications associated with childhood obesity The most common complication of obesity in young people stems from the social and psychological issues related to their increased weight. Such issues can drive longer term concerns related to self-esteem. Another manifestation is the development of physical bone alterations in the feet and lower legs. The extra weight being carried by the body stimulates bone remodelling and alterations as the epiphyseal plates in bones have not yet fused, allowing for changes in bone shape (see Chapter 20). These changes become permanent into adulthood. The development of acanthosis nigricans, thin velvety folds of skin around the neck, in the axilla and groin, occurs because of childhood obesity. This can be unsightly, causing more concern for those children and adolescents who may already be experiencing low self-esteem related to body image. Obesity can promote the early onset of puberty and the average age of menarche (the first menstrual period) in obese girls is 8 or 9 years of age — at least 2 years younger than the average for non-obese girls. In boys, obesity can cause gynaecomastia (breast development). Obese children experience headaches, including the less common pseudotumour cerebri (raised intracranial pressure accompanied by headaches and vomiting) — an urgent medical condition requiring treatment. Approximately half of all children presenting with pseudotumour cerebri are overweight or obese. Additional complications of childhood obesity are similar to those discussed for adults; namely, dyslipidaemia,
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hypertension, type 2 diabetes, gallstones, osteoarthritis and obstructive sleep apnoea.72 Perhaps one of the most significant consequences of childhood obesity is that it usually continues into adulthood, and this brings with it an increased risk of chronic disease and mortality later in life.72 Obesity in childhood is the strongest predictor of development of metabolic syndrome in adolescence and adulthood.73 Treatment of childhood obesity Goals for weight loss in children may be more appropriately directed at preventing further weight gain rather than decreasing weight, as phases of growth tend to see a lessening of the obesity. Parental education and support of the child are critical, and improved family lifestyle habits are effective in limiting weight gain. A range of other approaches include school and community group programs: community-based and population-wide programs targeting obesity are frequently promoted in Australia and New Zealand. Interestingly, there is some evidence that less regimented approaches may have greater success in children, such as decreasing television viewing time rather than increasing exercise time and a lower energy diet being consumed by the whole family rather than a prescriptive dieting program for the child. As children can find it difficult to choose appropriate lifestyle practices that control their weight, those lifestyle changes being adopted by the whole family can be a key approach to supporting the overweight child. A wide range of strategies are being developed to treat childhood obesity; however, the difficulty is often not just developing a program for the individual child, but ensuring the child adheres to such a program with the support of their parents. Prevention of childhood obesity is the preferable approach as, despite its prevalence, obesity is highly preventable. Strategies for the prevention of childhood obesity are currently the focus of much discussion in the literature. An important focus should be: • limiting screen time (e.g. television, electronic tablets and other devices) • encouraging outdoor play • limiting consumption of soft drinks and energy drinks. Issues that are more pertinent to children than adults include the need for entertainment — for children to engage in regular physical activity, they must obtain some level of amusement from the activity. Similarly, the importance of taste is critical to children in assisting with food intake — this can complicate the transition from processed, energy-dense foods to nutritious foods.74 The rights and protection of children Collecting measurements of children would be useful in improving the quality of data surrounding childhood obesity to enable improved population-level planning for education and treatment. The limitation of parental Continued
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consent restricts children from being measured in schoolbased programs.75 This becomes a balance between the requirements of information for groups seeking to address the problem of childhood obesity and parental perception of the importance of the information. Another complex and sensitive issue surrounding childhood obesity is the view that allowing children to become obese is a form of parental neglect, which places the child at substantial health risks.76 Although exposing children to lifestyle factors that contribute
F OC US O N L E ARN IN G
1 Describe and compare treatment options for obesity. 2 Discuss the complications associated with weight loss, including whether the benefits of weight loss might exceed any potential risks. 3 Discuss why childhood obesity is of particular concern. 4 Briefly state how childhood obesity may be treated.
Metabolic syndrome Metabolic syndrome is the cluster of risk factors linking obesity and the development of type 2 diabetes mellitus. While the relationship between obesity, metabolic syndrome and type 2 diabetes is not clear cut, substantial overlap in risk factors, signs and symptoms and chronic health effects indicates the likelihood of disease progression for many people. Metabolic syndrome is diagnosed in people who have central adiposity (increased waist circumference) and insulin resistance (in which blood insulin levels are between those seen in healthy people and those with diabetes) as well as other signs and symptoms as discussed below. People with metabolic syndrome are at an increased risk of developing cardiovascular disease and type 2 diabetes and therefore a diagnosis of metabolic syndrome can assist in making modifications to slow the progression to these chronic diseases. However, metabolic syndrome does not always lead to diabetes; similarly, some patients with type 2 diabetes would not be classified as either being obese or having metabolic syndrome. In addition to identifying those at risk of developing cardiovascular disease and diabetes, other important benefits of the diagnosis of metabolic syndrome include that it: • offers an explanation for patients to understand why they are developing multiple conditions simultaneously • illustrates the importance of, and interaction between, several modifiable risk factors • ensures that, by addressing the components of metabolic syndrome using the proven treatment of lifestyle modification, the onset of diabetes and cardiovascular disease is prevented and general health and wellbeing are improved.77
to obesity may be considered neglect on the behalf of parents, there is currently debate about whether healthcare professionals should notify child protection services about obese children and, if so, at what degree of obesity. On the other hand, this threat could discourage parents from seeking medical assistance for their obese children, thereby depriving the children of the opportunity for appropriate care. This ethical and legal issue is currently the topic of much discussion in the literature.
Evaluation of metabolic syndrome
Metabolic syndrome has been known by a number of other names, such as syndrome X and dysmetabolic syndrome. There are five components associated with the syndrome: • increased waist circumference • low HDL cholesterol • high triglycerides • high blood glucose levels • hypertension. These are detailed in Table 35.6. People with an increased waist circumference only need to have two of the other components to be classified as having metabolic syndrome.
TABLE 35.6 Criteria for the diagnosis of metabolic syndrome COMPONENT
MEASUREMENT
Abdominal obesity
Waist circumference (for those of European descent): Males ≥ 94 cm Females ≥ 80 cm
PLUS any two of the following Elevated triglycerides
≥ 1.7 mmol/L Or receiving specific treatment for elevated triglycerides
Lowered HDL cholesterol
Males < 1.03 mmol/L Females < 1.29 mmol/L Or receiving specific treatment for lowered HDL
Hypertension
Systolic ≥ 130 mmHg Diastolic ≥ 85 mmHg Or treatment of previously diagnosed hypertension
Elevated plasma glucose
Fasting plasma glucose ≥ 5.6 mmol/L Or previously diagnosed with type 2 diabetes
The syndrome is actually a debated collection of signs and symptoms, as four different classifications have been made by the World Health Organization and other professional organisations, focusing mainly on either diabetes or cardiovascular disease.78–81 Consequently, each definition has a slightly different emphasis and slightly different cut-off values for each criterion. Within this section, we use the criteria published by the International Diabetes Federation (see Table 35.6).82 This classification has lower cut-offs for fasting glucose and waist circumference and includes abdominal adiposity as a requirement. As a result, it includes more people and therefore increases estimates of prevalence, but this makes it less accurate in predicting the development of cardiovascular disease and diabetes.83 Because the classification criteria vary slightly with each definition of metabolic syndrome, care must be taken when reading data relating to the incidence and prevalence of this syndrome. Regardless of the choice of criteria used, diagnosing a patient with metabolic syndrome remains useful in management approaches to limit the progression of chronic disease.
Chronic complications associated with metabolic syndrome Coronary heart disease
People with metabolic syndrome have a greater burden of subclinical atherosclerosis, which reinforces the benefit of using metabolic syndrome to identify all risks together in patients.84 High levels of central adipose tissue are associated with dyslipidaemia, hypertension and cardiovascular disease. There is also evidence that metabolic syndrome predicts future cardiovascular risk, which underlines the importance of identifying all risk factors associated with metabolic syndrome in the development of atherosclerosis, not just the presence of obesity.
Type 2 diabetes
Increased amounts of central adipose are associated with insulin resistance, an important precursor to the development of type 2 diabetes. Elevated levels of glucose in the blood can indicate a pre-diabetic condition, which is an intermediate step between normal glucose handling and the development of type 2 diabetes (hyperglycaemia). Early diagnosis of alterations in blood glucose levels can allow
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for lifestyle changes to limit the progression to diabetes. An Australian study investigated the four published sets of criteria for the diagnosis of metabolic syndrome and found that none of these were superior to checking fasting glucose levels for predicting type 2 diabetes.77 Medical assessment should incorporate a range of fasting bloods to ensure complete risk assessment of patients. TREATMENT OF METABOLIC SYNDROME
One of the most important benefits of diagnosing a patient with metabolic syndrome is that it allows the individual to address the modifiable risk factors associated with obesity. The two main goals in the management of those with metabolic syndrome are to reduce the risk of developing atherosclerotic heart disease and to prevent the progression to type 2 diabetes. Weight loss is essential for the treatment of metabolic syndrome in order to alleviate the risk associated with the condition. Regular physical activity will reduce cardiovascular risk factors and has a strong protective effect against cardiovascular mortality with metabolic syndrome. This may also entail dietary changes to promote a reduction in fat intake in order to improve lipid profile and overall energy reduction for weight loss. Appropriate education and follow-up is essential if patients are to continue with adequate lifestyle changes. For example, in one study, patients who took part in a specific program of monthly nurse counselling meetings reduced their metabolic syndrome risk factors such as waist circumference and triglycerides compared with those who did not participate in the meetings.85 FOCU S ON L EA RN IN G
1 Discuss the criteria used in the classification of metabolic syndrome. 2 Briefly explain the potential benefits in being able to diagnose a patient as having metabolic syndrome. 3 List the main chronic complications associated with metabolic syndrome. 4 Discuss the relationships among obesity, metabolic syndrome, diabetes and cardiovascular disease.
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chapter SUMMARY The progression to overweight and obesity • Obesity occurs when energy intake is higher than energy use.
Evaluation of body size • Body mass index (BMI) is a commonly used tool to classify someone’s body size using height and weight measurements. • A BMI of 20–25 is considered normal weight and a BMI greater than 25 as overweight. Of those who are overweight, those with a BMI above 30 are more specifically classified as obese. • Although BMI is a useful indicator of body size, the measurement has its limitations. • The waist circumference is a useful measure of body size and can be used to identify those at increased risk or greatly increased risk of health complications. • Visceral obesity refers to adipose stores around the organs within the abdominal cavity, while subcutaneous obesity refers to superficial fat stores.
Obesity • An unhealthy diet increases the risk of becoming overweight and obese. An unhealthy diet includes increased consumption of energy-dense food and drinks and decreased consumption of fruits and vegetables. • Physical inactivity is seen increasingly in our community and is a risk factor for weight gain. • Stress may increase the risk of obesity, as well as occurring as a result of becoming obese. • Those who quit smoking are at an increased risk of weight gain. • Some metabolic disorders increase the likelihood of weight gain. Both genetic factors and lifestyle factors are involved in the development of obesity. • Abdominal fat is physiologically unique compared with fat from other areas of the body, as it is much more metabolically active in its involvement with other body processes. It places the individual at higher risk of health complications than do gluteal fat stores. • Adipose cells have a range of functions that extend well beyond merely storing excess energy. They secrete adipocytokines that signal to other body systems in a manner similar to hormones. • The hypothalamus contains a control centre for the regulation of appetite and food intake. This centre
• • • • • •
• • •
•
receives information from the cerebral cortex (conscious thought), hormones and neural signals from the digestive system and is also influenced by leptin from adipose cells. Obesity is a significant risk factor for the development of coronary heart disease and diabetes. Obesity is linked to an increased likelihood of some cancers. Respiratory disorders such as hypoxaemia and obstructive sleep apnoea occur in obese people. Other disorders associated with obesity include gallbladder disease, liver disease and osteoarthritis. There is a higher mortality rate in the obese compared with those of healthy weight. Dietary changes and physical activity are essential in weight loss and maintenance of weight in the longer term. Dietary changes for losing weight include decreasing intake of energy-dense foods and increasing intake of fruits, vegetables and fibre. Physical activity should be increased to at least moderate levels, with further increases causing further weight loss. Pharmacological agents and surgical treatment may be needed to help some obese patients to lose weight, particularly those with other comorbidity risks. Childhood obesity often occurs in families with obese parents. Psychological issues are usually associated with childhood obesity. Other physical alterations in children who are obese include bone abnormalities, acanthosis nigricans, early puberty in girls and late puberty in boys, and pseudotumour cerebri. Treatment of childhood obesity includes themes of dietary and exercise patterns similar to those for obese adults. Prevention of childhood obesity is encouraged.
Metabolic syndrome • Metabolic syndrome is characterised by increased waist circumference, low HDL cholesterol, high triglycerides, high blood glucose levels and hypertension. Those who have this syndrome are at increased risk of chronic health complications, particularly coronary heart disease and diabetes. • Treatment includes weight loss and addressing individual risks and symptoms.
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CASE STUDY
ADU LT Elise is a 47-year-old white female. She was diagnosed with bipolar disorder 8 years ago and was medicated after review with a psychiatrist. Unfortunately Elise had significant reactions to the majority of medications trialled which caused permanent liver damage. In addition, she gained significant weight during this period and now weighs 140 kg and is just 160 cm tall. Elise has successfully found a therapeutic solution with a team of allied health staff and has well controlled her disease symptoms. She is devastated by the weight she has gained and is ready to commit to lifestyle changes. Her general practitioner is supportive and referred her to several allied health professionals to manage her obesity.
1
2 3 4
5
Suggest which allied health professionals may be most appropriate and discuss what their role may be in the management of obesity. Discuss the treatment options that may be available to Elise and the order in which they may be trialled. Discuss some of the drawbacks associated with these treatments. What is an appropriate weight Elise could aim for and what is a reasonable rate of weight loss? How often should follow-up be scheduled and justify your answer. How could Elise help protect herself against weight regain?
CASE STUDY
P AEDIA TR IC Billy is a 9-year-old Samoan migrant who moved to Australia with his family when he was 3 years of age. Billy has always carried a heavy frame and his family were not concerned by his weight. At age 9 he stands 135 cm and weighs 62 kg. Billy’s school nurse was concerned and requested a discussion with Billy’s family due to the health risks associated with childhood obesity. Billy’s family were alarmed by the concern raised and willingly attended the appointment. 1 How would you best approach a sensitive situation such as obesity in a family setting. How could you address the issue of parental and subsequent childhood obesity? 2 Why is childhood obesity a concern? What are the associated conditions that may develop?
3
What lifestyle changes could you suggest for the parents to instigate at home and how could these be maintained? 4 Billy loves rugby league, and has been playing in a junior league for some time. Billy’s dad is reluctant to take Billy to more sport outings due to the time commitment. What are some alternative options to increase Billy’s physical activity? 5 You realise that Billy has been eating a lot of carbohydrates as a part of his diet which is still predominantly traditional in meals but high in takeaway. How could Billy’s family improve dietary choices without compromising the incorporation of traditional foods? How would this reduce Billy’s weight?
CASE STUDY
AGEING Frank is 71 years old and has recently been diagnosed with metabolic syndrome. His waist circumference is 98 cm and his blood pressure is 135/85. Results from blood tests show triglycerides 1.9 mmol/L, HDL 0.99 mmol/L and fasting plasma glucose level 5.4 mmol/L. Frank has been told that he needs to make some important changes to his lifestyle, such as having takeaway foods on occasion only and commence an exercise regimen. Frank has never really been interested in health and fitness and it is your role to assist him to understand why these lifestyle changes are necessary.
1
2 3
4
5
Explain why Frank’s waist circumference is of concern, as the current measurement does not actually place him in the ‘substantially increased’ risk category. Discuss the link between metabolic syndrome and the development of diabetes. Frank has not exercised for years. Outline a general type of approach that might be useful for him, in terms of how much exercise and what type of exercise to do. In language that can easily be understood by those in the community, explain why Frank’s triglycerides and HDL levels are of concern. Outline any other general lifestyle modifications that should be discussed with Frank.
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REVIEW QUESTIONS 1 Discuss the benefits and disadvantages of performing both (a) BMI and (b) waist circumference calculations to evaluate body size. 2 Compare visceral and subcutaneous obesity. 3 List and briefly discuss some of the main risk factors for the development of obesity. 4 Explain factors that are involved in the control of appetite. 5 Discuss how leptin may contribute to obesity. 6 Discuss the fact that cancer and cardiovascular disease are health complications associated with obesity.
7 Explain the issues that are of particular concern regarding children who are obese. 8 Describe the main dietary approaches that are appropriate for promoting weight loss. 9 Compare the main pharmacological treatments that are used for weight loss. 10 Describe the main surgical procedures that can be used for weight loss, including the disadvantages of each type.
Key terms blood glucose monitor, 1107 dawn phenomenon, 1107 diabetes mellitus, 1098 diabetic ketoacidosis, 1109 diabetic macular oedema, 1115 diabetic nephropathy, 1115 diabetic neuropathy, 1116 diabetic retinopathy, 1113 euglycaemia, 1104 glycaemic index (GI), 1104 glycated haemoglobin (HbA1c), 1108 glycosuria, 1099 hyperglycaemia, 1098 hyperglycaemic hyperosmolar state (HHS), 1111 hyperinsulinaemia, 1100 hypoglycaemia, 1102 ketoacidosis, 1110 non-alcoholic fatty liver disease (NAFLD), 1116 polydipsia, 1100 polyphagia, 1100 polyuria, 1100 Somogyi effect, 1107
CHAPTER
Type 2 diabetes
36
Carolien Koreneff
Chapter outline Introduction, 1098 Diabetes mellitus, 1098 The extent of the issue, 1098 Diagnosis of diabetes, 1099 Risk factors for the development of type 2 diabetes, 1101
Understanding the relationship between obesity and diabetes, 1103 Acute complications of diabetes, 1108 Chronic complications of diabetes, 1112
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Introduction Diabetes is a major long-term health complaint, with complications ranging from short-term imbalance of blood glucose levels through to long-term complications that substantially increase the risk of mortality. In particular, type 2 diabetes has strong links with the adoption of a Western lifestyle, including poor dietary choices, and lack of physical activity. Metabolic syndrome may be considered an intermediate condition between obesity and diabetes, as the presence of abdominal obesity and other characteristics of this syndrome are also risk factors for diabetes.
Diabetes mellitus Diabetes mellitus is Greek for passing through honey or sweet. This term is used because in people with diabetes mellitus, excess glucose is found in the bloodstream (hyperglycaemia) as well as the urine (glycosuria). This sweet taste had been noticed in urine by the Ancient Greeks, Chinese and other groups as early as 250 BC. In the context of diabetes mellitus, the word mellitus is commonly left unspoken, and hence this condition will simply be referred to as diabetes in this chapter. The definition of diabetes is that it is a group of metabolic diseases in which there are high levels of blood glucose over a prolonged period.1 In other words, diabetes is a condition where the body cannot maintain normal blood glucose levels, and it includes a number of disorders that are characterised by either insufficient or no release of insulin by the islets of the pancreas (see Chapter 10) or an ineffective response to insulin at the target cells (known as insulin resistance). The result of this is hyperglycaemia (an increased blood glucose level), as glucose remains circulating within the bloodstream rather than being taken into body cells for immediate use or storage. Homeostasis of blood glucose levels is not maintained. There are different types of diabetes. Type 1 diabetes is characterised by the complete destruction of islet cells and has an acute progression. Type 2 diabetes is characterised by insulin resistance at the target cells (see Table 36.1), and may progress to insufficient pancreatic insulin release and islet cell destruction. Gestational diabetes occurs as the changes in hormones during pregnancy suppress the
TABLE 36.1 Hormone levels in diabetes TYPE 1
TYPE 2
Plasma insulin
Low or absent
Normal to high (initially), progresses to low
Plasma glucose
Increased
Increased
Insulin sensitivity
Normal to increased
Reduced
Note that reduced insulin sensitivity is referred to as insulin resistance.
response to insulin, which is similar to the insulin resistance of type 2 diabetes — consequently, gestational diabetes is a risk factor for later development of type 2 diabetes. In this chapter, we focus mainly on type 2 diabetes, as this is the most common type that affects our populations in Australia and New Zealand, with rates on the rise; type 1 diabetes and gestational diabetes have a different underlying pathophysiology (see Table 36.2) and are discussed in more detail in Chapter 11.
The extent of the issue
More than 6% of the New Zealand population, or around 260 000 people,2 and 6% of the Australian population,
TABLE 36.2 Classification and characteristics of diabetes NAME
CHARACTERISTICS
Type 1 diabetes
Long preclinical period with abrupt onset of clinical manifestations Individual prone to hypoglycaemia and ketoacidosis Insulin dependent — always needs insulin, insulin doses require frequent adjustments Primary autoimmune and genetic environment Often affects young people around age of puberty; can occur at any age Immune infiltration of pancreatic islets
Type 2 diabetes
Generally responds well to oral agents, at least initially, eventually progresses to requiring insulin treatment Individual not ketosis prone (but may form ketones under stress/illness) Strongly related to obesity Generally occurs in those over age 35 years
Gestational diabetes
Glucose intolerance first recognised during pregnancy, most likely in the third trimester Much tighter glucose targets required due to fetal sensitivity to glucose Mainly treated with diet and exercise recommendations; 40% of women will require insulin treatment during the pregnancy After pregnancy, glucose may normalise, remain impaired or progress to diabetes Occurs in 2% of all pregnancies; 60% will develop diabetes within 15 years of gestation
CHAPTER 36 Type 2 diabetes
Diagnosis of diabetes
Generally, two abnormal test results that demonstrate hyperglycaemia are required to make the diagnosis of diabetes: either two fasting venous blood glucose levels of equal to or over 7.0 mmol/L, or two random venous blood glucose levels of equal to or over 11.1 mmol/L. The diagnosis can also be made with just one abnormal fasting or random blood glucose level if symptoms of hyperglycaemia are present. A plasma fasting blood glucose level of less than 6.1 mmol/L indicates diabetes is unlikely (see Table 36.3).7,8 In Australia, while the diagnosis is mainly on the fasting and random blood glucose levels, in New Zealand there is a preference for testing glycated haemoglobin (or HbA1c) levels.7,9,10 Diabetes is likely to be present if the HbA1c is equal to or higher than 6.5% (48 mmol/mol). The test provides an alternative, but does not replace, traditional glucose-based methods for diagnosis (glycated haemoglobin
TABLE 36.3 Oral glucose tolerance test, plasma glucose levels (mmol/L)
FASTING PLASMA GLUCOSE (MMOL/L)
2 HOURS FOLLOWING GLUCOSE INGESTION, PLASMA GLUCOSE (MMOL/L)
Normal glucose tolerance
< 6.1
< 7.8
Impaired fasting glucose
6.1–6.9
< 7.8
Impaired glucose tolerance
< 7.0
7.8–11.0
Diabetes
≥ 7.0
≥ 11.1
is discussed in more detail later in this chapter).11 Diabetes can also be indicated by the presence of glucose in the urine (glycosuria), but this should be confirmed using blood tests. The oral glucose tolerance test is used less frequently these days, except in pregnancy. It requires overnight fasting followed by consumption of a glucose drink which contains 75 grams of glucose; blood glucose levels are monitored after fasting and then again 2 hours after glucose ingestion. If the person does not have diabetes, the blood glucose level will rise as the glucose drink is absorbed into the bloodstream, but should then decrease to below 7.8 mmol/L after 2 hours (see Fig. 36.1). In a person with diabetes, the fasting blood glucose level is raised, and the blood glucose level remains over 11.1 mmol/L after 2 hours. Pre-diabetes is a condition in which glucose homeostasis is between the normal level of control and that seen with diabetes. Pre-diabetes includes impaired fasting glucose and impaired glucose tolerance. In impaired fasting glucose, the fasting blood glucose level is raised, but the response to the oral glucose tolerance test appears normal (see Table 36.3). Conversely, for impaired glucose tolerance, the fasting blood glucose level is normal, and there is a hyperglycaemic response to the oral glucose tolerance test, but to a lesser extent than seen with diabetes. Pre-diabetes should be considered as a warning that type 2 diabetes is developing and modifiable lifestyle factors should be changed.12 CLINICAL MANIFESTATIONS OF DIABETES
Hyperglycaemia results when there is insufficient action of insulin and therefore inadequate transport of glucose into
11.1 Blood glucose level (mmol/L)
approximately 1 200 00 people, have diabetes.3 Of these, the vast majority (86%) have type 2 diabetes. The rates in males are slightly higher than in females (5.7% and 4.6%, respectively, of the total population).4 The prevalence of diabetes in Australia has doubled in the last 20 years. In New Zealand, the prevalence of diabetes has been rising at an average of 7% per year.2 Approximately 280 Australians and 50 New Zealanders are diagnosed with diabetes every day. In Australia, one in ten deaths in 2014 had diabetes as an underlying and/or associated cause of death. Among Aboriginal and Torres Strait Islanders people, diabetes death rates and hospitalisations are four times as high as for non-Indigenous Australians with type 2 diabetes. A further 16% of the Australian population has a pre-diabetic condition of impaired glucose tolerance or impaired fasting glucose.3 These pre-diabetic conditions indicate a progression to diabetes, which can often be prevented or delayed by lifestyle changes. Diabetes is a Health Priority Area in both Australia and New Zealand due to its prevalence, range of chronic health complications, contribution to mortality and cost to the health system.5,6
1099
Diabetes
10.0 8.9 7.8 6.7
Normal
5.6 4.5
0
1
2
Hours
3
4
5
FIGURE 36.1
Blood glucose levels in a non-diabetic and a diabetic in the oral glucose tolerance test. In a healthy individual, the blood glucose level rises and then declines within approximately 2 hours, in response to the oral glucose tolerance test. However, for the individual with diabetes, the blood glucose level increases to much higher levels, which stay elevated for a much longer period of time.
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the liver and skeletal muscle cells from the bloodstream. Hyperglycaemia is common to all types of diabetes. Hyperglycaemia results in excess glucose being filtered but unable to be reabsorbed at the kidneys. As all of the glucose cannot be reabsorbed, glucose appears in urine, known as glycosuria. The glucose exiting the body in the urine takes water with it, as the glucose in the urinary filtrate prevents adequate water reabsorption. As a result, the patient suffers from polyuria (passing large volumes of urine). To replenish the lost fluid volume, the patient experiences increased thirst, and drinks a lot (polydipsia). Finally, because of the glucose in the blood being unable to adequately enter cells, the cells become starved of a main nutrient group, which signals to the brain that the body is starving of nutrients, and the patient experiences hunger that requires increased eating (polyphagia). Therefore, the main symptoms of hyperglycaemia are polyuria, polydipsia and polyphagia. These are classical symptoms of those with both type 2 and type 1 diabetes, and accordingly are discussed in detail in Chapter 11. Indeed, the severity of these symptoms is often the trigger to investigate and leads to diagnosis of type 1. Clinical manifestations of type 2 diabetes are often milder and nonspecific. The individual is often overweight or obese, and in many cases the individual has hypertension and/or dyslipidaemia. This combination of medical conditions is often referred to as metabolic syndrome (see Chapter 35 and below). The onset of type 2 diabetes is generally slow and insidious, making early diagnosis difficult. Some of the classic symptoms of diabetes may be present, but more often there will be nonspecific symptoms, such as pruritus, recurrent infections, visual changes and paraesthesias (see Table 36.4). PATHOPHYSIOLOGY
In type 2 diabetes, there are usually two issues at play: a relative shortage of insulin (or insulin deficiency) and an ineffective response to insulin at the target cells (insulin resistance). In most cases, the insulin secretion by the pancreas is initially increased, resulting in hyperinsulinaemia to compensate for the insulin resistance (or lack of insulin response) in peripheral tissues. Over time, this excessive production of insulin leads to fatigue of the pancreatic beta cells that produce insulin, and can reach the point where these cells become unable to produce insulin. In the longer term, insulin production by the pancreas is almost completely diminished, as these pancreatic beta cells undergo apoptosis. This results in a severe lack of insulin, such that the patient experiences hyperglycaemia with a lack of insulin.
Insulin resistance
The process of insulin resistance is characterised by failure of the target cells to respond adequately to insulin (see Fig. 36.2). As a result, hyperglycaemia persists. This can be referred to as insulin resistance, as the insulin receptors do not respond in the normal way to the presence of insulin. This has also been referred to as a loss of insulin sensitivity — the cells are no longer sensitive to the presence of insulin.
TABLE 36.4 Clinical manifestations and mechanisms for type 2 diabetes MANIFESTATIONS
MECHANISMS
Recurrent infections (e.g. boils and carbuncles), skin infections and prolonged wound healing
Growth of microorganisms is stimulated by increased glucose levels; impaired blood supply hinders healing
Genital pruritus
Hyperglycaemia and glycosuria favour fungal growth; candidal infections, resulting in pruritus, are a common presenting symptom in women
Visual changes
Blurred vision occurs as water balance in the eyes fluctuates because of elevated blood glucose levels; diabetic retinopathy and cataracts may ensue
Paraesthesias
Abnormal sensations are common manifestations of diabetic neuropathies due to metabolic and vascular changes in response to hyperglycaemia. This leads to nerve degeneration and delayed conduction
Fatigue
Metabolic changes result in poor use of nutrients, which in turn leads to acute and chronic hyperglycaemic episodes, hypoglycaemia, and fatigue
As the body is unable to use glucose for energy, it will turn to lipids for fuel. This leads to an increased lipid content of the liver and skeletal muscles, and hence is linked with obesity (see Chapter 35). Insulin resistance is common in those with type 2 diabetes. Decreased beta cell responsiveness to plasma glucose levels is also an important part of the pathophysiology of type 2 diabetes, as the beta cells become no longer stimulated to secrete insulin in response to hyperglycaemia (see Fig. 36.3).
Beta cell destruction
A progressive decrease in the size and number of beta cells occurs in type 2 diabetes. Beta cells are extremely sensitive to high levels of glucose (and free fatty acids as well), so the persistent hyperglycaemia can contribute to the destruction of pancreatic beta cells. In longstanding type 2 diabetes, beta cell mass is decreased by 20–40%,13 but the number of functional cells is considerably lower and will eventually decline over time. The beta cells die by apoptosis. Pancreatic fibrosis, occurring in 33–66% of individuals with type 2 diabetes, occurs with loss of beta cell function. Furthermore, a variety of cytokines, including tumour necrosis factor-alpha (TNF-α) and interleukin 1-beta (IL1β), have also been shown to be toxic to beta cells.
CHAPTER 36 Type 2 diabetes
Hyperglycaemia
B
Hyperglycaemia
stimulates Pancreas to secrete insulin Insulin binds to insulin receptors on target cells
negative which results in feedback— no further Glucose transported secretion into cells of insulin is needed which leads to
stimulates Pancreas to secrete insulin
but there is
A decreased number of insulin receptors on target cells
Lowering of blood glucose levels which achieves Glucose levels restored to homeostasis
which results in
and also
A decreased intracellular response to insulin by the target cells
Insufficient levels of glucose transported into cells
positive feedback— further secretion of insulin is required
CONCEPT MAP
A
1101
which means that Hyperglycaemia persists and stimulates Further secretion of insulin
FIGURE 36.2
The relationship between hyperglycaemia and insulin secretion in early stages of type 2 diabetes. A In a healthy individual, hyperglycaemia stimulates insulin secretion, which targets the liver and skeletal muscle for uptake of glucose. B In a person with type 2 diabetes, despite secretion of insulin, there is insufficient response at the target cells. This is probably due to a combination of low levels of insulin receptors and a decreased response inside the cells, preventing glucose from entering. As a result, hyperglycaemia persists and stimulates further insulin secretion, but the insulin resistance at the target cells remains.
Interestingly, intraabdominal fat produces these adipocytokines, which have excessive rates of free fatty acid release. It is currently believed that the combinations of excess nutrients, obesity, inflammatory cytokines and the production of obesity-related adipokines are major contributors to insulin resistance and beta cell death in type 2 diabetes. This strongly relates diabetes to obesity (discussed Chapter 35).
Risk factors for the development of type 2 diabetes
Lifestyle factors such as poor diet and lack of physical activity will increase the risk of developing type 2 diabetes. There is even an increasing incidence of type 2 diabetes in children, due to inactivity and inappropriate food intake. Other risk factors include being over the age of 35, being overweight or obese, a family history of type 2 diabetes, having gestational diabetes in the past and metabolic syndrome. Interactions of metabolic, genetic and environmental factors also affect the prevalence of type 2 diabetes.14
Obesity
The most powerful risk factor for type 2 diabetes is obesity, especially abdominal obesity. The risk for developing type 2 diabetes increases 10 times with severe obesity. Over half of those who are obese will develop diabetes.15 Excessive energy intake predisposes an individual to type 2 diabetes by contributing to obesity. In obese individuals, insulin is less able to facilitate the entry of glucose into the liver, skeletal muscles and adipose tissue. This may be due to: • a decreased number of insulin receptors in the cell membranes, causing decreased insulin binding • cellular responses to insulin being impaired by intracellular satiety signals • release of free fatty acids interfering with insulin signalling and impeding cellular metabolism of glucose • inflammatory cytokines (TNF-a and interleukin 6) disrupting insulin signalling • hyperinsulinaemia from overeating inducing insulin resistance — this may be to protect the body from
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A
high glucose
high insulin
blood
intracellular process beta cell
B
high glucose
lack of intracellular response
blood
beta cell
FIGURE 36.3
Pancreatic beta cell secretion of insulin in early and late stages of type 2 diabetes. A Early in the development of type 2 diabetes, the presence of high glucose causes the pancreatic beta cells to secrete high concentrations of insulin. Because the insulin is not effective at its target cells, hyperglycaemia persists, which leads to a cycle whereby hyperglycaemia stimulates further insulin production, leading to hyperinsulinaemia. B By later stages of type 2 diabetes, the fatigued beta cells are no longer able to respond to hyperglycaemia by secreting sufficient insulin (or even any insulin at all), resulting in lack of insulin. Hyperglycaemia persists.
Percentage
60
Overweight
Obese
40 20 0
Diabetic
Non-diabetic
FIGURE 36.4
The proportion of overweight and obese people with and without diabetes. There are higher proportions of obesity in the population of those with diabetes than those who are non-diabetic.
hypoglycaemia that could occur with an enhanced response to high levels of insulin. In any event, the mechanism responsible for insulin-receptor binding or intracellular response may be reversed through weight loss. People with diabetes are more likely to be overweight than people without diabetes. When classified according to BMI, a staggering 80% of Australians with type 2 diabetes are overweight or obese, including 57% who are obese (see Fig. 36.4).16 The percentage of Australians without diabetes who are obese is much lower, at 19%.
RESEARCH IN F CUS Mitochondrial diabetes In the last decade, a number of gene mutations that represent a high risk for the development of diabetes have been discovered. Carriers of this gene mutation have up to 100% chance to develop diabetes during their life span. It is now believed that around 1% of all cases of diabetes are due to mutations in the mitochondrial DNA. Mitochondrial diabetes, along with maturity onset diabetes in the young (MODY), are monogenetic forms of diabetes. MODY is a form of type 2 diabetes which occurs in young people, is strongly related to obesity and consists of insulin resistance which usually progresses to insulin dependence. Latent autoimmune diabetes in adults, or LADA, is a form of type 1 diabetes that is somewhat slower to progress and is usually diagnosed in adulthood. People with mitochondrial diabetes often have a strong family history of diabetes and deafness, particularly on the maternal side of the family. Hence this form of diabetes is sometimes referred to as maternally inherited diabetes and deafness (MIDD). It is the bilateral hearing impairment in conjunction with the maternal transmission that discriminates mitochondrial diabetes from MODY. The hearing impairment is identified by audiometry and reflected by a decrease in perception of frequencies above 5 kHz. The hearing impairment generally pre-dates the diagnosis of diabetes by at least a few years. The final evidence for the presence of this rare type of diabetes is found through genetic analysis, where the mutation of mitochondrial DNA is confirmed. Carriers of this gene mutation often also present with changes in the pigmentation of the retina. The clinical features of mitochondrial diabetes are very similar to type 1 and type 2 diabetes (depending on the severity of the insulin deficiency), and hence patients with mitochondrial diabetes can be easily misdiagnosed as having either type 1 or type 2 diabetes. The mitochondrial dysfunction in the pancreatic islet cells leads to beta-cell dysfunction, which will eventually and gradually progress to a reduction in beta-cell size and insulin deficiency. Mitochondrial diabetes is initially treated with oral hypoglycaemic agents, but early use of insulin is commonly needed due to the insulin deficiency. The insulin sensitivity is usually not affected. The average age of diagnosis varies from 11 to 68 years of age, though the majority of cases are diagnosed between the ages of 35 and 40 years.
The accumulation of fat in non-adipose tissue (ectopic fat) is common in type 2 diabetes and insulin-resistance states. Lipid accumulation in pancreatic islets is associated with impaired insulin secretion, and excess fat in muscle has been correlated with insulin resistance. The pathogenesis of ectopic fat is poorly understood but is clearly related to overnutrition.
Understanding the relationship between obesity and diabetes Australia is becoming a leading country in rates of obesity, with 25% of adults and 10% of children being obese.17 It is estimated that three out of ten New Zealanders are obese, with obesity rates highest in the Pacific Islander and Maori populations.18 A number of risk factors are common to obesity and diabetes, such as an unhealthy diet, physical inactivity, smoking and dyslipidaemia. It therefore comes as no surprise to learn that obesity and diabetes often, but not always, develop together. ‘Diabesity’ is the term often used for diabetes occurring in the context of obesity; it represents a substantial economic burden.19 In many people, an increased waist circumference is the first major step in the process of developing diabetes. Modifying risk factors associated with either diabetes or obesity will usually improve the other condition too. The discussion on these conditions demonstrates that both obesity (see Chapter 35) and diabetes are also strongly related to cardiovascular disease (see Chapter 23) and renal disease (see Chapter 30). The development of coronary heart disease is a major complication common to both obesity and diabetes. Coronary heart disease is one of the main causes of morbidity and mortality in contemporary Australia and New Zealand, and this highlights the importance of understanding the progression from obesity and diabetes.20 Diabetes attracts not only the inconvenience of a lifelong commitment to controlling and monitoring blood glucose levels, but also substantial health risks such as end-stage kidney disease and lower limb amputations (as discussed later in this chapter). Diabetes can be a chronic debilitating disease that has substantial effects on the affected individual and the healthcare system. In recent years, life expectancy has been increasing, largely due to a decrease in cardiovascular risks such as cholesterol, hypertension and smoking.21 However, the recent surge in the incidence of obesity has led to a lowering of life expectancy. In fact, one estimate is that obese individuals have a life expectancy 7 years shorter than those of a healthy weight.22 Having a lower life expectancy in an era of great modern medicine and research is of grave concern. Efforts to improve education about and modification of risk factors of obesity, cardiovascular disease and diabetes are necessary in order to develop healthier communities. This requires making changes in patients’ attitudes and their perceived ability to actually improve their own condition.23 Structured education and treatment programs may bring about a sustained improvement in patient outcomes, reduced utilisation of hospital services and mortality.24,25 This is the challenge for healthcare professionals.
Pre-diabetes
Pre-diabetes includes impaired fasting glucose and impaired glucose tolerance (see Table 36.3); although the oral glucose
CHAPTER 36 Type 2 diabetes
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FOCU S ON L EA RN IN G
1 Outline the single most important factor in the management of diabetes. 2 Discuss the relationships among obesity, metabolic syndrome, diabetes and cardiovascular disease.
tolerance tests are not used frequently, the fasting plasma glucose levels assist with diagnosis. The presence of hyperglycaemia in pre-diabetes can enhance the transition from impaired glucose tolerance to diabetes. For this reason, identification and education of those with pre-diabetes is important to allow for lifestyle changes, as increased physical activity and healthy eating can slow or stop the progression to diabetes.16 Pre-diabetes is usually present for years before it progresses to diabetes, which provides an opportunity for screening and limiting the progression to diabetes. Both Australia and New Zealand currently have recommendations for screening programs for diabetes7,25,26 which allow early detection and treatment. Impaired fasting glucose and impaired glucose tolerance affects more than 16% of Australians (5.8% with impaired fasting glucose and 10.6% with impaired glucose tolerance).27
Metabolic syndrome
Metabolic syndrome (discussed in Chapter 35) incorporates abdominal obesity, elevated blood glucose levels, hypertension and dyslipidaemia, all of which increase the progression to type 2 diabetes. In a similar manner to pre-diabetes discussed above, the progression from metabolic syndrome to diabetes is enhanced by unsuitable lifestyle choices and the diagnosis of this syndrome provides a window of opportunity to slow or prevent the development of diabetes. Note that these risks associated with metabolic syndrome are also important risks for cardiovascular diseases (see Chapter 23).
Physical inactivity
Undertaking 150 minutes of physical activity per week for adults and at least double for persons under the age of 18 years (see Chapter 35) is an important recommendation for the prevention of type 2 diabetes.16,28,29 Exercise can decrease the progression from impaired glucose regulation to diabetes30 by increasing the effectiveness of insulin at the target cells. However, most Australians do not achieve this level of activity — 70% of those aged 15 and over do not undertake the recommended amount of exercise. Physical activity is also particularly beneficial for those who already have diabetes, as it significantly improves glycaemic control in those with type 2 diabetes,16 by making glucose utilisation more efficient and by increasing insulin sensitivity. Despite this, 75% of Australians who have been diagnosed with diabetes do not undertake the recommended level of physical activity — this is actually slightly worse than the overall national average of 70%.
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Unhealthy diet
Unhealthy dietary choices were described in the previous chapter in relation to obesity and include an excessive intake of fats and simple sugars (or simple carbohydrates), combined with an inadequate intake of whole foods. Simple sugars are found in high amounts in processed and refined foods. Of particular interest are sugary carbonated soft drinks, which are energy dense and rich in simple sugars. The amount of soft drinks being consumed in our society is sufficient to cause serious concern regarding health complaints — in a recent study, four out of five teenagers in New Zealand had consumed soft drink in the previous week and one in four toddlers aged 2–3 had consumed soft drink in the previous 24 hours.31 The high concentrations of sugars in products such as soft drinks can quickly result in high levels of hyperglycaemia. This requires increased secretion of insulin, which increases the likelihood of target cells developing resistance to the effects of insulin — the underlying pathophysiology of type 2 diabetes. In particular, carbohydrate foods can be classified by their glycaemic index (GI), which is an indicator of the extent of how they will raise the blood glucose level. Foods of a high GI (70 and above) are those that will raise the blood glucose level higher and quicker, while those of low GI (55 and below) cause a less severe rise in blood glucose, which occurs more slowly. As high GI foods cause substantial increases in blood glucose levels, this requires secretion of large quantities of insulin, which places further risks on the development of type 2 diabetes. It is not only glucose and carbohydrates that are concerning, as saturated fats actually decrease the function of insulin. Reducing saturated fat intake can decrease the risk of diabetes, thereby increasing the body’s ability to use insulin adequately. This can allow for improvements in glucose homeostasis.29,32
Tobacco smoking
Smoking increases the risk of developing diabetes by 30–40% and increases the risk of related conditions such as cardiovascular disease and damage to capillaries. Approximately 12% of the Australian population are currently smoking (in 2016), and although this has declined from 19% smoking in 2008,33 it remains a substantial risk factor in our community. The more cigarettes one smokes, the higher the risk for developing type 2 diabetes. Those who smoke are more likely to have trouble controlling blood glucose levels, no matter what type of diabetes they have, and insulin doses are much harder to control (refer below to treatment). Smokers with diabetes are more likely to have serious health problems from diabetes and are at higher risk of developing serious complications. Quitting smoking will have immediate health benefits as it generally leads to better glycaemic control.29,34
Genetic factors
Type 2 diabetes in families is a risk factor in itself and results from a combination of genetic susceptibility and
environmental factors. Although the genetics of type 2 diabetes are complex and not clearly defined, the pathogenesis of type 2 diabetes involves genes that influence either cellular responses to insulin or beta cell function or viability, or both. A discussion on the genetic and lifestyle factors is in Chapter 38. MANAGEMENT OF DIABETES
The goal of treatment of diabetes is restoration of euglycaemia (a normal blood glucose level) and correction of related metabolic disorders. Lifestyle changes are the cornerstone of effective management of type 2 diabetes. Dietary measures, including a restriction in total energy intake, are of primary importance in overweight individuals. In both type 1 and type 2 diabetes, the ratio of fats, carbohydrates and protein is important, and both cholesterol and saturated fats should be restricted (see Table 36.5). Selection of low GI carbohydrates is important to avoid hyperglycaemia. High-fibre diets also improve diabetic control. As the obese individual with type 2 diabetes loses weight, the body’s resistance to insulin often diminishes so that weight loss results in improved glucose tolerance.35
Glucose lowering oral therapies
Oral glucose lowering agents target a number of different mechanisms. There are some that depend on some level of secretion of insulin from the pancreas, and so are effective only in type 2 diabetes (in type 1 diabetes, there is inability to secrete insulin). These agents are often referred to as oral hypoglycaemic agents, as they can lower blood glucose levels (BGLs); however, because they lower blood glucose, these can increase the risk of hypoglycaemia (where the blood glucose becomes too low), which can become a life-threatening emergency (see below). It is essential that all patients receiving these drugs are adequately educated about how to manage this risk. The amount and timing of doses may need to be modified in conjunction with dietary changes to achieve glucose homeostasis. Taking medications with meals can lower the risk of hypoglycaemia. There are also anti-hyperglycaemic agents, so-called as they will lower high BGLs but are less likely to cause hypoglycaemia. Generally, the oral diabetes treatments are not appropriate for people with type 1 diabetes.36,37 The biguanides, of which metformin is the most well known, are the most commonly used group of medications. They have been used in Australia since the 1960s, and are commonly referred to as ‘first-line treatment’, which means they would be chosen for the treatment of type 2 diabetes before any of the other agents. Metformin increases glucose uptake and usage at target tissues. Metformin can cause gastrointestinal side effects, which are generally minimised by starting lower doses and increasing the treatment slowly, over a few weeks or months, to maximum tolerated doses. Metformin is currently the only oral agent that can be used in combination with insulin for the treatment of type 1 diabetes. The sulfonylureas (e.g. gliclazide, glimepiride, and glipizide) have been traditionally used as second-line agents,
CHAPTER 36 Type 2 diabetes
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TABLE 36.5 Nutritional therapy for diabetes FACTOR
TYPE 1
TYPE 2
Total kilojoules
Increased intake possibly necessary initially to achieve Reduction in intake desirable for overweight or desirable body weight and restore body tissues; otherwise obese patient similar to people who do not have diabetes
Effect of diet
Diet and insulin necessary for glucose control
Diet alone possibly sufficient for glucose control in some individuals
Distribution of kilojoules
Equal distribution of carbohydrates through meals or adjustment of carbohydrates for insulin usage is recommended
Equal distribution recommended; low-fat diet desirable; consistency of carbohydrate at meals desirable
Can vary intake if adjusting rapid-acting insulin doses according to carbohydrate, protein and fat intake, exercise and blood glucose levels (carbohydrate counting) Consistency in daily intake
Necessary for glucose control, unless carbohydrate counting with insulin dose adjustments
Desirable for weight reduction and moderation of blood glucose levels
Lower carb diets will require a reduction in insulin doses and can result in hypoglycaemia if doses aren’t changed appropriately Uniform timing Crucial for some of the older-style insulin regimens, but of meals not as important if on a basal-bolus regimen or if on insulin pump therapy
Desirable but not essential for those on oral antihyperglycaemic medications Essential for those on sulfonylureas or certain insulin regimens
Inter-meal and Frequently necessary if on premixed or older-style insulins Frequently necessary to avoid hypoglycaemia. bedtime snacks Recommended to avoid hunger, and hence could Not as essential on basal-bolus regimen or if on pump reduce total kilojoule intake therapy Nutritional supplement for exercise programs
Individual advice is recommended as supplementation will depend on type of exercise, duration of exercise, glycaemic control before, during and after and individual goals To avoid hypoglycaemia, the person generally needs carbohydrates 20 g/h for moderate physical activities
until more recent times. ‘SUs’, as they are more commonly termed, are a group of medications that act on the pancreatic beta cells to increase the secretion of insulin, and they can also increase the response to insulin at the target tissues. Hence if SUs are taken, but unexpected changes to patterns occur such as meals are delayed, meals are lower in carbohydrate, the person has increased their physical activity or suffers severe renal disease, these types of medications can cause hypoglycaemia. Thiazolodinediones, also known as glitazones or TZDs (pioglitazone, rosiglitazone), increase glucose uptake and usage at target tissues. Rosiglitazone in particular has been used less commonly since the early 2000s, because of concerns of increased risk of myocardial infarction. The main side effects of TZDs are water retention, leading to oedema and weight gain, and decompensation of (previously unnoticed) heart failure. There is also an increased risk of osteoporosis, and pioglitazone may be associated with a higher risk of the development of bladder cancer.38 Acarbose can be used to slow the digestion and absorption of carbohydrates from the digestive system. By slowing
May be necessary if patient is on sulfonylurea or if hypoglycaemia becomes an issue Insulin dose reductions may reduce the need for nutritional supplements and hence may aid weigh management Individual advice is recommended depending on treatment targets and individual goals
the breakdown of disaccharides to monosaccharides, the rise in blood glucose level is delayed and less prominent, thereby limiting hyperglycaemia. Gastrointestinal side effects, in particular flatulence and diarrhoea, are common and hence acarbose is not commonly used in Australia. One very important factor to remember for patients on acarbose is that if the person has hypoglycaemia, they will only respond to glucose (either oral or IV), and that other treatments for hypoglycaemia such as juice, chocolate and most lollies, will not work quickly enough to raise the blood glucose level. There are two types of medications in a group of glucose-lowering medications called incretins: DPP4 inhibitors and GLP-1 receptor agonists. DPP4 inhibitors (sitagliptin, saxagliptin, linagliptin and vildagliptin) are oral agents that lower blood glucose levels by inhibiting the DPP4 enzyme and blocking glucagon release; this increases insulin secretion, decreases gastric emptying and hence improves glycaemic control. GLP-1 receptor agonists (exenatide, liraglutide) are injections which lower blood glucose levels, aid in weight loss and help with satiety. The
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risk of hypoglycaemia is low when using incretins on their own or in combination with metformin. SGLT-2 inhibitors are the newest class of oral anti-diabetes agents. SGLT stands for: sodium-glucose like transporter; there are two main ones discovered so far: SGLT-1 and SGLT-2. SGLT-2 in particular contributes to renal glucose absorption. In hyperglycaemia SGLTs are saturated with the filtered glucose, which will lead to glycosuria. SGLT-2 inhibitors block the activity of naturally occurring SGLT-2 and as such promote increased glycosuria. This in turn leads to a loss in kilojoule uptake and hence lowers blood glucose levels. It can also lead to some weight loss and a
slight drop in blood pressure, both of which are useful side effects in most people with type 2 diabetes. SGLT-2 inhibitors are also known as gliflozins; examples are canagliflozin, dapagliflozin and empagliflozin.36,37 Most patients require increased doses of medication and multiple different agents over time. Some of the abovementioned medications are contraindicated in those with liver disease, renal disease and the elderly. Special care is required in prescribing and monitoring pharmacologic therapies in older adults.39 This can limit the options for pharmacological management of type 2 diabetes in many patients.
The majority of children who are diagnosed with type 2 diabetes are overweight or obese at the time of their diagnosis, which demonstrates the very strong link between obesity and diabetes. In addition to being overweight, the children usually have hyperglycaemia and glycosuria, but polyuria and polydipsia are much less common than in adult diabetes. Children most at risk usually also have first-degree relatives with type 2 diabetes and are of Aboriginal or Torres Strait Islander descent.40,41 Evidence suggests that type 2 diabetes in youth is different not only from type 1 diabetes, but also from type 2 diabetes in adults and has unique features, such as a more rapidly progressive decline in beta-cell function and accelerated development of diabetes complications.42 Puberty increases the risk of developing diabetes, as this developmental period is characterised by a surge in growth hormone. As discussed previously, growth hormone increases blood glucose levels, which can contribute to hyperglycaemia and lead to diabetes.
F OC US O N L E ARN IN G
1 Explain how diabetes and related pre-diabetes conditions are diagnosed. 2 List and describe the 3 main symptoms of hyperglycaemia. Include an explanation for the appearance of glucose in the urine of people with diabetes. 3 Compare and contrast insulin resistance and beta cell destruction. 4 Briefly describe risk factors for developing diabetes. 5 Discuss why childhood diabetes is of particular concern.
Insulin
Insulin is a hormone produced by the beta cells in the pancreas. Insulin regulates metabolism of carbohydrates, proteins and fats, and it is particularly well known for its role in promoting glucose entry into cells, and hence lowers
Many children are first diagnosed with type 2 diabetes around the onset of puberty. Some children are diagnosed with maturity-onset diabetes of the young (MODY), which is a subset of type 2 diabetes. This condition has a strong association with genetic factors and it affects 50% of first-degree relatives. The onset of type 2 diabetes in children and adolescents increases the risk of diabetic complications at a younger age than the standard population.40,41 In particular, the blood vessels, which are particularly prone to diabetic changes, will have been exposed to the adverse consequences of hyperglycaemia for a much longer time than in those who develop type 2 diabetes later in adult life. Children with poorly controlled type 2 diabetes have high risk for macrovascular complications within a few decades.43 This means that they could be at a high risk of cardiovascular disease and stroke from approximately 30–35 years of age.44
blood glucose levels. In type 1 diabetes, as the beta cells are destroyed by an autoimmune reaction, and as no new beta cells can be made, insulin can no longer be produced or secreted into the blood, and will therefore need to be replaced. It is important to emphasise that there are no other processes within the body that can perform the role of insulin, including there being no other hormone that lowers blood glucose levels. This makes genetically produced, artificial (synthetic) insulin an essential medication for all people with type 1 diabetes.37 As insulin medication is essential for these patients, type 1 diabetes was previously referred to as insulin-dependent diabetes mellitus (or IDDM). Because of the progressive nature of type 2 diabetes, insulin therapy is eventually required when oral medications fail to maintain euglycaemia. Over time, the patient with type 2 diabetes has lack of insulin production as the beta cells fatigue and undergo apoptosis, which leads to the requirement to medicate using insulin. Type 2 diabetes used to be referred to as non-insulin dependent diabetes mellitus (NIDDM), even though people
PAEDIATRICS
Paediatrics and diabetes
CHAPTER 36 Type 2 diabetes
often would become insulin requiring as the disease progressed. The terms IDDM and NIDDM should no longer be used as they lead to too much confusion and potential misdiagnoses. Pharmacological insulin is often needed for control of gestational diabetes, as women with this condition have a relative shortage of insulin. As insulin medications do not cross the placenta it is a much safer treatment option than oral agents.45 There are a number of different formulations of insulin based on their duration of action; from a rapid onset of action in around 15 minutes through to a duration of 24 hours (see Fig. 36.5). The choice of formulation and dosage depends on individual patient factors such as lifestyle, weight, diet, exercise and stress. Some insulins are clear in appearance, while others are cloudy looking; it is essential that the cloudy insulins are mixed thoroughly before used. Insulin is a protein-based molecule, so it cannot be given orally or it would be digested along with proteins on reaching the stomach and small intestine and would not reach the blood as intact insulin. It is injected subcutaneously; absorption varies depending on the injection site, hence changing sites should be avoided, although it is necessary to vary the injections to slightly different spots within the chosen sites. The preferred sites are the abdominal area or the buttocks, although injecting in the upper arms or thighs can also be acceptable (Fig. 36.6). It is important to avoid injecting into the muscles as this would change the absorption of the insulin dramatically and could lead to hypoglycaemia. Lipodystrophy is the hypertrophy or atrophy of subcutaneous tissue, which may occur in response to regular injections at the one location. It can cause erratic absorption of insulin medication, so rotation of injection sites is important. There are a large range of injection devices available these days, making the injections very easy. Although syringes will remain the preferred method in many institutions, most patients will learn to inject themselves by using one of the insulin pen devices. The needle length
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will be determined by the amount of insulin to be injected; most people can use the shorter 4–6 mm pen needles.46 A 45 degree angle should be used when administering insulin with a syringe when using a needle length ≥ 8 mm.
Complications of pharmacological insulin treatments
The Somogyi effect is a unique combination of hypoglycaemia followed by rebound hyperglycaemia. The rise in blood glucose occurs because of counter-regulatory hormones (adrenaline, growth hormone, cortisol), which are stimulated by hypoglycaemia. They produce gluconeogenesis. Excessive carbohydrate intake may contribute to the rebound hyperglycaemia. The clinical occurrence of the Somogyi effect is controversial. It can be managed by lowering the dosage of insulin, as the original cause was hypoglycaemia. The dawn phenomenon is an early morning rise in blood glucose concentration with no hypoglycaemia during the night. It is related to nocturnal elevations of growth hormone, which decrease the metabolism of glucose by muscle and fat. Increased clearance of plasma insulin may also be involved. Altering the time and dose of insulin administration manages the problem.
Monitoring blood glucose control
People with diabetes often have to check their own BGLs. A small self-test device known as a blood glucose monitor, or glucometer, allows patients to monitor the effectiveness of their lifestyle measures and diabetes medications. This is a measure of the current blood glucose level, and hence indicates short-term BGLs. Depending on the type of medication used, patients will be asked to check their BGLs one or more times per day. Common times for monitoring
Insulin activity
rapid short intermediate long
6
12 Hours
18
24
FIGURE 36.5
FIGURE 36.6
Insulin pharmacokinetics. Curves indicate approximate times of onset, peak and duration of hypoglycaemic activity of the main types of insulin formulations.
Injection sites for insulin. Main preferred injection sites include the abdomen and buttocks, and arms and thighs may also be used.
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are either prior to meals, or 2 hours postprandial (after eating). A pin-prick to the finger provides a drop of blood to be measured, so the test can be performed quickly and easily. Each patient will be given individual targets for their BGLs, depending on their type of diabetes, duration of diabetes, age, medication used and any other health issues or comorbidities that may be present. If glycaemic targets are not being met, changes to medication dosage, medication type, diet or physical activity may be required. This is usually done by the patient, under the guidance of a qualified healthcare professional.47 Measuring glycated haemoglobin (HbA1c) is used as a general indication of glycaemia over recent weeks, and hence indicates blood glucose levels on the longer term than using a glucometer. Glucose molecules bind to haemoglobin, to form glycated haemoglobin — this is an irreversible reaction, so once the glucose is bound, it remains attached. A build-up of glycated haemoglobin within the red cells reflects the average level of glucose to which the cells have been exposed during their 120-day life. In an individual with persistent hyperglycaemia (poorly controlled diabetes), increases in the quantities of glycated haemoglobin (principally HbA1c) are observed. Traditionally, HbA1c was reported in a percentage value; however, there are a number of factors now identified that could affect this result. The newer laboratory analysis method produces values to be reported in mmol/mol, to avoid potential confusion. In New Zealand, the preferred unit for determining glycated haemoglobin has changed to the new IFCC (mmol/mol) value, whereas Australia currently continues to use the percentage value (but generally both values are reported). In most cases HbA1c levels should be less than or equal to 7% (52 mmol/mol) to indicate good glucose control; however, this target should be individualised.7,47 Levels above this indicate blood glucose levels have been higher than desirable in the longer term, and hence diabetes management has not been ideal.48 Approximately 75% of people with diabetes in New Zealand who attended regular assessment had a result of less than or equal to 8% (64 mmol/mol),49 which indicates good glucose control. The figure was slightly lower for the Māori and Pacific Islander people (where 60–70% achieved a HbA1c target of < 8%).49 However, some caution should be applied when considering these statistics, as it is possible that those who are most attentive to managing their diabetes are the ones who participate in regular assessment.
Acute complications of diabetes
The major acute complications of diabetes are hypoglycaemia, and two conditions associated with hyperglycaemia: diabetic ketoacidosis and hyperglycaemic hyperosmolar state (see Table 36.6).
Hypoglycaemia
Hypoglycaemia, or hypo for short, occurs when the blood glucose level falls below 4 mmol/L, although it is possible
to develop symptoms of hypoglycaemia at higher blood glucose levels. In particular, it should be highlighted that blood glucose levels may be much lower than what is usual for the patient. This means that if a patient has persistently high blood glucose levels, a lowering may present the patient with symptoms of hypoglycaemia, even if glucose is still higher than healthy values, because the glucose levels are substantially lower than what the patient usually experiences. For this reason, it is important to always obtain as much information from the patient as possible. Hypoglycaemia results from insulin excess alone, or it can be the result of insulin excess with ineffective glucose regulation.50 Hence hypoglycaemia can occur in any type of diabetes, but is more common in people who take insulin injections. It can also occur in people who are being treated with sulfonylurea therapy, either alone or in combination with other oral agents, as hypoglycaemia occurs when there is more insulin in the bloodstream than required for the amount of glucose that is in the bloodstream. Hypoglycaemia in diabetes is sometimes called insulin shock or insulin reaction when it occurs as a result of insulin medication. It can also occur if the amount of exercise is more than planned, if carbohydrate intake is inadequate, or as a result of excessive alcohol consumption. High-risk patients include the elderly, those with renal impairment and people with diabetes on multiple daily injections. In addition, those who experienced a recent hospital admission are also high-risk patients, as medications are often increased for the inpatient scenario, to allow for the increased blood glucose due to the effects of hospital-related stress, and not readjusted to changes in food intake and activity levels once the patient is back at home.51 Hypoglycaemia usually has a sudden onset and can be categorised as: • mild — where there is little or no interruption of activities and no assistance needed to manage symptoms • moderate — where there is some interruption of activities and no assistance needed to manage symptoms • severe — when assistance is needed from others to manage symptoms; this could be with or without medical assistance. Mild hypoglycaemia consists of tachycardia, pallor, sweating (diaphoresis), tremors, hunger and restlessness. These signs occur when the blood glucose level drops to approximately 3.5–4.0 mmol/L.52 If the level drops to 2.5 mmol/L and the hypoglycaemia remains untreated, it is a medical emergency as it can progress to brain damage, seizures, coma and death (see Fig. 36.7). Many people underestimate and underreport the frequency of the occurrence of hypoglycaemia.53 Some studies have suggested that for every documented episode of hypoglycaemia there would be at least one episode during that same period that wasn’t recognised or recorded. Frequent hypoglycaemia can lead to a reduction in hypoglycaemic symptoms and hence can lead to hypoglycaemia unawareness, or a lack of hypoglycaemia awareness, as the repeated low blood glucose levels impair
CHAPTER 36 Type 2 diabetes
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TABLE 36.6 Common acute complications of diabetes HYPOGLYCAEMIA
DIABETIC KETOACIDOSIS
HYPERGLYCAEMIC HYPEROSMOLAR STATE
Those at risk Individuals with type 1 diabetes Individuals with rapidly fluctuating blood glucose levels Individuals with type 2 diabetes using sulfonylureas or insulin
Individuals with type 1 diabetes and up to 10% Elderly or very young individuals of individuals with type 2 diabetes with type 2 diabetes, those with renal insufficiency, individuals with Individuals with severe, intercurrent illnesses, undiagnosed diabetes or non-adherent to medical regimen or undiagnosed diabetes
Predisposing factors Excessive insulin or hypoglycaemic agent intake, lack of sufficient food intake, excessive physical exercise, abrupt decline in insulin needs (e.g. renal failure, immediately postpartum, some cases of insulin reaction), simultaneous use of insulin-potentiating agents
Stressful situations, such as infection, accidents, trauma, emotional stress; insulin deficiency; factors that antagonise insulin, such as steroids, glucagon and growth hormone; lipolysis Issues with continuous subcutaneous insulin infusions (insulin pumps)
High-carbohydrate diets (e.g. tube feedings, total parenteral nutrition), prolonged mannitol diuresis, peritoneal dialysis or haemodialysis with hyperosmolar dialysate, medications antagonising insulin
Deliberate omission of insulin Use of SGLT-2 inhibitors
Typical onset Rapid
Slow to rapid
Slowest
Malaise, dry mouth, headache, polyuria, polydipsia, weight loss, nausea, vomiting, pruritus, abdominal pain, lethargy, shortness of breath, Kussmaul breathing, fruity or acetone odour to breath
Osmotic diuresis with polyuria, polydipsia, hypovolaemia, dehydration (parched lips, poor skin turgor), hypotension, tachycardia, hypoperfusion, weight loss, weakness, nausea, vomiting, abdominal pain, hypothermia, stupor, coma, seizures
Glucose levels > 14.0 mmol/L, pH < 7.3, reduction in bicarbonate concentration, increased anion gap, increased plasma levels of β-hydroxybutyrate, acetoacetate and acetone
Glucose levels > 30 mmol/L, lack of ketosis, serum osmolarity above 350 mOsm/L, elevated blood urea nitrogen and creatinine
Presenting symptoms Neurogenic reaction: pallor, sweating, tachycardia, palpitations, hunger, restlessness, anxiety, tremors Cellular malnutrition: fatigue, irritability, headache, loss of concentration, visual disturbances, dizziness, hunger, confusion, transient sensory or motor defects, convulsions, coma, death
Laboratory analysis Serum glucose below 0.6 mmol/L in newborn (first 2–3 days) and below 3.5 mmol/L in adults
the release of counter-regulatory and stress hormones. Unless recognised and treated by someone else, serious problems such as seizures and death can occur.54 The treatment of hypoglycaemia is to provide an immediate replacement of glucose. Initially, a quick-acting carbohydrate is recommended, such as half a glass of fruit juice, 3 teaspoons of sugar or honey, or 6–7 jellybeans. After waiting approximately 15 minutes, this may be followed with another quick-acting carbohydrate, or a slow-acting carbohydrate such as a sandwich or a piece of fruit.52 An intramuscular dose of glucagon can be given to assist raising blood glucose levels, although this is generally reserved only for people with type 1 diabetes. Intravenous glucose is another treatment option. Prevention of hypoglycaemia is achieved with individualised treatment, blood glucose monitoring and education.
Hyperglycaemia
Hyperglycaemia is a clinical feature of diabetes. A gradual worsening of hyperglycaemia can lead to neurological changes, fatigue, blurred vision, headache, nausea and vomiting. It may progress to seizures, coma and death, and hence high levels of hyperglycaemia can be a medical emergency. Treatment of hyperglycaemia involves administration of insulin or oral hypoglycaemic agents. Two specific conditions relating to hyperglycaemia are diabetic ketoacidosis and hyperglycaemic hyperosmolar state. DIABETIC KETOACIDOSIS
Diabetic ketoacidosis is a serious complication characterised by extreme hyperglycaemia and usually occurs following
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Cell G I –G Blood
I
G G I
I
1. Excess insulin in blood
G I–G I
2. Increased transport of glucose into cells
G
I = Insulin G = Glucose
3. Hypoglycaemia Decreased CNS function
SNS 4. Stimulates SNS
Clinical signs • weakness, confusion • pallor • diaphoresis • tremors • tachycardia
5. Increased gluconeogenesis
6. Excess insulin transports glucose into cells
Glucose intake
7. No glucose intake
Return to normal state
8. Blood glucose levels decrease further 9. Neurons cannot function 10. Coma and death
FIGURE 36.7
Hypoglycaemic shock. Excess insulin, beyond what is required, leads to hypoglycaemia, which can result in severe activation of sympathetic nervous system responses. If the liver can produce sufficient glucose through gluconeogenesis, then the blood glucose can return to normal. However, if the hypoglycaemia becomes too low, without sufficient glucose to balance, this can lead to severe neuronal dysfunction, which may lead to coma and death.
a stress such as infection, or omission of insulin. It is related to a deficiency of insulin and an increase in the insulin counter-regulatory hormones (adrenaline, cortisol, glucagon, growth hormone). In response to these hormones, hepatic glucose production increases and peripheral glucose usage decreases, resulting in hyperglycaemia. Insufficient insulin leads to the breakdown of fat stores to be used as energy instead of glucose. However, ketones are released as a result of the fat breakdown. These ketones are acidic and hence the result is ketoacidosis (see Fig. 36.8), with blood pH below 7.3 due to the acidic conditions (low pH = high
amount of acid). High levels of ketones can be found in the urine as well as the blood.55 The resulting hyperglycaemia can cause an osmotic diuresis, as the high concentration of glucose in the blood draws water out of cells. As glucose passes through the kidneys and into the urine it also draws water into the urine, causing diuresis and leading to dehydration. The classical symptom of this syndrome is acetone breath, where the breath smells sweet and fruity, somewhat like the smell of rotten apples. Other symptoms include an increased respiratory rate, abdominal pain, nausea and
CHAPTER 36 Type 2 diabetes
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Decreased insulin secretion or increased insulin-resistant cells
Decreased glucose transport into cells
Lipolysis
Glycogenolysis Polyphagia
Hyperglycaemia
(hunger)
(high blood glucose)
and
(catabolism)
Gluconeogenesis
Ketone bodies (acidic waste — formed in large amounts)
Glycosuria (excess glucose spills into urine)
Polydipsia (thirst)
Polyuria (osmotic diuresis — large volume)
Ketoacidosis
Ketonuria
Electrolyte imbalance (loss in urine)
Dehydration
Acidosis
FIGURE 36.8
The development of diabetic ketoacidosis. In diabetic ketoacidosis, the inability of glucose to enter cells can lead to usage of lipids as cell fuel instead of glucose. As a result, ketone bodies are formed, which are highly acidic, and can lead to ketoacidosis. The severe lack of glucose in cells can also lead to production of glucose, which can occur by both glycogenolysis — breakdown of glycogen stores into glucose, and by gluconeogenesis — creation of glucose from non-glucose sources. This may lead to hyperglycaemia, which causes glycosuria and polyuria, with the dehydration contributing to acidosis.
vomiting. Thirst also occurs to counteract the dehydration. Diabetic ketoacidosis is a medical emergency that, if untreated, can lead to coma and death. The key aspect of treatment is the replacement of insulin. In addition, fluids are administered to correct the dehydration, potassium may need to be replaced, and bicarbonate may be used to lessen the acidosis. The frequency of diabetic ketoacidosis peaks in adolescence,56 as it is more common in those with type 1 than type 2 diabetes. Approximately 1–5% of people with type 1 diabetes experience this condition at least once in their lifetime.57 People with diabetes who are on SGLT-2 inhibitors may be at higher risk of developing ketoacidosis, even with normal blood glucose levels. This can occur as these drugs reduce glucose reabsorption by the kidney, increase serum ketoacids and increase glucagon production.
Hyperglycaemic hyperosmolar state
Hyperglycaemic hyperosmolar state or HHS (previously known as hyperosmolar non-ketotic syndrome or HONK) is an uncommon but significant complication of type 2 diabetes with a high overall mortality of approximately
15%.58 It occurs more often in elderly individuals, particularly in those with other comorbidities such as infections, cardiovascular disease or renal disease. It is also associated with a high-carbohydrate diet and use of medications that impair the action of insulin, such as high dose steroid treatment. Poor glucose control results in high levels of serum glucose (more than 30 mmol/L) and high serum osmotic pressures that lead to severe dehydration. Because of the large amount of glucose going through the kidneys and into the urine (glycosuria), water is drawn into the urine (polyuria), which can lead to hypovolaemia and hypotension (low blood volume and low blood pressure, respectively) as a result of dehydration. As a consequence, the osmolality (or concentration) of the blood becomes extremely high, due to high levels of glucose and low amounts of water. This syndrome is similar to diabetic ketoacidosis, as both are characterised by hyperglycaemia. However, in the hyperglycaemic hyperosmolar state, there is sufficient insulin to prevent breakdown of fat stores for production of glucose and therefore ketoacidosis is avoided. Hence blood pH can remain normal.
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Hyperglycaemic hyperosmolar state is a medical emergency, as it can lead to drowsiness, stupor, coma and death. Treatment mandates aggressive fluid and electrolyte resuscitation and strict control of serum glucose levels.59
Chronic complications of diabetes
Persistent high blood glucose levels can damage various body organs over time, irrespective of what type of diabetes the person has. This damage is referred to as diabetes-related complications. While these complications are serious and can be life threatening, with appropriate lifestyle changes (by being physically active, eating healthily, not smoking and losing weight if needed) and attention to blood glucose, blood pressure and lipid control, people with diabetes can substantially reduce the risk of these complications. For this reason, adequate patient education is critical for lowering the risk of complications. The longer the person has diabetes, and the less well controlled their blood glucose levels are, the higher the risk of developing complications.60 The chronic complications of diabetes are mainly associated with hyperglycaemia, as tight control of blood glucose, particularly avoiding hyperglycaemia, significantly reduces complications.60 The range of organs that are affected
Brain Stroke (Atherosclerosis) Eyes Cataract Retinopathy Heart Myocardial infarction Arrhythmias Kidneys Nephropathy and infection
by diabetes are shown in Fig. 36.9. Even if the individual with diabetes has little experience of the severe acute complications, there is a strong likelihood of progressing to debilitating chronic complications due to the progressive nature of this disease and the consequences of even mildly elevated blood glucose levels. There may be other factors at play in the development of diabetes-related complications, as some people will develop complications with relatively normal blood glucose levels. The complications of diabetes are roughly divided into microvascular (affecting small capillaries) and macrovascular (associated with larger diameter vessels) complications, and neuropathies (damaged nerve fibres; can be peripheral or autonomic).
Mechanisms of microvascular disease and macrovascular disease
Microvascular disease due to hyperglycaemia results from thickening of the capillary basement membrane and endothelial hyperplasia (enlarged cells), which emerges over 1–2 years. Decreased tissue perfusion and hypoxia eventually result. The development of this process appears to be proportional to the duration of the disease (more or less than 10 years) and blood glucose levels. Microvascular
Diabetes Decreased insulin available Increased blood glucose Altered lipid and protein metabolism
Neuropathy Impotence and infertility Urinary incontinence Autonomic neuropathy Peripheral neuropathy Numbness, weakness Peripheral vascular disease Ulcers Delayed healing Gangrene
Acute complications Hypoglycaemic shock Hyperglycaemic hyperosmolar state Diabetic ketoacidosis
FIGURE 36.9
Organs affected by diabetes. Main organs affected by the complications of diabetes include the brain, eye, heart, kidneys, neurons, and peripheral tissues.
CHAPTER 36 Type 2 diabetes
disease occurs in the retinas and kidneys. If carefully evaluated at the time of presentation, many individuals with type 2 diabetes will be found to have microvascular complications because of the long duration of asymptomatic hyperglycaemia that generally precedes diagnosis. This underscores the need to screen adults for diabetes annually from the time of diagnosis.7 Macrovascular disease causes morbidity and mortality, particularly among individuals with type 2 diabetes. Unlike microangiopathy, atherosclerotic disease is unrelated to the severity of diabetes and often is present in those with merely an impaired glucose tolerance.61 (Atherosclerosis is discussed in Chapter 23.) Atherosclerosis has many contributing factors. Molecules with glucose attached are deposited in the walls of blood vessels and promote changes leading to atherosclerosis.62
Cardiovascular disease
A profile of dyslipidaemia is common, which relates to the development of atherosclerosis. Elevated triglycerides and low density lipoprotein (LDL) cholesterol are more prevalent in those with diabetes than those without the condition (see Fig. 36.10). In addition, high density lipoprotein (HDL), which tends to protect vessels, is present in only low concentrations in individuals with diabetes compared with the general population. This overall lipid profile is more atherogenic in those with diabetes. The presence of other risk factors, including hypertension, increases vulnerability to atherosclerosis (see Fig. 36.11). Cardiovascular diseases are discussed fully in Chapter 23. The risk of coronary heart disease for those with diabetes is higher than for the general population, even when hypertension and hyperlipidaemia are taken into account.63 Coronary heart disease is the most common cause of death 70 60
High triglycerides
High cholesterol
Low HDL
Percentage
50 40 30 20 10 0
Diabetic
Non-diabetic Males
Diabetic
Non-diabetic Females
FIGURE 36.10
The proportion of Australians with dyslipidaemia in those with and without diabetes. There is a higher proportion of people with diabetes who have dyslipidaemia, compared with those without diabetes.
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in individuals with type 2 diabetes because of insulin resistance, high levels of LDL and triglycerides, low levels of HDL, platelet abnormalities and endothelial cell dysfunction.64 Mortality is high for both men and women. In general, the prevalence of coronary heart disease increases with the duration but not the severity of diabetes.65 Myocardial infarction causes death in 20% of those with diabetes. In addition, the incidence of congestive heart failure is higher in individuals with diabetes, even without myocardial infarction. This may be related to the presence of increased amounts of collagen in the ventricular wall, which reduces the mechanical compliance of the heart during filling. Increased platelet adhesion and decreased fibrinolysis promote thrombus formation in persons with diabetes.66
Stroke
Stroke is much more common in those with diabetes than in the non-diabetic population (5% of those with diabetes and 2% of those without diabetes for people over 25).16 The survival rate for individuals with diabetes after a massive stroke is typically shorter than for non-diabetic individuals. Hypertension and hyperglycaemia are definite risk factors (see Chapter 9).
Visual disturbances
Temporary blurring of vision can be a consequence of hyperglycaemia. In addition, hyperglycaemia causes some tissues such as the lens to accumulate sorbitol and this, coupled with decreased fluid in the lens, can also contribute to blurred vision. Diabetic eye diseases consist of a group of eye conditions that can affect people with both type 1 and 2 diabetes, and include cataract (the most common eye problem in the Australian population), age-related macular oedema (the second most common issue), diabetic retinopathy and glaucoma.67 Diabetic retinopathy involves changes to the retinal blood vessels that can cause them to haemorrhage or leak fluid (Fig. 36.12). It is a microvascular complication of diabetes, which is influenced by blood vessel changes, growth hormone, metabolic control and activation of other metabolic processes. The prevalence and severity of diabetic retinopathy are strongly related to the age of the individual and/or the duration of the diabetes. Diabetic retinopathy appears to develop more rapidly in individuals with type 2 than type 1 diabetes, because of the likelihood of longstanding hyperglycaemia before diagnosis. The majority of individuals with diabetes will eventually develop diabetic retinopathy if normoglycaemia is not maintained. Hence all people with diabetes are at risk of developing diabetic retinopathy — it affects up to 80% of people who have had diabetes for 20 or more years, and is also the leading cause of blindness for people aged 20–64 years. Diabetic retinopathy can be detected via examination when the eye is dilated (fundal examination) prior to the appearance of symptoms, and early detection and treatment can prevent blindness.68–70 Approximately 75% of people with diabetes under the annual health assessment plan in
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HYPERGLYCAEMIA INFLAMMATORY CYTOKINES
HYPOINSULINAEMIA (relative to glucose) ENDOTHELIAL DYSFUNCTION
↓ Reduced nitric oxide production (impaired vasodilation)
LDL
OXIDATIVE STRESS
Expression of adhesion molecules
Oxidised LDL
Adhesion and subendothelial migration of macrophages
FOAM CELL
SMOOTH MUSCLE CELL MIGRATION AND PROLIFERATION
FIBROUS PLAQUE
COMPLICATED ATHEROSCLEROTIC LESION
Extracellular matrix production FIGURE 36.11
Diabetes and atherosclerosis. Diabetes with its associated hyperglycaemia, relative hypoinsulinaemia, oxidative stress and pro-inflammatory state contributes to atherogenesis by causing arterial endothelial dysfunction (impaired vasodilation and adhesion of inflammatory cells), dyslipidaemia and smooth muscle proliferation.
New Zealand have had their eyes screened within the previous 2 years. The stages of retinopathy are: • Stage I: No apparent retinopathy — as the name implies, there are no diabetes-related changes to the retina • Stage II: Mild non-proliferative diabetic retinopathy (NPDR) — which is only detectable by fundal examination. There are no symptoms and patients mostly have normal vision. Small microaneurysms (usually just 1–2 spots) appear; they cause characteristic changes to the retina and may contribute to the development of diabetic macular oedema • Stage III: Moderate non-proliferative diabetic retinopathy (NPDR), which is characterised by an increase in retinal capillary permeability, vein dilation, increased
microaneurysm formation and superficial (flame-shaped) and deep (blot) intraretinal haemorrhages or venous beading • Stage IV: Severe non-proliferative diabetic retinopathy (NPDR) — a progression of retinal ischaemia with areas of poor perfusion that culminate in infarcts. Hard exudates and microaneurysms can result in loss of vision • Stage V: proliferative diabetic retinopathy (PDR) — at this advanced stage, growth factors secreted by the retina trigger the proliferation of new blood vessels, of neovascularisation and cause a progression of retinal ischaemia with areas of poor perfusion that culminate in infarcts. These new vessels are fragile, making them more likely to leak and bleed. Accompanying scar tissue
CHAPTER 36 Type 2 diabetes
A
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B
Haemorrhages
Optic disc
Fovea
Central retinal vein
Macula
Abnormal growth of blood vessels Aneurysm
Central retinal artery
‘Cotton wool’ spots Retinal venules Retinal arterioles
Hard exudates
FIGURE 36.12
Diabetic retinopathy. A Normal retina. B Retina from a case of diabetic retinopathy showing several aneurysms.
can contract and lead to vitreous detachment, which can lead to permanent vision loss.69,71 Diabetic macular oedema, in which blood vessels leak their contents into the macular region, can occur at any stage and is the leading cause of decreased vision among individuals with diabetes. Ten per cent of people with diabetes will have vision loss related to macular oedema. If macular oedema is present, it can be classified as mild, moderate or severe, depending on the distance of exudates and thickening from the centre of the fovea. A large percentage of visual loss can be prevented through laser treatment, pharmacological means or surgical treatment. This highlights the importance of the proper detection and classification of patients with diabetic retinopathy, especially those with severe NPDR who are at great risk for developing visual loss.69,70
Kidney damage
Diabetes is the most common cause of terminal end-stage kidney disease (see Chapter 30). Diabetic nephropathy (or diabetic kidney disease) is a progressive disease caused by damage to the capillaries in the glomeruli of the nephrons. Renal failure is another of the microvascular complications of diabetes, and is among the most debilitating complications of diabetes, being the prime reason for dialysis in many countries. Diabetes is the cause of one-third of cases of end-stage kidney disease in Australia and is the main cause of renal dialysis in 39% of cases in New Zealand.16,61 The Australian Institute of Health and Welfare notes: ‘The burden of [end-stage kidney disease] from diabetes, particularly type 2 diabetes, is likely to increase further as both the age of the population and prevalence of diabetes are projected to rise.’72 In diabetes, there is microvascular destruction of the kidneys. The glomeruli are injured by high glucose levels
causing protein denaturation, such that protein shape is altered. Other contributing factors to glomerular injury are hyperglycaemia with high renal blood flow (hyperfiltration) and intraglomerular hypertension, exacerbated by systemic hypertension. Renal glomerular changes occur early in diabetes, occasionally preceding the overt manifestation of the disease. Hence, it is recommended to check urine albumin levels immediately after the diagnosis of type 2 diabetes and 5 years after diagnosis for people with type 2 diabetes.7,9,68 Progressive changes include glomerular enlargement, glomerular basement membrane thickening with proliferation of support cells. This results in diffuse intercapillary glomerulosclerosis (hardening of the glomerulus) and decreased blood flow. Alterations in glomerular membrane permeability occur with loss of negative charge and albuminuria. Microalbuminuria (small amounts of the protein albumin appearing in the urine) is the first manifestation of renal dysfunction.9 Continuous proteinuria generally heralds a life expectancy of less than 10 years.73 Before proteinuria, no clinical signs or symptoms of progressive glomerulosclerosis are likely to be evident. Later, hypoproteinaemia, reduction in plasma oncotic pressure, fluid overload, anasarca (generalised body oedema) and hypertension may occur. As renal function continues to deteriorate, individuals with type 1 or type 2 diabetes may experience hypoglycaemia, which necessitates a decrease in insulin therapy. This hypoglycaemia may occur for various reasons, such as patients becoming anorexic (suffering from loss of appetite), leading to a reduction in glycogen stores and, as commonly used diabetes medications are renally excreted and have a prolonged half-life, they may require a decrease in oral hypoglycaemic agents.74 As the glomerular filtration rate drops below 10 mL/ min, uraemic signs, such as nausea, lethargy, acidosis,
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anaemia and uncontrolled hypertension, occur (see Chapter 30 for a discussion of chronic kidney disease). Impaired kidney function also accelerates retinopathy. People with diabetes and renal disease should consider reducing their salt intake to at least less than 5–6 grams per day, in keeping with current recommendations for the general population.29 Death from end-stage kidney disease is much more common in individuals with type 1 diabetes than in those with type 2 diabetes because the appearance of proteinuria in these individuals is strongly correlated with death from cardiovascular disease.73
Liver disease
Non-alcoholic fatty liver disease (NAFLD) is common in those with type 2 diabetes and is the most common chronic liver disease in Australia, accounting for nearly 90% of cases.75 NAFLD predicts the development of type 2 diabetes and vice versa.76 In people with type 2 diabetes non-alcoholic steatohepatitis (NASH), in which the fatty infiltration of the liver progresses to liver inflammation, is much more common than those without diabetes,77 and may result in hepatic failure and cirrhosis. Liver cancer is also more common in people with diabetes. While liver failure is a serious chronic condition, the progression and prevalence of complications in other organs is usually of greater concern. Possible risk factors for advanced liver disease include affiliated metabolic syndrome, obesity (refer to Chapter 35), older age, increased duration of diabetes, and family history of diabetes. The presence of NAFLD in type 2 diabetes is also associated with increased mortality, so regular monitoring for this condition should be performed.78
Nervous system alterations
Diabetic neuropathy (neuron degeneration) is the most common cause of neuropathy in the Western world, and is the most common complication of diabetes, affecting up to 50% of people with diabetes.79 Hence all patients with type 2 diabetes should be screened for diabetic peripheral neuropathy at diagnosis and thereafter annually, and all people with type 1 diabetes should be assessed annually from 5 years after diagnosis.68,80 This neuropathy affects all peripheral nerves including pain fibres and motor neurons, as well as the autonomic nervous system and it can therefore affect all organs and systems as all are innervated. The underlying pathological mechanism includes both metabolic and vascular factors related to hyperglycaemia. Glucose attaches to molecules, which changes their structure and function, and which also occurs for neurons. In addition, because neurons do not require insulin for glucose entry, hyperglycaemia leads to high levels of glucose entering neurons from the blood. As a result, the neurons are susceptible to damage from hyperglycaemia, and nerve degeneration and delayed conduction occur. Sensory deficits and symptoms are more common than motor involvement, although loss of proprioception, the sense of where the limb is in space, is affected early on and can lead to trouble with balance. Signs and symptoms can vary depending on the nerves affected.
Common symptoms of peripheral neuropathy include numbness, tingling and decreased sensation in the feet.7 This can also contribute to lower limb disease (discussed below). The longer nerve fibres are affected to a larger degree than the shorter ones, because the nerve conduction is slowed in proportion to the nerve’s length, which helps to explain why neurons in the legs and feet are particularly susceptible to this damage. In peripheral diabetic neuropathy, decreased sensation and loss of reflexes occurs first in the toes on each foot (is always bilateral) and then extends upwards towards the knee. Patients can suffer from either painful or painless neuropathy. The pain can feel like burning, stinging, can be sharp or dull, can feel like pins and needles or like ‘ants crawling on the skin’. Patients with peripheral diabetic neuropathy, although many of them feel pain all the time, often cannot feel it when they injure themselves, for example by stepping on a foreign body like a splinter or a rusty nail, or when they are developing a blister or callous from ill-fitting footwear. As a result they are at high risk of developing ulcers and infections on the feet and legs, which could lead to amputation if not treated appropriately.81 Some neuropathies are progressive, but many — such as third nerve palsy, mononeuropathy (wristdrop, footdrop), diabetic amyotrophy, diabetic neuropathic cachexia and visceral manifestations associated with autonomic neuropathy (e.g. delayed gastric emptying, diabetic diarrhoea, altered bladder function, orthostatic hypotension) — may spontaneously appear to improve. Neuropathy may occur during periods of ‘good’ glucose control and may be the initial clinical manifestation of diabetes. Chronic hyperglycaemia can also cause cognitive dysfunction.
Infection
The individual with diabetes is at an increased risk for infection throughout the body due to: • The senses. Impaired vision caused by retinal changes and impaired touch and pain sensation from neuropathy diminish the prevention of breaks in the skin by decreasing the early warning systems • Hypoxia. Once skin integrity is compromised, tissues’ susceptibility to infection increases as a result of hypoxia. In addition, the glycated haemoglobin in the erythrocytes impedes the release of oxygen to tissues • Pathogens. Some pathogens proliferate rapidly because of increased glucose in body fluids, which provides them with an excellent source of energy • Blood supply. Decreased blood supply results from vascular changes and decreases the supply of white blood cells to the affected area • White blood cells. These cells suffer impaired function, including abnormal chemotaxis and defective phagocytosis. People with diabetes are particularly at higher risk of developing lower respiratory tract infections, urinary tract infections, bacterial skin and mucous membrane infections
CHAPTER 36 Type 2 diabetes
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FIGURE 36.13
Classic neuropathic diabetic foot ulcer. This image shows severe ulceration through layers of the skin, which becomes difficult to treat.
and the risk for these infections increases with recurrence of common infections.82
Lower limb disease and amputation
The increased incidence of peripheral vascular disease, ulcers (see Fig. 36.13), gangrene (tissue death) and amputation of the lower limb, foot or toes in the individual with diabetes has been well documented.83 It is estimated that 15% of people with diabetes will develop a foot ulcer during their lifetime.83 Many individuals with type 2 diabetes have evidence of peripheral vascular disease at the time of their initial diagnosis.1 People with diabetes are more likely to have atherosclerosis that appears at a younger age, and that advances more rapidly than vascular changes that appear in people without diabetes. Age, duration of diabetes, genetics and additional risk factors influence the development of peripheral vascular disease. Neuropathy and decreased sensation, combined with increased susceptibility to infection, contribute to lower limb disease. Because of occlusions of the small arteries and arterioles, most gangrenous changes of the lower extremities occur in patchy areas of the feet and toes (see Fig. 36.14).84 The lesions begin as ulcers, and may progress to osteomyelitis (bone infection) or gangrene requiring amputation.83 Nearly half of lower limb amputations involve above or below the knee amputations; the remainder involve toes or feet and are classified as minor.85 Amputations and diabetic foot ulcers severely reduce a person’s quality of life and have major impacts on health-related problems, disability and premature death. There were 4190 lower limb amputations provided in Australia in 2012–13, in hospital-admitted patients with a diagnosis of either diabetes or peripheral vascular disease. The majority of these amputations (3570 or 85%) were for patients with diabetes and, of these, 12% also had peripheral vascular disease.
These procedures were more common in males (72%; females 28%) and for those aged 65 and over (61%). The risk of amputations is highest among people living in very remote areas, in the lowest socioeconomic groups and among Indigenous Australians.85 Approximately half of all lower-limb amputations in New Zealand are due to diabetes.6
Mortality
There is a higher mortality rate associated with those with diabetes than in those without diabetes. Estimating mortality due to diabetes is challenging, because most people with diabetes die of a related vascular complication such as renal failure or cardiovascular disease.86 Over 5 years, people with previously diagnosed diabetes are twice as likely to die as those with normal glucose tolerance.87 In Australia, diabetes is the underlying or an associated cause of death in 10% of deaths and is within the top 10 leading causes of death.4 Similarly, in New Zealand almost 6% of all deaths are directly attributable to type 2 diabetes.88 In Australia endocrine disorders accounted for 2.4% of the total disease burden in 2011; 96% of this burden came from diabetes.20 FOCU S ON L EA RN IN G
1 Compare and contrast the 2 main methods for assessing blood glucose levels. 2 Describe the acute complication of hypoglycaemia, including why it needs immediate treatment. 3 Explain the complications associated with diabetic ketoacidosis, including treatment. 4 Discuss the complications of the hyperglycaemia hyperosmolar state and its treatment. 5 Describe the chronic complications due to diabetes.
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DIABETES
ANGIOPATHY Macrovascular
Atherosclerosis
Thrombosis
NEUROPATHY
Microvascular
Sensory
Motor
Autonomic
Hypoperfusion
Loss of pain sensation
Muscle atrophy
Decreased sweating
Gait abnormalities
Dry skin
Skin atrophy Ulceration
TRAUMA • Mechanical • Thermal • Chemical INFECTION
Ulceration
Pressure points
Cracks, fissures
GANGRENE
FIGURE 36.14
Pathogenesis of leg gangrene. Gangrene is a consequence of vascular and neural changes, which may be aggravated by infection and traumatic injury of the leg.
chapter SUMMARY Diabetes mellitus • Diabetes mellitus results when there is insufficient or no insulin production (or insufficient insulin response) to the effects of hyperglycaemia. • Type 2 diabetes is of great concern in Australia and New Zealand. • Fasting or random venous blood glucose levels and the oral glucose tolerance test are used to diagnose diabetes. Some patients will be classified as having prediabetes, whereby their ability to maintain glucose homeostasis is no longer normal but has not yet progressed to type 2 diabetes. • Pre-diabetes is an important early indicator of developing type 2 diabetes. If detected early, it allows individuals to modify their lifestyle to reduce the likelihood of developing diabetes. • Metabolic syndrome is an important risk for developing type 2 diabetes. • Polyphagia, polyuria and polydipsia are common symptoms of hyperglycaemia. Glycosuria also occurs. • In type 2 diabetes insulin resistance occurs as insulin is no longer as effective at the target cells. The pancreas
can respond to the hyperglycaemia by increasing secretion of insulin, but the insulin resistance means that most glucose remains in the blood. • Destruction of pancreatic beta cells usually occurs in type 1 diabetes and with the progression of type 2 diabetes. • Obesity is a strong risk factor for the development of type 2 diabetes. Obesity can result in insulin resistance as well as other cellular changes.
Understanding the relationship between obesity and diabetes • Lifestyle risk factors are common to obesity and diabetes. • Coronary heart disease is a serious complication associated with both obesity and diabetes. • Effective education can assist with the prevention, treatment and decreased complications associated with obesity and diabetes. • While physical inactivity is a risk for developing type 2 diabetes, most people in our community do not undertake recommended levels of exercise. Unhealthy
• • • •
•
• •
•
CHAPTER 36 Type 2 diabetes
diet is strongly linked to the progression of type 2 diabetes. Tobacco smoking and genetic factors can also contribute. Childhood type 2 diabetes is strongly linked with obesity and family history. Puberty and diagnosis of type 1 and type 2 diabetes often occur at similar times. Children with diabetes are at increased risk of diabetes related complications in adulthood. Oral glucose lowering medications can work through a number of mechanisms. Biguanides are commonly used as first line treatment in type 2 diabetes. Hypoglycaemia is a risk associated with some of these agents. Insulin is essential for all persons with type 1 diabetes and may also be needed for those with type 2 diabetes. Insulin formulations can be rapid, short, intermediate or long acting and are targeted to the needs of the individual. Monitoring blood glucose control adequately allows minimisation of adverse effects associated with hypoglycaemia and hyperglycaemia. Hypoglycaemia usually has a sudden onset and it can be characterised by tachycardia, sweating and restlessness and may progress to seizures, coma and death if left untreated. Treatment requires an immediate source of fast acting glucose. Diabetic ketoacidosis results in hyperglycaemia and increased release of fats into the blood as a fuel source.
•
• • • • •
• •
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The classic symptom is acetone breath, nausea and vomiting and treatment is immediate replacement of insulin and rehydration to prevent coma and death. The hyperglycaemic hyperosmolar state results with hyperglycaemia but does not have ketoacidosis. It requires rehydration and electrolyte resuscitation to prevent coma and death. Cardiovascular disease is a main complication of diabetes, with a substantial association with morbidity and mortality. Stroke has a higher prevalence in people with diabetes compared with those who do not have diabetes. Visual disturbances are characteristic in diabetes and may include diabetic retinopathy, cataracts and blindness. Kidney damage can be severe in diabetes, resulting in end-stage renal disease, which is a main cause of death for people with diabetes. Diabetic neuropathy causes disturbances in neuronal functioning that occur particularly with sensory neurons. The effects can be widespread. It can be painful or painless. Infection is common in people with diabetes. It can increase the progression of foot ulcers to gangrene, leading to amputation. Diabetes increases the risk of premature death.
CASE STUDY
ADU LT Barbara is a 42-year-old Indigenous grandmother. She has come into hospital from a remote community with her daughter Shirley as an escort. Barbara speaks little or no English and an interpreter has to be used. She was diagnosed with type 2 diabetes when she was 25. Her glycated haemoglobin is 12.1%, BMI 25, BP 170/97. Her random glucose level is 14.9 mmol/L. She has not eaten yet today as she was flown in by Careflight after having a suspected myocardial infarction. Via interpreter, Barbara states she has not taken any tablets for ‘long time’ because they make her feel ill. She does not give her own insulin. Another daughter does this for her. However it does not occur on a daily basis. According to the report from the local health clinic, Barbara is supposed to be taking metformin, gliclazide, a long-acting insulin, antihypertensives and cholesterol tablets.
1 2
3
4
5
Explain the relationship between myocardial infarction, glycated haemoglobin and blood pressure. Barbara is not taking her medications because she feels ill when she takes them. Can you explain to Barbara which medications may make her feel ill and the importance of why she should take her tablets and also her insulin daily. Barbara’s daughter explains that her nieces and nephews play with Barbara’s glucometer and this is why she does not check her blood glucose levels at home. Can you explain why it is important to check blood glucose levels and when Barbara should check her blood glucose levels? What would be appropriate treatment targets for glycaemic control for this patient? What would Barbara need to do if her blood glucose levels are not to target? What other information would you need from Barbara?
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CASE STUDY
A GEING George is an 85-year-old gentleman. He emigrated from Greece to Australia in 1956. His wife of 62 years passed away last year; George now lives alone. His son lives interstate and runs his own business. His daughter lives nearby and has four children and six grandchildren of her own. George complains of frequent urination, particularly at night and feels tired all the time. He went to the GP for a regular check-up and was told he now has diabetes. The GP reports that George’s fasting BGL was 8.0 mmol/L and the HbA1c is 7.3%. George tells you that according to his GP his blood pressure and lipids are well controlled on current medications.
1
2
3 4 5
What type of diabetes is George most likely to have? Explain to George what diabetes is, and what the symptoms are. What would be appropriate treatment targets for glycaemic control for this patient? Explain why these targets are different (or not) from Barbara’s treatment targets. What treatment would be best for this patient? Explain potential side effects and risks of the medications. Why is it important to know details of George’s social situation? Should George be monitored for complications? If so, when would this need to start and what complications should we be screening for?
REVIEW QUESTIONS 1 Describe the underlying pathophysiology of type 2 diabetes. 2 Compare blood glucose levels in normal glucose tolerance, pre-diabetes and diabetes. 3 What are the risk factors for the development of type 2 diabetes? 4 What are the treatment options for people with type 2 diabetes? 5 Identify the main treatment goals for managing the acute complications of hypoglycaemia, diabetic ketoacidosis and the hyperglycaemic hyperosmolar state.
6 Which are the microvascular and which are the macrovascular complications of diabetes? 7 Describe the stages of diabetic retinopathy. 8 How does diabetic neuropathy impact on the person with diabetes? 9 Discuss the progression to lower limb amputation in people with diabetes. 10 Describe the relationship between obesity and diabetes.
Key terms adenocarcinomas, 1123 adjuvant chemotherapy, 1150 alopecia, 1153 anaemia, 1145 anaplasia, 1129 angiogenesis, 1130 apoptosis, 1125 asbestos, 1139 autocrine stimulation, 1125 autonomy, 1129 benign tumours, 1122 biopsy, 1143 cachexia, 1148 cancer, 1122 carcinogens, 1136 carcinomas, 1123 chromosome amplifications, 1126 chronic inflammation, 1134 combination chemotherapy, 1149 conjugated antibodies, 1151 debulking surgery, 1152 DNA repair genes, 1128 dose intensity, 1150 fatigue, 1148 leukaemias, 1123 lymphomas, 1123 malignant tumours, 1122 metastasis, 1130 monoclonal antibodies, 1151 mutagens, 1128 neoadjuvant chemotherapy, 1150 neoplasm, 1122 oncogenes, 1126 paraneoplastic syndromes, 1148 passive smoking, 1137 point mutations, 1126 primary tumour, 1130 radon, 1140 relapse, 1122 remission, 1122 sentinel nodes, 1143 staging, 1143 therapeutic index, 1150 thrombocytopenia, 1145 tumour markers, 1143 tumour-suppressor genes, 1126 vascular endothelial growth factor, 1130
CHAPTER
Cancer
37
Sarah List and Julija Sipavicius
Chapter outline Introduction, 1122 Cancer is a chronic disease, 1122 Cancer characteristics and terminology, 1122 What is cancer? 1122 Carcinogenesis, 1123 Cancer names, 1123 The genetic basis of cancer, 1123 Types of gene mutations in cancer, 1124 Alteration of progrowth and antigrowth signals — epigenetics, 1124 Genetics and cancer risk in families, 1128 Cancer growth rates, 1128 Cancer growth, spread and metastasis, 1129 Cancer, immunity, inflammation and infection, 1133 Cancer and the immune system, 1133 Chronic inflammation, 1134 Viral causes of cancer, 1135 Bacterial causes of cancer, 1136 Gene–environment interaction, 1136 Factors that increase the risk of cancer, 1137 Cancer prevention, 1141 Diagnosis and evaluation of cancer, 1142 Tumour markers, 1143 Evaluation, 1143 Clinical staging, 1143 Clinical manifestations of cancer and cancer treatments, 1144
Infection, anaemia and thrombocytopenia, 1144 Pain, 1147 Fatigue, 1148 Cachexia, 1148 Paraneoplastic syndromes, 1148 Cancer treatments, 1149 Chemotherapy, 1149 Hormone therapy, 1150 Immunotherapy, 1151 Gene therapy, 1152 Radiation, 1152 Surgery, 1152 Complementary and alternative cancer treatments, 1152 Adverse effects of cancer treatments, 1152 Cancers of greatest significance in Australia and New Zealand, 1154 The incidence and mortality rates of specific cancers, 1154 The role of cancer screening, 1157 Cervical cancer, 1157 Breast cancer, 1157 Colorectal cancer, 1158 Melanoma, 1158 Prostate cancer, 1158 Cancer across the life span, 1160
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Introduction Cancer is a leading cause of death and disease burden in Australia and New Zealand, with the risk of developing cancer increasing with age.1 However, cancer can also occur in younger individuals. Many decades of research have led to an improved understanding of this complex and often frightening disease. Cancer is the name given to a collection of related diseases, caused by an accumulation of genetic alterations. Genetic changes that cause cancer may be inherited from our parents, or indeed what occurs most of the time is that cancers arise during a person’s lifetime as a result of environmental factors that alter normal gene function. In recent decades our increased understanding of the pathophysiology of cancer has contributed to the development of more effective treatment options. In this chapter, we define types of cancers, and the cell growth that lead to cancer. We focus on the most common cancers in Australia and New Zealand. In terms of the cancers with the highest incidence (the number of new cases diagnosed each year) and the highest mortality (causes of death), those that impact on the greatest number of people are lung cancer, colorectal cancer, breast cancer, prostate cancer, melanoma and pancreatic cancer.2
Cancer is a chronic disease
Relative survival proportion (%)
The 5-year survival rate is used to indicate the percentage of people who are alive 5 years after their initial diagnosis of cancer. When data from all cancer types are combined, the latest information indicates that 68% of Australians diagnosed with cancer are still alive after 5 years2 (see Fig. 37.1). The improved survival rates are largely a result of improved screening and effective treatment options. Historically, cancer was seen as a death sentence; however, for many cancer types it is now seen as a chronic disease that people will live with for a number of years (sometimes 70 60
Males
Females
50 40 30 20 10 0
1982–1986
1992–1997 Diagnosis period
2009–2013
FIGURE 37.1
Increased 5-year survival rate for all cancers, Australia. This shows that a greater percentage of people with cancer are now alive 5 years after being diagnosed.
many years). Cancers that are treated effectively may go into remission (a disappearance of the signs and symptoms of cancer), but then may relapse (return of the cancer, or the signs and symptoms of cancer) months to years later. Thus the patient with cancer may not be ‘cured’ completely, and will require regular monitoring and self-awareness for signs and symptoms of reappearance. As a result of the improvements in treatments and supportive care, outcomes for those affected by cancer have also improved.
Cancer characteristics and terminology What is cancer?
Cancer is an uncontrolled proliferation (growth and multiplication) of cells that can arise from any cell type in the body. Normally the cells of the body grow and divide to form new cells in an ordered manner as the body requires. Damaged or old cells are removed, and replaced by new cells. In cancer, this ordered process becomes deranged. Abnormal or damaged cells survive and grow and divide at an uncontrolled rate, growing beyond normal tissue boundaries. The term cancer comes from the Greek word for crab, karkinoma, which the physician Hippocrates used to describe the appendage-like projections extending from tumours. A malignant tumour (also called a neoplasm or cancer), is not self-limiting in its growth, survives the normal signals for damaged cells to be destroyed, is capable of invading adjacent tissues and of spreading to distant tissues. Conversely, a benign tumour or growth does not spread into or invade nearby tissues and, once removed, usually does not have the ability to reappear again. Hypertrophy refers to an increase in size (of a cell or organ), which is not always detrimental. For example, hypertrophy of a skeletal muscle in response to training is a normal, healthy response. Hyperplasia refers to an increase in the number of cells, and an example is benign prostatic hyperplasia, in which the prostate gland becomes enlarged (see Chapter 32). Cancer is essentially a disease of uncontrolled hyperplasia (refer to Chapter 4 on altered cell function). The initial stages of cancer development can often be detected as dysplasia, in which the cells start becoming abnormal, although not yet cancerous (Fig. 37.2). Benign tumours do not possess the properties of malignant tumours. They are usually well encapsulated, the cells and tissues appear normal in structure, and they do not spread to regional lymph nodes or distant locations. Benign tumours, however, can grow large and, depending on the location, may result in adverse or even life-threatening symptoms in the individual. For example, a benign growth at the base of the skull may cause devastating symptoms by compressing the adjacent normal brainstem, even if the tumour is not particularly large. Benign tumours are generally named according to the tissues from which they arise, with the suffix — oma. For example, adenoma is a benign growth of glandular tissue.
CHAPTER 37 Cancer
Normal
Dysplasia
Localised neoplasm
1123
Invasive neoplasm
Muscularis mucosae of gut
Submucosa
FIGURE 37.2
The progression of dysplasia to neoplasm. A sequence of cellular and tissue changes progressing from dysplasia to localised neoplasia and then to invasive neoplasia is seen often in the development of cancer. In this diagram, as in real life, distinguishing between dysplasia and localised neoplasia is difficult. Loss of normal tissue architecture signifies the development of neoplasia. The localised neoplasms are most commonly found in the squamous epithelium of the uterine cervix, the epidermis of sun-exposed skin, and colonic and gastric mucosa after longstanding inflammation. The altered cell turnover during inflammation probably allows local environmental factors to cause genetic abnormalities leading to neoplasia.
Cancers (or malignant tumours) are distinguished from benign tumours by their more rapid growth rates and alterations in microscopic appearance, such as loss of cell differentiation and absence of normal tissue organisation. Malignant tumours are not enclosed in a capsule; can undergo invasion into blood vessels, lymphatics and surrounding structures and can spread to distant locations (metastasis). There are several hallmarks of malignant cells, which include anaplasia (loss of cell differentiation), nuclear irregularities and loss of normal tissue structure (Fig. 37.3). Table 37.1 illustrates some key differences between benign and malignant cells. We explore these concepts later in the chapter when discussing how cancers spread. Despite the general characteristics of benign tumours, it is important to emphasise that in some cases, a benign growth may develop into a malignancy. One well-defined disease is colorectal cancer — benign polyps within the large intestine retain the characteristics of being benign for years, but over time may progress into colorectal cancer. For this important reason, the preference with such benign intestinal polyps is usually to remove them to avoid them potentially progressing to cancer.
Carcinogenesis
Carcinogenesis is the process by which normal cells transform into malignant cells; it is not one single event that causes cancer to develop, but a series of events that cause cells to transform into cancerous cells. The three key events in the process of carcinogenesis are: (1) initiation
— the initial event when the cell is exposed to an initiating factor (carcinogen); (2) promotion — a secondary event when the cell is exposed to additional factors (co-carcinogens) that promote growth of the transformed cells; and (3) progression — the third stage when the cellular changes become irreversible and express malignant characteristics (Fig. 37.4).
Cancer names
Cancers are named according to the cell type of origin (see Table 37.2). Cancers arising in epithelial tissue are called carcinomas and those arising from ductal or glandular epithelium are named adenocarcinomas. Hence, a malignant tumour arising from breast glandular tissue is known as a mammary adenocarcinoma. Cancers of lymphatic tissue are called lymphomas, whereas cancers of blood-forming cells are known as leukaemias. In addition, there are other cancers named for historical reasons that do not follow this naming convention; for example, non-Hodgkin’s disease is now referred to as either B cell lymphoid neoplasm or mature T and NK cell neoplasms.3 It is worth noting the differences in the names of cancers, as the previous names may still be referred to in clinical practice.
The genetic basis of cancer Cancer is a genetic condition — it arises from a series of abnormalities or mutations in genes. (See Chapter 5 for an introduction to genes and their functioning.) The
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Self-sufficiency in growth signals Insensitivity to anti-growth signals
Limitless replication
Hallmarks of cancer cells
Tumour invasion and metastases
Angiogenesis
Evading apoptosis
Lack of immune rejection
FIGURE 37.3
Hallmarks of cancer cells. Cancer cells have specific properties which allow them to avoid the body’s normal removal mechanisms, and hence they are capable of persisting.
TABLE 37.1 Comparison of the features of normal cells and cancer cells PROPERTY/ FUNCTION
NORMAL CELLS
Metabolism and growth
Predictable, controlled Uncontrolled and and orderly disorderly
Maturation and specialisation
Develop into fully mature cells and take up specialised functions
Reproduction and death
Cell production equals Uncontrolled cell death and varied growth without programmed apoptosis
Contact inhibition/ Recognition
Cells recognise like or similar cells and grow towards these. Growth is inhibited when in contact with cells that are dissimilar and thus remain in tissue boundaries
CANCER CELLS
Develop abnormally without maturation and do not take up specialised functions
Lose abilities of cell inhibition and recognition. Grow away from cells in which they arose and beyond tissue boundaries
regulation of genes and how they influence body function (epigenetics; see Chapter 38) are of equal importance in understanding cancer development.4 The reasons why genes or their expression becomes abnormal continues to be extensively researched. The delicate balance between a genetic predisposition to cancer, and the environmental and lifestyle contributions to gene alterations that lead to cancer, is not fully understood; however there is evidence that both an individual’s environment, and their genetic makeup, are involved. In this chapter, we will explore some environmental and lifestyle factors; first, we look at genetic alterations.
Types of gene mutations in cancer Alteration of progrowth and antigrowth signals — epigenetics
Whether by environmental or genetic factors, an individual’s genes have been altered permanently in the case of cancer, and the subsequent DNA sequence that programs the resulting genes is abnormal. This permanent change is referred to as a mutation. Different genetic mutations are possible, and it is likely that a number of cellular control pathways must be altered for a cell to become
CHAPTER 37 Cancer
Initiator carcinogen (e.g. environmental factors; lifestyle factors; infectious agents)
1125
No cancer
Normal cell Initiation
Damage to cellular production of proteins
Formation of reactive molecules
Damaged cell
Repair of DNA damage
Cell division Initiated cell • Altered gene expression (epigenetics) Promotion • Suppressed immune response • Altered and enhanced cell division Pre-cancerous cell • Expression of oncogenes • Suppression of tumour suppressor genes p53 Progression • Additional mutations • Continued altered gene expression (epigenetics)
Benign tumour cell
Cancer cell
FIGURE 37.4
The three key events of carcinogenesis. The broad events in carcinogenesis are the initiation, promotion and progression of cancer.
TABLE 37.2 Examples of tumour nomenclature CELL/TISSUE
ORIGIN
Carcinomas
Arise from endothelial and epithelial tissues, such as hepatocellular carcinoma
Sarcomas
Arise from connective tissues, such as osteogenic sarcoma
Adenoma
Benign tumour arising from glandular or ductal epithelium
Adenocarcinomas
Carcinomas arising from glandular or ductal epithelium, such as mammary adenocarcinoma
Terato-
Arise from germ cells (teratocarcinoma)
fully malignant.4 First, cancer cells must have mutations that enable them to behave abnormally and have the ability to proliferate uncontrollably. Normal cells listen to signals from neighbouring cells to stop growing when they encroach on nearby tissue. Cancer cells, however,
gain control of their own growth signals and continue to multiple uncontrollably beyond. To achieve this, some cancers secrete growth factors that stimulate their own growth, a process known as autocrine stimulation (see Fig. 37.5A). Other cancers have an increase in growth factor receptors; for example, in breast cancer, the epidermal growth factor (erbB2) receptor is upregulated, which means that even when the epidermal growth factor is at very low levels, the cell still receives the signal to grow (see Fig. 37.5B). Normal cells have a mechanism that induces them to self-destruct when growth is excessive, or when the cell becomes abnormal. This self-destruct mechanism, called apoptosis, is a way of ensuring that old or abnormal cells are destroyed to preserve the health of the body (see Chapter 4). But apoptosis is actually disabled in cancers. The most common mutations that allow cancer cells to resist apoptosis occur in the p53 gene (see below), allowing them to become ‘immortal’. Furthermore, cancer cells are able to continue to restore their telomeres (by the enzyme telomerase). A telomere is
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Growth factor
Growth factor receptors Growth factors
FIGURE 37.5
Cancer cell growth. Cancer cells can support their own growth by either A, secreting growth factors (known as autocrine stimulation) or B, increasing the numbers of growth factor receptors.
BOX 37.1
Cancer and telomeres
As normal cells divide, their telomeres become shortened. With repeated cell division, shorter telomeres make the chromosomes prone to fragmenting and dying. Because most normal cells do not divide frequently, they do not require regeneration of telomeres. Cancer cells, however, are different, as they divide rapidly, losing parts of the telomere each time. In order for the chromosomes to survive this process, they are regenerated by the telomerase enzyme that repairs the telomeres, thereby maintaining the health of the chromosomes and allowing the cancer cells to live. Researchers Elizabeth Blackburn, Carol Greider and Jack Szostak were awarded a Nobel Prize for research in this field in 2009.
located at the end of each chromosome and, in a normal cell, these shorten slightly after each cycle of cell division. As the telomeres become shorter, they are unable to protect the ends of the chromosomes; as a result, the chromosomes fragment and the cell dies. This is another important mechanism for causing death of aged cells. On the other hand, cancer cells are able to restore their telomeres, thereby protecting their chromosomes and allowing them to divide over and over (see Box 37.1).5–7
Oncogenes, tumour-suppressor genes and DNA repair genes
There are essentially three types of mutations to genes that occur in cancer: oncogenes, tumour-suppressor genes, and DNA repair genes. 1 Proto-oncogones are genes that code for proteins in a cell to help regulate normal cell growth. A change in the DNA sequence of a proto-oncogene gives rise to an oncogene, which subsequently results in loss of normal cell regulation. This mutation in the proto-oncogene, into an oncogene, allows unregulated cell proliferation
TABLE 37.3 Familial cancer syndromes caused by tumour-suppressor gene function loss SYNDROME
GENE
Familial melanoma
p16INK,7 CDK4
Familial adenomatous polyposis (colorectal cancer)
APC
Breast cancer
BRCA1, BRCA2
and differentiation that subsequently results in the development of cancer. Several types of genetic events can activate oncogenes. Perhaps the most common are small changes in DNA (known as point mutations), which lead to the alteration of one or a few components of the gene, which consequently have profound effects on normal protein activity. This causes an oncogene to become more active, thereby increasing the development of cancer. Oncogenes can also contribute to the development of cancer by chromosome amplifications, whereby a small piece of a chromosome is duplicated over and over again, so that instead of the normal two copies of a gene, there are tens or even hundreds of copies. This results in increased expression (activity) of an oncogene or even drug-resistant genes. For instance, the epidermal growth factor receptor (erbB2) is amplified in 20% of breast cancers8 — an increase in the amount of receptors for this growth factor allows the growth of the cancerous cell to be stimulated (see Fig. 37.5B). 2 Tumour-suppressor genes (such as p53) are responsible for slowing or stopping cell division, in order to initiate either the repair of faulty DNA, or to initiate apoptosis. In this way, they ensure that abnormal cells are either corrected or destroyed. However, when mutated, they lose these important cell controls, and no longer switch off cell division, nor do they signal to repair errors in DNA, nor have the ability to tell cells to die. Examples of conditions where loss of tumour suppressor function leads to cancers are given in Table 37.3. One of the best
CHAPTER 37 Cancer
known examples of a tumour-suppressor gene is the p53 gene, which codes for a protein that regulates the cell cycle. Its activity leads to ensuring that either the cell cycle is stopped to allow for corrections in DNA errors, or else apoptosis of cancerous cells, thereby preventing the cancerous cell from dividing. Some individuals can inherit abnormalities in the p53 gene and are more prone to developing cancers. Thus it is well understood that p53 gene has important protective mechanisms against the development of cancer (see Fig. 37.6).
Abnormalities in genes
Environmental factors
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Although oncogenes can become activated to contribute to cancer development by a single mutation, tumour-suppressor genes must be inactivated to enable cancer to occur (see Fig. 37.7). There are two chromosomal copies, or alleles, of each gene, one from each parent. It therefore takes two ‘hits’ to inactivate both copies of a tumour-suppressor gene. The first copy of a tumour suppressor is often inactivated by point mutations. If the remaining gene is mutated, then another step towards cancer occurs (see Fig. 37.8).
Lifestyle factors
Infectious agents
DNA damage Tumour-suppressor gene activity (p53) Cell cycle stopped, cell cannot replicate (unless DNA is repaired)
DNA repair
if ineffective
Apoptosis, cell death
if effective Cell becomes normal
FIGURE 37.6
The role of p53 in correcting abnormalities in the cell DNA. In response to damaged DNA, the tumour-suppressor gene p53 can stop the cell cycle, cause cell apoptosis or control DNA repair.
A
First hit
Second hit
FIGURE 37.7
Two distinct hits are required to inactivate a tumour-suppressor gene. Tumour-suppressor genes are often inactivated by a mutation (first hit) followed by complete loss of an entire region of chromosome encompassing the remaining normal allele (second hit).
B
FIGURE 37.8
Silencing of tumour-suppressor genes. A One allele is inactivated. In this example, the first copy of a gene is turned off by gene silencing without mutation. B Mutation of the other allele results in no functional protein production. In this example, the remaining normal gene is inactivated by mutation.
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Oncogenes activated by DNA mutations cancer promoting
Normal tumour suppressor genes cancer preventing
FIGURE 37.9
An imbalance in cancer-promoting oncogenes and cancerpreventing tumour-suppressor genes leads to cancer. When oncogenes are activated this can lead to uncontrolled cell growth and replication.
Egg
Sperm
Fertilised egg Mutation
Reproductive
Bone
Liver
Brain
FIGURE 37.10
Germline mutation. In a germline mutation, an abnormality is passed to the offspring at the time of conception.
3
DNA repair genes (over 200 have been identified). Mutations or abnormalities in the DNA of these genes, or in their expression, result in cancer (see Fig. 37.9). Repair genes encode proteins that are involved in repairing damaged DNA — DNA damage may occur due to environmental and lifestyle causes, or even the very process of DNA replication during cell division is prone to error. Loss of repair gene function leads to increased mutation rates. Inherited mutations can also disrupt the repair gene function. For example, in a type of colon cancer, hereditary nonpolyposis colorectal
cancer (HNPCC, particularly with genetic mutations in MLH1 and MSH2), there is an inherited defect in DNA repair, and affected individuals have a high rate of colon cancer.9
Genetics and cancer risk in families
Most of the genetic alterations that cause cancer occur during the lifetime of the individual. The frequency of these events can be altered by exposure to mutagens — that is, agents causing mutations — and by defects in DNA repair that increase the rate of mutations. Because these genetic events occur in the individual’s mature body cells, as opposed to the germline cells (the cells that produce gametes, i.e. eggs or sperm), they are not passed on to future generations. Even though they are genetic events, they are not inherited. It is possible, however, for cancer-predisposing mutations to occur in germline cells (see Fig. 37.10). Mutations present in germline cells result in the transmission of cancer-causing genes from one generation to the next, producing families with a high incidence of specific cancers. These inherited mutations that predispose to cancer are almost invariably in tumour-suppressor and DNA repair genes (see Table 37.3), and hence protection from cancer is lessened. Fortunately, such inherited mutations are uncommon. Although rare, members of families with a high risk of developing cancer demonstrate that inheritance of a mutated gene can cause cancer. In these families, inheritance of one mutant allele predisposes the individual to a specific form of cancer: individuals who inherit the germline mutant allele are quite likely to develop the tumour, as they have only one allele (from the other parent) that is normal. Types of cancers that can be inherited from an inherited faulty gene include some forms of breast cancer (such as altered BRCA1 gene) and a type of colon cancer (familial adenomatous polyposis coli, FAP, mutation of the APC gene; see Fig. 37.11). Characterisation of cancer-causing genes and other genetic factors help to identify individuals at high risk of developing cancer. Individuals known to carry mutations in tumour-suppressor genes, such as women with BRCA1 mutation, are targeted more intensely for cancer screening to facilitate early cancer detection and therapy.10
Cancer growth rates
Cancer is predominantly a disease of ageing (see Fig. 37.12). The incidence of cancer — that is, the percentage of individuals who develop cancer — increases significantly with age. Some cancers may take many years to develop from the initial stages until diagnosis, and therefore it is more likely that they will occur in older age groups. Exposure to lifestyle and environmental risks, as well as the genetic changes, increase over time. When sufficient genetic mutations have occurred, cancer develops, as the cell growth rates start to significantly increase. For example, an individual mutation may occur in a single cell
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NORMAL EPITHELIUM Loss or mutation of APC tumour suppressor gene HYPERPROLIFERATIVE EPITHELIUM Loss of DNA normal processes EARLY ADENOMA Genetic mutation forming oncogene INTERMEDIATE ADENOMA Loss of another tumour suppressor gene LATE ADENOMA Loss of another tumour suppressor gene CARCINOMA
FIGURE 37.11
The development of colorectal cancer. In cancer, multiple steps are required in order for cancer to develop. In this example, the original cause is a mutation of the APC gene, which leads to various other abnormalities, resulting in colorectal cancer.
such that it may acquire a characteristic of cancer — say, increased growth rate. That cell may then quickly divide and become an early-stage tumour. In this example, because the gene was altered, the cellular process changed (namely, increased growth rate), which resulted in the development of cancer. One organ in which this relationship of genetic effects and clinical progression has been especially well studied is the colon.11 The colon is accessible to direct inspection with a colonoscope (a flexible tube with a light and camera), so abnormal growths of varying size can readily be detected and removed. Abnormal growths in the colon such as benign intestinal polyps can form the first stage in the development of colon cancer. Small polyps tend to have only a few genetic mutations, while large polyps have more mutations. This strongly supports the notion that several genetic changes are required for the development of cancer, and as cancer progresses it also has the ability to develop more mutations over time (Fig. 37.13). As discussed above, the potential for these benign growths with fewer genetic mutations to develop further mutations and become malignant illustrates the importance of removing benign growths where possible.
Cancer growth, spread and metastasis
After the genetic changes occur that allows a cell to become cancerous, the cell replicates. This one cancer cell divides to become two cancer cells, each of which then divides
further and replicates (divides) rapidly and uncontrollably to produce more cancerous cells. In this way, the original cancer cell can form a large number of cancer cells, which may eventually become life threatening to the individual (see Fig. 37.13). The rate of tumour growth varies between types of cancers and is dependent on three factors: cell cycle time — the time taken to complete an entire cell cycle (described in Chapter 5); growth fraction — the percentage of cells dividing; and the rate of cell loss — the total number of cells that die or leave the tumour through migration or metastasis. Cancer cells have two important properties: autonomy and anaplasia. Autonomy refers to the cancer cell’s independence from normal cellular controls, such as its ability to avoid apoptosis. Anaplasia is the loss of differentiation (the ability to develop into mature, specialised cells for a particular function such as neurons or the mature blood cells), which normally gives the cell its specialised organisation and functions. Anaplasia is characterised by an increase in the size of the nucleus due to rapid DNA replication and cell division. The normal function of the cell is lost as the cell becomes cancerous. For example, a benign bone tumour retains the ability to make bone, whereas in a malignant bone tumour, new bone formation is rare. Cancers spread locally as the increasing number of cells occupies more room. This leaves less space for normal cells, and contributes to loss of normal cell and tissue function. Furthermore, in order for cancers to enlarge they need an adequate blood supply to deliver oxygen
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55–59
60–64
65–69
70–74
75–79
80–84
85+
55–59
60–64
65–69
70–74
75–79
80–84
85+
50–54
45–49
40–44
35–39
30–34
20–24
15–19
10–14
5–9
25–29
Males Females Persons
4000 3500 3000 2500 2000 1500 1000 500 0 0–4
Rate (per 100 000)
A
Age group years
50–54
45–49
40–44
35–39
30–34
20–24
15–19
10–14
5–9
25–29
Males Females
4000 3500 3000 2500 2000 1500 1000 500 0 0–4
Incidence rate (cases per 100 000)
B
Age group years FIGURE 37.12
The total incidence of cancer increases with age. A The incidence of cancer in Australians. B The incidence of cancer in New Zealanders.
and nutrients (see Fig. 37.14). Tumours are said to follow a Gompertzian model of tumour growth, that predicts that the larger the tumour, the smaller the proportion of its cells that are actively dividing, because the larger the tumour, the less efficient the blood supply with oxygen and nutrients for the tumour growth (Fig. 37.15). Therefore, larger tumours are more resistant than smaller tumours to drugs directed at actively dividing cancer cells, as a smaller percentage of those abnormal cells are actively dividing. The process of angiogenesis is the development of new blood vessels, which occurs normally during growth such as in childhood or with increased muscle size from physical training. Angiogenesis is also necessary for continued cancer growth (see Fig. 37.14). The growth of small cancers is limited as they lack the ability to grow new blood vessels; however, more advanced cancers secrete substances such as vascular endothelial growth factor that stimulate angiogenesis. Some drugs work against cancer by inhibiting the process of angiogenesis, thereby preventing further
capillary growth and limiting the growth of the cancer. For example, bevacizumab inactivates vascular endothelial growth factor and is used in combination with other drugs for colorectal cancer, non-small-cell lung cancer and breast cancer to limit the cancer growth.12,13 Advanced cancers may be locally advanced or metastatic. Metastasis is the spread of cancer cells from the site of the original tumour to distant tissues and organs throughout the body. In solid tumours, the original site of the cancer is known as the primary tumour. Metastasis causes the development of new tumours at another organ, which are referred to as secondary growths (see Fig. 37.16). Interestingly, when cells which have travelled from the original tumour have formed a new tumour elsewhere, it is still the same cancer as the original. For example, breast cancer that has metastastised to the lungs is named metastatic breast cancer in the lungs. Tumours that are very advanced with widespread metastases may contain cells that are so undifferentiated that the original tumour cells are unable to be identified. In this case, the abnormal cells being found
CHAPTER 37 Cancer
Blood vessel
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Blood vessel Chemotactic Enzymes factors Tumour
Tumour angiogenic factors
FIGURE 37.14
Angiogenesis. Malignant tumours, especially those in metastatic sites, induce the formation of blood vessels, which serve as routes for the transport of nutrients into the tumour. The drug bevacizumab blocks vascular endothelial growth factor.
FIGURE 37.13
Development of cancer. A A normal cell can have one or two minor genetic changes and actually repair the DNA using caretaker genes to return to normal. B A number of genetic mutations lead to the development of an abnormal cell. If the cell undergoes apoptosis, it is removed. However, cells that can avoid apoptosis can replicate, forming a large tumour growth; this can stimulate angiogenesis, as well as spread to other body areas by metastasis.
in various locations makes it very difficult to identify the primary site; this is known as metastatic cancer of unknown origin. Metastasis is one of the many defining characteristic of cancer, contributing significantly to the pain and suffering caused by cancer, and is a major cause of death from cancer. While localised, cancers can often be cured by a combination of surgery, chemotherapy and radiation. This is less likely to be successful if the cancer is advanced but localised (such as cancers in the brain). Alternatively, some cancers that have metastasised are potentially curable such as testicular cancer. However, generally in advanced cancer with far-reaching
and multiple sites of metastatic disease, treatment eventually becomes ineffective. In Australia, for women with localised breast cancer (that has not spread to the lymph nodes), the 5-year survival rate is 97%. However, in women whose cancer has spread to the lymph nodes, the 5-year survival rate is lowered to 80%.14 Those cancers which do metastasise are usually more aggressive, with a less-promising patient prognosis. During metastasis, cancer cells can break away from the original tumour and travel through vascular and lymphatic pathways, and subsequently may end up in any part of the body. Many of these cells die, although some will seed themselves in the new tissue or organ and grow into new tumours. The blood and lymphatic vessels within tumours offer malignant cells direct access into the blood and lymph circulation. Often cancers spread to the next downstream set of lymph nodes, and thus the lymph nodes are often assessed first for possible metastasis (see ‘Diagnosis and evaluation of cancer’ below). Cancers also spread to the tissues downstream from the venous drainage of the affected organ. The most common sites of metastasis are the liver (which receives blood from multiple organs of the abdominal cavity), bone, lungs and brain (see Fig. 37.17). Some cancers metastasise to predictable areas: breast cancer often metastasises to lymph nodes and bones but rarely to the kidneys or spleen, whereas lymphomas often spread to the spleen but not usually to the bone. As an example, the location of lung cancer metastasis in a patient is shown in Fig. 37.18. It is thought this tissue selectivity is due to specific interactions between the cancer cells and specific receptors on the small blood vessels in different organs. The sites of metastasis of some main cancers are listed in Table 37.4. It is also difficult to conclude immediately if surgical removal of a cancer has been an effective treatment, as the presence of microscopic levels of cells which have
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Number of cells
Gompertzian growth
1012
40 doublings
Tumour 1 kg weight
109
30 doublings
Tumour 1 gram weight
Time FIGURE 37.15
The Gompertzian model. This model predicts that the larger the tumour, the smaller the proportion of its cells that are actively dividing because the larger the tumour, the less efficient the blood supply with oxygen and nutrients for the tumour to grow.
TABLE 37.4 Common sites of metastasis
metastasised elsewhere in the body cannot be detected, either before, during or after surgery. Indeed, it is only when these have grown to a measurable size that they can be detected. Therefore, months may need to pass to allow the potential development of any metastatic growth to this detectable size, before the cancer removal can be considered truly successful. Patients may be advised to receive chemotherapy to protect against any small areas of metastasis from growing.
PRIMARY TUMOUR
MAJOR ANATOMICAL PATHWAY
COMMON SITE OF DISTANT METASTASIS
Lung
Pulmonary vein, left ventricle
Multiple organs, including brain
Colorectal
Mesenteric lymphatics, portal venous system
Liver
Inferior vena cava, right ventricle, pulmonary artery
Lungs
Prostate
Regional lymphatics and veins
Bones (especially lumbar spine), liver
Breast
Axillary, transpectoral and internal mammary lymphatics
Bone, lungs, brain, liver
FOCU S ON L EA RN IN G
In-transit lymphatics, lungs, liver, brain, gastrointestinal tract
2 Compare benign and malignant growths.
Melanoma Regional lymphatics
1 Describe the naming system used for cancers. 3 Discuss the altered growth signals of cancer cells. 4 Compare oncogenes and tumour-suppressor genes. 5 Describe why cancers are more prevalent in older people. 6 Discuss angiogenesis and metastasis.
CHAPTER 37 Cancer
a. Primary tumour b. Proliferation/ c. Detachment/ angiogenesis c. invasion
Lymphatics, venules, capillaries e. Extravasation
Adherence to vessel wall
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d. Embolism/ circulation
Interaction with platelets, lymphocytes and other blood components
Cease travel within organs
Transport
Lung
Heart
Metastasis
Establishment of a microenvironment
Proliferation/ angiogenesis
FIGURE 37.16
The multistep nature of metastasis. As the primary cancer undergoes proliferation, it also promotes angiogenesis. Cells can detach from the primary cancer, and circulate through the body via the blood or lymphatic vessels. After travelling, these cancer cells then establish a new growth in another location, known as metastasis. This secondary cancer can also undergo proliferation and angiogenesis.
Cancer, immunity, inflammation and infection Cancer and the immune system
The immune system reacts to infection and tissue and cell damage; it also recognises non-self and foreign antigens (see Chapter 12). The immune system plays a complex role in the prevention and development of cancer.15 Immune surveillance recognises some early stage cancers as ‘foreign’ and suppresses or eliminates them before they develop further. Key components of the immune system that play an important role in suppressing cancer development include cytotoxic T lymphocytes and natural killer cells. Macrophages contribute by performing phagocytosis of foreign substances. A generalised inflammatory response is also part of the process of defending the body from a foreign agent. While the immune defences appear to be effective against a very small number of cancer cells, it appears that immunity is not able to destroy larger numbers of abnormal cells. Furthermore, normal immune processes are altered in the presence of cancer. As a consequence, the immune system
will continue to be activated during proliferation of cancer in an attempt to rid the body of the foreign substance, although unfortunately the cancer will not be effectively destroyed and removed. Cytokines are chemical signals that are released by immune cells to signal between immune system processes. Cytokines that are particularly associated with the response to cancer are: • interleukin-1 (IL-1), IL-6 and IL-8 from macrophages (a type of antigen presenting cell) to induce the inflammatory response • interleukin-2 (IL-2) from helper T lymphocytes to increase the function of natural killer cells • tumour necrosis factor-alpha (TNF-α) from macrophages, which is toxic to tumour cells • interferons from leucocytes, which are toxic to cancer cells and inhibit cell growth. An increasing knowledge of how the immune system works in targeting cancer is the basis for much of the research into the development of new cancer treatments that manipulate the immune system to fight cancer more effectively. Examples of such therapies include monoclonal
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B B
A
C
Brain and cerebrospinal fluid Lung
Liver
D
Adrenals
Bone
E
F
FIGURE 37.17
The main sites of blood-borne metastasis. A Sites of haematogenous metastasis. B Metastasis in bone. C Metastasis in the brain. D Metastasis in the liver. E Metastasis in the adrenals. F Metastasis in the lungs. Blood-borne tumour metastasis leads to growth of secondary tumours in several main sites. The macroscopic appearances of bone metastasis are shown in B, where lesions are seen in the vertebrae. Numerous metastases from a neoplasm of the stomach are seen in the brain in C. The liver is the most common site for metastases from tumours in the gastrointestinal tract, as seen in D, which arose from a colonic neoplasm. In E, metastatic tumour has replaced both adrenal glands, as is commonly seen with spread from lung and breast tumours. The lung, F, is the most common site for blood-borne metastases from tumours outside the spinal tract, particularly mesenchymal tumours.
antibodies (e.g. daratumumab) or immune-modulating therapies (e.g. lenolidamide); both are used in the treatment of multiple myeloma. These cancer therapies have contributed to improved cancer outcomes, with more still being developed. The role of the immune system in cancer is complex. The immune system protects us against cancer, as it has the ability to destroy damaged or abnormal cells. However, the immune system is less effective if the cancer is larger. Also, a weakened or defective immune system is not as efficient in its responses to foreign and abnormal cells. Cancers weaken the immune system and have the ability to avoid immune system surveillance. Defects of the immune system, due to infections such as HIV or treatments such as chemotherapy, immunosuppressive therapy, can increase the risk of developing some cancers, such as lymphomas,
acute myeloid leukaemia or human papillomavirus causing cervical cancer.16,17 However, patients receiving immunosuppression after an organ transplant have little or no increase in the most prevalent cancers, such as breast, prostate and colon cancers, strongly suggesting that immune surveillance is not important in preventing all types of cancers.
Chronic inflammation
Chronic inflammation is a form of immune response that has been recognised since the 1860s as an important contributing factor to the development of cancer.18,19 For example, people with ulcerative colitis (chronic inflammation of the large intestine) have a substantially higher risk of developing colon cancer, while individuals
CHAPTER 37 Cancer
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FIGURE 37.19 FIGURE 37.18
Metastatic non-small-cell lung cancer (NSCLC). This 54-year-old woman had a NSCLC resected from the left upper lobe. Five years later, these studies were obtained. The positron emission tomography (PET) scan shows metastatic lesions in the brain, right shoulder, mediastinal and cervical lymph nodes, as well as the liver, left pelvis and proximal femur. (Left) PET whole body image. (Right) Whole body PET/CT scan image of the same patient. The pattern of spread is most likely from the primary tumour to the large mediastinal lymph nodes, followed by lymphatic spread to the cervical nodes.
The intimate association of inflammation and cancer. Cancers attract inflammatory cells, and can then 1 secrete cytokines, which allows the cancer cells to regulate the inflammatory cell function. The inflammatory cell response is 2 secretion of angiogenesis factors (in addition to the cancer cell also secreting substances to promote angiogenesis) and 3 secretion of growth factors for the cancer. These responses of the inflammatory cell can contribute to the success of the cancer growing. Reprinted with permission of Springer Nature from Karin M: Inflammation and cancer: the long reach of Ras. Nature Med 11(1):20–21, 2005.
TABLE 37.5 Viral causes of cancer with chronic viral hepatitis B or C (causing chronic inflammation of the liver) have a substantially higher risk of liver cancer. The reasons for the inflammation leading to cancer are complex. After injury, inflammatory cells release cytokines and growth factors that stimulate local cell proliferation, vascular growth and wound healing. In chronic inflammation, these factors combine to promote continued proliferation (see Fig. 37.19). In addition, inflammatory cells release other substances that can both promote mutations and block the cellular response to DNA damage. Notably, increased abundance of the enzyme cyclo-oxygenase 2 (COX-2), which generates prostaglandins during acute inflammation, has been associated with colon and other cancers. Non-steroidal anti-inflammatory drugs, such as aspirin and ibuprofen, inhibit COX-2, prevent the formation of inflammatory mediators and protect against colon cancer development.
Viral causes of cancer
A number of viruses are implicated in the development of cancer (carcinogenesis)20 and it is estimated that approximately 15% of cancers have a viral cause.21 Hepatitis B and C viruses (which affect the liver) and
VIRUS
CANCER ASSOCIATION
Epstein-Barr virus (EBV)
Lymphoma and nasopharyngeal cancer
Hepatitis B (HBV), Hepatitis C (HCV)
Cancer of the liver
Human papillomavirus (HPV)
Cancer of the cervix
Human T lymphotrophic virus type 1 (HTLV-1)
Adult T-cell acute lymphoblastic leukaemia
Human T lymphotrophic virus type 2 (HTLV-2)
Hairy cell leukaemia
Human herpes virus (HHV-8)
Kaposi’s sarcoma
human papillomavirus (HPV — which affects the cervix) are common viral causes of cancer in Australia and New Zealand (Table 37.5); cancers of the liver and cervix account for about 80% of virus-linked cancers. The initial acute infection with hepatitis B or C is not associated with liver cancer; instead, it is the chronic viral hepatitis that markedly increases cancer risk. Widespread use of the hepatitis B vaccine is expected to significantly decrease the incidence of chronic hepatitis B and hence also decrease liver cancers.
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Up to 70% of cases of cervical cancer are due to infection with specific subtypes of HPV. Although there are over 100 types of HPV, only a few are implicated in the development of cervical cancer: the majority of HPV infections cause only minor problems such as genital warts.21 HPV is spread primarily through genital contact (oral, touching or sexual intercourse); therefore, condoms are not necessarily protective. The HPV viral DNA becomes accidentally integrated into the infected cervical basal cell chromosome and directs the production of viral oncogenes. Early oncogenic HPV infection is readily detected by Papanicolaou (Pap) smear, an examination of cervical epithelial cells. Early detection of abnormal cells in a Pap smear often leads to the detection of cervical carcinoma while it is still localised and can be easily and effectively treated. In Australia and New Zealand, routine Pap smears are recommended for all women, and fortunately cases of cervical cancer are now uncommon. Vaccines against HPV (e.g. Gardasil™) have proven effective in preventing infection and have the potential to significantly reduce cancer mortality; however, there are disparities in vaccine uptake and thus efficacy as a cancer prevention strategy (see Research in Focus: ‘Cervical cancer vaccination’).22
RESEARCH IN F CUS Cervical cancer vaccination The cervical cancer vaccine protects from cancer by providing protection from a number of strains of the human papillomavirus. The technology used to create the vaccine was developed by Professor Ian Frazer’s research team in Brisbane. After 15 years, the vaccine was ready, which led to Professor Frazer being named Australian of the Year in 2006. The vaccine, known as Gardasil™, was added to the National Immunisation Program in Australia in 2007 and New Zealand in 2009. The goal is to offer protection from this viru